WO2019028150A1

WO2019028150A1 - Compositions for use in methods of treatment of hemoglobin disorders

Info

Publication number: WO2019028150A1
Application number: PCT/US2018/044825
Authority: WO
Inventors: Ramin FARZANEH-FAR; Anna Zuk; Emil Morada DEGOMA
Original assignee: Akebia Therapeutics, Inc.
Priority date: 2017-08-01
Filing date: 2018-08-01
Publication date: 2019-02-07

Abstract

The present disclosure relates to hypoxia inducible factor (HIF) prolyl hydroxylase inhibitor compounds and pharmaceutically acceptable salts thereof, to compositions comprising the HIF prolyl hydroxylase inhibitor compounds (e.g., Compound 1), and to methods for treating or preventing hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle β thalassemia, and β thalassemias, including βo-(major) thalassemia and β+-(minor) thalassemia. In addition, the present disclosure relates to specific doses of HIF prolyl hydroxylase inhibitor in treating or preventing hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle β thalassemia, and β thalassemias, including βo-(major) thalassemia and β+-(minor) thalassemia.

Description

COMPOSITIONS FOR USE IN METHODS OF TREATMENT

OF HEMOGLOBIN DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Patent Application no. 62/539,877, filed August 1, 2017, which is hereby incorporated by reference in its entirety.

1 FIELD OF THE INVENTION

[0002] The present disclosure relates to hypoxia inducible factor (HIF) prolyl

hydroxylase inhibitor compounds and pharmaceutically acceptable salts thereof, to compositions comprising the HIF prolyl hydroxylase inhibitor compounds, and to methods for treating or preventing hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin disease, and sickle β thalassemia, and β thalassemias, including β°- (major) thalassemia and P⁺-(minor) thalassemia. In addition, the present disclosure relates to specific doses of HIF prolyl hydroxylase inhibitor in treating or preventing hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle β thalassemia, and β thalassemias, including β°-(π^ 0Γ) thalassemia and β⁺- (minor) thalassemia.

2 BACKGROUND

[0003] Hemoglobin disorders, such as β thalassemias and sickle cell diseases, are highly prevalent genetic red blood cell disorders that affect how oxygen is carried in the body. Over 300,000 people with severe hemoglobin disorders are born each year. While 5% of people worldwide are carriers of a gene implicated in causing a hemoglobin disorder, the percentage of people who are carriers of such a gene is as high as 25% in some regions.

[0004] In sickle cell disease, one amino acid substitution in the β globin chain results in the generation of sickle hemoglobin. The misshapen cells lack plasticity and can block small blood vessels, impairing blood flow. The sickled red blood cells undergo hemolysis, causing tissue ischemia and organ infarction. Symptoms of sickle cell disease include painful crises, acute chest syndrome, and eventual potentially life-threatening complications, including renal insufficiency, retinitis, osteonecrosis, osteomyelitis, aplastic crises, functional asplenism, stroke, priapism, and severe pulmonary hypertension. [0005] β thalassemias, which are also inherited blood disorders, produce a deficiency of β globin chains. In β thalassemia, the unmatched a globin chains aggregate inside red blood cells and their progenitors, leading to shortened red blood cell survival and resulting in anemia, transfusion-dependence, iron overload, organ failure, and early death.

[0006] Despite tremendous investment of resources by many laboratories for several decades, there has been little progress in the development of therapeutic regimens for hemoglobin disorders, in large part due to the lack of identified drugable targets. There is a critical need in the art for compositions and methods which exhibit improved efficacy for the treatment of hemoglobin disorders, including sickle cell diseases and thalassemias, while overcoming the safety concerns of existing therapeutic modalities.

3 SUMMARY OF THE INVENTION

[0007] Described herein is a method for treating a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, and Compound 13 or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

[0008] Also provided herein are methods for reducing the frequency of a symptom of a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1,

Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7,

Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

[0009] The methods provided herein can be used to efficaciously administer to a patient a compound in the form of a HIF prolyl hydroxylase inhibitor to treat a hemoglobin disorder. Such hemoglobin disorders include any disorder associated with an alteration in the amount, structural integrity, or function of adult hemoglobin, specifically adult β globin. Hemoglobin disorders include, but are not limited to, sickle cell diseases, including sickle cell anemia, hemoglobin SC disease; sickle β thalassemia, β thalassemias, including p°-(major) thalassemia and P⁺-(minor) thalassemia; and disorders involving ineffective erythropoiesis,

[0010] Described herein is a method for increasing the plasma levels of fetal hemoglobin in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

[0011] Described herein is a method for increasing the plasma levels of γ subunits of hemoglobin in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of: a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1,

Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

[0012] Described herein is a method for reducing sickle hemoglobin (HbS) in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

[0013] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, is unresponsive to treatment with other therapeutic agents. In specific embodiments, the compound is Compound 1 or

Compound 7. In embodiments, a compound is an isotopologue such as any one of

Compounds 14-98.

[0014] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, has or is at risk of developing a complication secondary to a hemoglobin disorder. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

[0015] In certain embodiments, a compound as disclosed herein, such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,

Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof may be administered in combination with a second pharmaceutically active agent. In specific embodiments, the compound is Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98. Such combination therapy may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Additionally, when administered as a component of such combination therapy, the compound provided herein (see Section 4.2) and the second pharmaceutically active agent may be synergistic, such that the daily dose of either or both of the components may be reduced as compared to the dose of either component that would normally be given as a monotherapy. Alternatively, when administered as a component of such combination therapy, the compound provided herein (see Section 4.2) and the second pharmaceutically active agent may be additive, such that the daily dose of each of the components is similar or the same as the dose of either component that would normally be given as a monotherapy.

[0016] A HIF prolyl hydroxylase inhibitor, or pharmaceutically acceptable addition salts or hydrates thereof, can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous, and intravenous injections.

[0017] Pharmaceutically effective doses for the methods disclosed herein are specific doses and unit dosage forms of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7,

Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, or pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In specific embodiments, the compound is

Compound 1 or Compound 7. In embodiments, a compound is an isotopologue such as any one of Compounds 14-98.

4 DETAILED DESCRIPTION OF THE INVENTION

4.1 Overview

[0018] Provided herein are methods of treating hemoglobin disorders in a subject. The methods provided herein comprise administering to the subject in need thereof an effective amount of HIF prolyl hydroxylase inhibitor or HIF stabilizer to treat a hemoglobin disorder in a subject. General methods of treatment are described in Section 4.5. The specific patient populations to be treated with the compounds and methods described herein are described in Section 4.6. Combination therapies using the compounds described herein are described in Section 4.7. Formulations and routes of administration of the compounds described herein are described in Section 4.8. Dosing regimens using these compounds are set forth in Section 4.9.

4.2 Definitions

[0019] As used herein, an "effective amount" refers to that amount of a compound or a pharmaceutically acceptable salt, solvate or hydrate thereof sufficient to provide a therapeutic benefit in the treatment of the disease or to delay or minimize symptoms associated with the disease.

[0020] As used herein, the terms "prevent," "preventing," and "prevention" refer to reducing the frequency of, or delaying the onset of, a symptom of a medical condition in a subject

[0021] As used herein, the terms "treat," "treating," and "treatment" refer to the reversing, ameliorating, reducing, or arresting a symptom, clinical sign, and/or underlying pathology of a condition or disease.

[0022] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable salts are sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, ammonium (including alkyl substituted ammonium), amino acids (e.g., lysine, ornithine, arginine, or glutamine), tromethamine, and meglumine salts. Other suitable non-toxic acid salts include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p- toluenesulfonic acid salts. Other examples of salts are well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 22nd ed., Pharmaceutical Press, (2012).

[0023] In certain embodiments, "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0024] As used herein, the term "hydrate" means a compound provided herein or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.

[0025] As used herein, the term "solvate" means a compound provided herein or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non- stoichiometric amount of a solvent, other than water, bound by non-covalent intermolecular forces. [0026] The term "isotopically enriched" refers to an atom of a specific position of a compound having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. As used herein, an "isotopologue" is an isotopically enriched compound. Isotopologues of the compounds provided herein are provided in Section 4.4.

[0027] The term "isotopic enrichment" refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.

[0028] As used herein, a "deuterium" group is a stable isotope of hydrogen having one proton and one neutron.

[0029] With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%.

[0030] With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%). A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, at least 1000 (15%> deuterium

incorporation), at least 2000 (30%> deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom.

[0031] It is understood that one or more deuteriums may exchange with hydrogen under physiological conditions. [0032] The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0033] As used herein, and unless otherwise indicated, the term "about" or

"approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value is disclosed, then "less than or equal to" the value, "greater than or equal to the value," and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "10" is disclosed, then "less than or equal to 10" as well as "greater than or equal to 10" is also disclosed. It is also understood that throughout the application data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0034] As used herein, the term "subject" includes mammal, which includes human. In certain embodiments, the term subject or patient can refer to a mammal, such as a human, mouse, dog, donkey, horse, rat, guinea pig, bird, or monkey. In specific embodiments, a subject or a patient is a human subject or patient.

[0035] The term "topical" as used herein includes any route of administration that enables the compounds to line the mucosal tissue; i.e., it includes any route of administration other than parenteral or per os.

4.3 Compounds

[0036] Prolyl hydroxylase inhibitors are described, e.g., in U.S. Patent Nos. 7,811,595 and 9,701,636, each of which is incorporated herein by reference in its entirety. The synthesis of such prolyl hydroxylase inhibitors is described in U.S. Patent Publication No. 2012/0309977, which is incorporated herein by reference in its entirety. Such compounds inhibit HIF prolyl hydroxylase, thereby stabilizing HIFa.

[0037] In certain embodiments, a compound for use with the methods provided herein is a modulator of a HIF prolyl hydroxylase. In more specific embodiments, a compound for use with the methods provided herein is a modulator of a HIF-l-alpha prolyl hydroxylase. In other, more specific embodiments, a compound for use with the methods provided herein is a modulator of a HIF-2-alpha prolyl hydroxylase. In certain, even more specific embodiments, a compound for use with the methods provided herein is a modulator of a HIF-2-alpha prolyl hydroxylase that is more active against HIF-2-alpha prolyl hydroxylase than HIF- 1 -alpha prolyl hydroxylase by 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%. Thus, in certain embodiments, a compound provided herein for use with the methods provided herein preferentially stabilizes HIF-2-alpha over HIF- 1 -alpha. To determine preferential

stabilization of HIF-2-alpha over HIF- 1 -alpha, the concentrations of HIF- 1 -alpha and HIF-2- alpha in a subject with and without test compound can be determined using a HIF- 1 -alpha and a HIF-2-alpha ELISA kit. Care should be taken that the primary antibodies in the respective kits are not cross-reactive with the other HIF (i.e., the primary antibody against HIF- 1 -alpha reacts immunospecifically with HIF- 1 -alpha and does not cross-react with HIF- 2-alpha; the primary antibody against HIF-2-alpha reacts immunospecifically with HIF-2- alpha and does not cross-react with HIF- 1 -alpha).

[0038] In certain embodiments, a compound used in the methods described herein, which is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, is a heterocyclic carboxamide. In certain such embodiments, the heterocyclic carboxamide is selected from a pyridyl carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.

[0039] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (I):

Formula (I) or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof, wherein

R and R¹ are each independently:

(i) hydrogen

(ii) substituted or unsubstituted phenyl; or

(iii) substituted or unsubstituted heteroaryl;

said substitution selected from:

(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) halogen;

(viii) cyano;

(ix) HC(0)R⁴;

(x) C(0) R^5aR^5b; and

(xi) heteroaryl; or

(xii) two substituents are taken together to form a fused ring having from 5 to 7 atoms;

R⁴ is a C1-C4 alkyl or C3-C4 cycloalkyl;

R^5a and R^5b are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl;

(iii) C3-C4 cycloalkyl; or (iv) R^5a and R^: are taken together to form a ring having from 3 to 7 atoms;

R² is selected from:

(i) OR⁶

(ii) R^7aR^7b; and

R⁶ is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl;

R^7a and R^7b are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl or C3-C4 cycloalkyl; or

(iii) R^7a and R^7b are taken together to form a ring having from 3 to 7 atoms;

R³ is selected from hydrogen, methyl, and ethyl; L is a linking unit having a structure -[C(R^8aR^8b)]n-

R^8a and R^8b are each independently selected from hydrogen, methyl and ethyl;

n is an integer from 1 to 3; and

R⁹ is selected from hydrogen and methyl.

[0040] In certain, more specific embodiments, in Formula (I) R and R¹ are not both hydrogen.

[0041] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (II):

Formula (II) or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof, wherein A is selected from the group consisting of CR', N, N⁺-0^" and N⁺(Ci-C₆ alkyl);

R' is selected from the group consisting of H, Ci-C₆ alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, C4-C7 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, H2, HR", N(R")₂, HC(0)R", R"C(0)R", F, CI, Br, I, OH, OR", SH, SR", S(0)R", S(0)₂R", S(0) HR", S(0)₂ HR", S(0) R"₂, S(0)₂ R"₂, C(0)R", CO2H, CO2R", C(0) H₂, C(0) HR", C(0) R"₂, CN, CH2CN, CF3, CHF2, CH2F, H(CN), N(CN)₂, CH(CN)₂, C(CN)₃; and

R" is independently selected from the group consisting of Ci-C₆ alkyl, C3-C6

cycloalkyl, C4-C7 heterocycloalkyl, C₆-Cio aryl and C5-C10 heteroaryl; and wherein Ci-Ce alkyl, C₃-C₆ cycloalkyl, or C4-C7 heterocycloalkyl are optionally substituted with oxo, H2, NHR", N(R")₂, F, CI, Br, I, OH, OR", SH, SR", S(0)R", S(0)₂R", S(0)NHR", S(0)₂NHR", S(0)NR"₂,

S(0)₂NR"₂, C(0)R", CO2H, CO2R", C(0)NH₂, C(0)NHR", C(0)NR"₂, CN, CH2CN, CF₃, CHF2, CH2F, NH(CN), N(CN)₂, CH(CN)₂, C(CN)₃; and wherein C6-C10 aryl or C5-C10 heteroaryl are optionally substituted with Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C2-C6 alkenyl, C₃-C₆ cycloalkenyl, C2-C6 alkynyl, C₄- CT heterocycloalkyl, Ce aryl, Cs-Ce heteroaryl, NH2, NHR", N(R")₂,

NHC(0)R", NR"C(0)R", F, CI, Br, I, OH, OR", SH, SR", S(0)R", S(0)₂R", S(0)NHR", S(0)₂NHR", S(0)NR"₂, S(0)₂NR"₂, C(0)R", CO2H, CO2R", C(0)NH₂, C(0)NHR", C(0)NR"₂, CN, CH2CN, CF₃, CHF2, CH2F, NH(CN), N(CN)₂, CH(CN)₂, or C(CN)₃; and wherein two R" groups on a nitrogen can be taken together to form a ring having from 2 to 7 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur including the nitrogen atom to which the two R' ' groups are bonded;

R² is selected from:

(i) OR⁶;

(ii) NR^7aR^7b; and

R⁶ is selected from hydrogen and C1-C4 alkyl or C₃-C₄ cycloalkyl;

R^7a and R^7b are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl or C₃-C₄ cycloalkyl; or

(iii) R^7a and R^7b are taken together to form a ring having from 3 to 7 atoms.

[0042] In certain embodiments, the HIF stabilizer is a compound having a structure of Formula (III)

Formula (III) or a pharmaceutically acceptable salt, solvate isotopologue, or hydrate thereof, wherein R is chosen from

(i) -OR¹; or

(ii) - R²R³; or

(iii) -OM¹;

R s:

(i) hydrogen; or

(ii) Ci-C₆ alkyl or C3-C6 cycloalkyl;

R² and R³ are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl or C3-C4 cycloalkyl; or

(iii) R² and R³ can be taken together to form a ring having from 2 to 7 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur including the nitrogen atom to which R² and R³ are bonded; and

M¹ is a cation; and

R⁴ is:

(i) -OH; or

(ii) -OM²; and

M² is a cation.

[0043] In certain embodiments, the HIF stabilizer is a compound having a structure of Formula (IV)

Formula (IV) or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof, wherein

R is chosen from

(i) -OR¹; or

(ii) - R²R³; or

(iii) -OM¹;

R s:

(i) hydrogen; or

(ii) Ci-Ce alkyl or C3-C6 cycloalkyl;

R² and R³ are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl or C3-C4 cycloalkyl; or

M¹ is a cation; and

R⁴ is:

(i) -OH; or

(ii) -OM²; and

M² is a cation.

[0044] HIF prolyl hydroxylase inhibitor compounds described herein are unsubstituted or substituted 3-hydroxy-pyridine-2-carboxamides, having the structure shown in Formula (V) below:

Formula (V) and pharmaceutically acceptable salts, isotopologues, solvates, hydrates, and tautomers thereof, wherein: L is Ci-6 alkyl; and wherein R¹ and R² are independently H or Ci-6 alkyl.

[0045] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is { [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1):

Compound 1 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0046] In certain embodiments, the HIF stabilizer is Compound 2 having the structure:

Compound 2 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0047] In certain embodiments, the HIF stabilizer is Compound 3 having a structure

Compound 3 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0048] In certain embodiments, the HIF stabilizer is Compound 4 having a structure

Compound 4 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0049] In certain embodiments, the HIF stabilizer is Compound 5 having the structure

Compound 5 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0050] In certain embodiments, the HIF stabilizer is Compound 6 having the structure

Compound 6 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0051] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 having the structure:

Compound 7 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0052] In certain embodiments, the HIF stabilizer is Compound 8 having the structure:

Compound 8

or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0053] In certain embodiments, the HIF stabilizer is Compound 9 having a structure

Compound 9

[0054] In certain embodiments, the HIF stabilizer is Compound 10 having a structure

Compound 10

[0055] In certain embodiments, the HIF stabilizer is Compound 11 having the structure

Compound 11

[0056] In certain embodiments, the HIF stabilizer is Compound 12 having the structure

Compound 12 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.

[0057] In certain embodiments, the HIF stabilizer is Compound 13 having the structure

Compound 13 having a name N-(2-aminoethyl)-3-hydroxy-pyridine-2-carboxamide, including

pharmaceutically acceptable salts, isotopologues, and tautomers thereof. Tautomers of Compound 13 include the following:

[0058] In certain embodiments, the HIF stabilizer is Compound 98 having the structure:

Compound 98

[0059] In certain embodiments, a metabolite of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13, or isotopologues thereof, can be used with the methods provided herein. In certain more specific embodiments, such a metabolite, is a phenolic glucuronide or an acyl-glucuronide.

Metabolite 1 Metabolite 2

[0060] Compound 13 can be prepared using reagents and methods known in the art, including the methods provided in Chinese Patent Application Publication No. CN 85107182 A, published on April 8, 1987, and German Patent Application Publication No. DE 3530046 Al, published on March 13, 1986, the entire contents of each of which are incorporated herein by reference.

[0061] As used herein, an "alkyl" group is a saturated straight chain or branched non- cyclic hydrocarbon having, for example, from 1 to 12 carbon atoms, 1 to 9 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -^-propyl, -/7-butyl, -/7-pentyl and -/7-hexyl; while branched alkyls include -isopropyl, -sec-butyl, -/^'so-butyl, -tert-butyl, -zso-pentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0062] Ci-6 alkyl units include the following non-limiting examples: methyl (Ci), ethyl (C2), 7-propyl (C3), zso-propyl (C3), /7-butyl (C₄), sec-butyl (C₄), zso-butyl (C₄), tert-butyl (C₄), /7-pentyl (C5), tert-pentyl (C5), «eo-pentyl (C5), zso-pentyl (C5), sec-pentyl (C5), 3-pentyl (C5), /7-hexyl (C₆), zso-hexyl (C₆), «eo-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.

[0063] As used herein, an "alkenyl" group is a partially unsaturated straight chain or branched non-cyclic hydrocarbon containing at least one carbon-carbon double bond and having, for example, from 1 to 6 carbon atoms. Representative alkenyl groups include propenyl and the like.

[0064] As used herein, an "alkynyl" group is a partially unsaturated straight chain or branched non-cyclic hydrocarbon containing at least one carbon-carbon triple bond and having, for example, from 2 to 6 carbon atoms. Representative alkynyl groups include propynyl, butynyl and the like. [0065] As used herein, an "alkoxy" group is an alkyl-O- group in which the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, «-propoxy, isopropoxy and «-butoxy.

[0066] As used herein, an "cycloalkyl" group is a saturated cyclic alkyl group of from 3 to 6 carbon atoms having a single cyclic ring. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.

[0067] As used herein, an "cycloalkenyl" group is a partially unsaturated cyclic alkyl group containing at least one carbon-carbon double bond and from 3 to 6 carbon atoms having a single cyclic ring. Representative cycloalkenyl groups include cyclopropenyl and cyclobutenyl.

[0068] As used herein, a "cycloalkoxy" group is a cycloalkyl-O- group in which the cycloalkyl group is as defined herein. Representative cycloalkoxy groups include

cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.

[0069] As used herein, a "haloalkyl" group is an alkyl group as defined herein above with one or more (e.g., 1 to 5) hydrogen atoms are replaced by halogen atoms. Representative haloalkyl groups include CF₃, CHF₂, CH₂F, CC1₃, CF₃CH₂CH₂ and CF₃CF₂.

[0070] As used herein, a "halocycloalkyl" group is a cycloalkyl group as defined herein above with one or more (e.g., 1 to 5) hydrogen atoms are replaced by halogen atoms.

Representative halocycloalkyl groups include 2,2-difluorocyclopropyl, 2,2- dichlorocyclopropyl, 2,2-dibromocyclopropyl, tetrafluorocyclopropyl, 3,3-difluorocyclobutyl and 2,2, 3 ,3 -tetrafluorocy clobutyl .

[0071] As used herein, a "heterocycloalkyl" group is a saturated ring of 4 to 7 atoms, preferably 5 or 6 ring atoms, wherein 1 or 2 ring members are selected from the group consisting of O, S and R" and the remaining atoms are carbon. There are no adjacent oxygen and/or sulfur atoms in the rings. Representative heterocycloalkyl groups are piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3- dioxolanyl, 1,4-dioxanyl, oxazolinyl, tetrahydrofuranyl, tetrahydrothiophenyl and

tetrahydrothiopyranyl .

[0072] As used herein, an "aryl" group is an aromatic monocyclic or multi-cyclic ring system comprising 6 to 10 carbon atoms. Representative aryl groups include phenyl and naphthyl.

[0073] As used herein, a "heteroaryl" is a single ring, bicyclic or benzofused

heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included. Representative single-ring heteroaryl groups include pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Representative bicyclic heteroaryl groups are naphthyridyl (e.g., 1,5 or 1, 7), imidazopyridyl,

pyridopyrimidinyl and 7-azaindolyl. Representative benzofused heteroaryl groups include indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thianaphthenyl),

benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and

benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4- pyridyl.

[0074] For the purposes of the present disclosure the terms "compound," "analog," and "composition of matter" stand equally well for the HIF prolyl hydroxylase enzyme inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, tautomers, and the like. The compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following are non-limiting examples of anions that can form pharmaceutically acceptable salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like. The following are non- limiting examples of cations that can form pharmaceutically acceptable salts of the anionic form of acidic substituent groups on the compounds described herein: sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, and the like. The following are non-limiting examples of cations that can form pharmaceutically acceptable salts of the anionic form of phenolic, aryl alcohol, or heteroaryl alcohol substituent groups on the compounds described herein: sodium, lithium, and potassium. In certain embodiments, terms "compound,"

"analog," and "composition of matter" are used interchangeably throughout the present specification.

[0075] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

[0076] In particular, a therapeutic effect of a HIF prolyl hydroxylase inhibitor (e.g., any of the compounds described herein) can be assessed using known techniques (See Barazia et αί , 2015, Blood 22:251 1-2517). During the course of treatment, real-time fluorescence intravital microscopy is used to monitor neutrophil adhesion and platelet-neutrophil aggregation in the venules of the mice. Survival rates are also examined.

[0077] For example, HU and Akti XII are injected into Berkeley mice 3 and 0.5 hours, respectively. Neutrophils and platelets are isolated as described previously. (See Kim et al , 2013, Blood 122: 1052-1061 ; Hahm et al, 2013, Blood 121 : 3789-3800.) Platelets are suspended in HEPESTyrode buffer (20 mM HEPES, pH 7.3, 136 mM NaCl, 2.7 mM KC1, 3.3 mM NaH₂P0₄, 1 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose, and 0.1% BSA) at a concentration of 3 x 108 cells/ml. The concentrations of neutrophils are adjusted to 1 x 107 cells/ml in Hank' s balanced salt solution. Neutrophils and platelets are stimulated with 10 μΜ fMLF for 2 minutes at 37 °C or 0.05 U/mL thrombin for 2 minutes at 37 °C, respectively. Equal amounts of proteins (50 μg) in cell lysates are immunoblotted with antibodies against phosphoAKTl or AKT2 or total AKT, followed by densitometry.

[0078] Following intravital microscopy, mouse lungs are removed, washed with ice-cold PBS, and fixed in 10% formalin for 48 hours. The lungs are then placed in 70% ethanol, embedded in paraffin, sectioned, and mounted on slides. Slides then are rehydrated by 5 minute subsequent incubations in xylene (twice), 100%) ethanol (twice), 95% ethanol, 70% ethanol, and water. Neutrophils then are stained with a Naphthol AS-D Chloroacetate (specific esterase) kit (Sigma). The slides then are stained with hematoxylin and mounted with Vectashield containing DAPI. Images are taken using a Zeiss Axioplan 2 microscope equipped with a Plan-Neofluar ^χ40/1.3 NA oil objective lens and are recorded with a digital camera. Neutrophils are manually counted in the field of view (1 10 mm²).

[0079] Cultured human umbilical vein ECs (HUVECs) are pretreated with 1 - 100 μΜ SNP 5 minutes prior to stimulation with 20 ng/ml TNF-a. Six hours after treatment with TNF-a and SNP, cells are lysed with RIPA buffer containing proteinase inhibitors (20 mM Tris-HCl, pH 7.4 containing 1% Triton-XlOO, 0.05% SDS, proteinase inhibitor cocktail, and 1 mM PMSF). Equal amounts of lysate proteins are subjected to SDS-PAGE, followed by immunoblotting using polyclonal antibodies against ICAM-1.

[0080] Mouse neutrophils and platelets are isolated from Berkeley mice as described above. Neutrophils (2 x 106) or platelets (3 x 107) are incubated with vehicle or various doses of SNP for 2 minutes at 37°C,4 followed by stimulation with 10 μΜ fMLF neutrophils) or 0.05 U/ml thrombin (platelets) for 2 minutes at 37°C. Cells are lysed as described above. Cell lysates are immunoblotted using polyclonal antibodies against pAKT2 and total AKT2, followed by densitometry. 4.4 Isotopologues

[0081] Deuterium-enriched isotopologues of prolyl hydroxylase inhibitors are described, e.g., in International Patent Application Publication No. WO 2016/153996, which is incorporated herein by reference in its entirety.

[0082] In certain embodiments, a deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VI):

Formula (VI) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

R and R¹ are each independently selected from:

(i) hydrogen

(ii) substituted or unsubstituted phenyl; or

(iii) substituted or unsubstituted heteroaryl;

said substitution selected from:

(i) Ci-C₄ alkyl;

(ii) C3-C4 cycloalkyl;

(iii) C1-C4 alkoxy;

(iv) C3-C4 cycloalkoxy;

(v) C1-C4 haloalkyl;

(vi) C3-C4 halocycloalkyl;

(vii) halogen;

(viii) cyano;

(ix) NHC(0)R⁴;

(x) C(0)NR^5aR^5b; and

(xi) heteroaryl; or

R⁴ is a C1-C4 alkyl or C3-C4 cycloalkyl;

R^5a and R^5b are each independently selected from: (i) hydrogen;

(ii) Ci-C₄ alkyl;

(iii) C3-C4 cycloalkyl; or

(iv) R^3a and R^5b are taken together to form a ring having from 3 to 7 atoms; R² is selected from:

(i) OR⁶;

(ii) R^7aR^7b; and

R⁶ is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl;

R^7a and R^7b are each independently selected from:

(i) hydrogen;

(ii) C1-C4 alkyl or C3-C4 cycloalkyl; or

(iii) R^7a and R⁷ are taken together to form a ring having from 3 to 7 atoms;

R³ is selected from hydrogen, methyl, and ethyl;

L is a linking unit having a structure -[C(R^8aR^8b)]n-

R^8a and R^8b are each independently selected from hydrogen, methyl and ethyl;

n is an integer from 1 to 3; and

R⁹ is selected from hydrogen and methyl,

wherein at least one hydrogen is replaced by a hydrogen isotopically enriched with deuterium.

[0083] In certain more specific embodiments, the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VII):

Formula (VII) a pharmaceutically acceptable salt, solvate or hydrate thereof,

R is selected from:

(i) Y⁸; or

(ii) substituted or unsubstituted phenyl; said substitution selected from:

(iv) Y¹²;

(v) Y¹³;

(vi) Y¹⁴;

(vii) Y ; or

(viii) Y¹⁶; wherein one or more Y atoms (i.e., Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, and/or Y¹⁶) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s). In particular embodiments, one, two, three, four, five, six, seven, or eight of the indicated Y atoms is/are isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen(s). In one

embodiment, all of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, and Y are isotopically enriched with deuterium.

[0084] In certain more specific embodiments, all of Y¹, Y⁴, and Y⁵ are hydrogen.

[0085] In certain embodiments, one or more Y atoms of a compound of Formula (VII) is/are deuterium-enriched. For example, particular isotopologues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium-enriched atomic position, i.e., a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance:

Table 1

[0086] In certain more specific embodiments, the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VIII):

Formula (VIII)

or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof,

wherein one or more Y atoms (i.e., Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, and/or Y¹¹) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s). In particular embodiments, one, two, three, four, five, six, seven, or eight of the indicated Y atoms is/are isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen(s). In one embodiment, all of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, and Y¹¹ are isotopically enriched with deuterium.

[0087] In certain more specific embodiments, all of Y¹, Y⁴, and Y⁵ are hydrogen.

[0088] In certain embodiments, one or more Y atoms on the phenyl portion of a compound of Formula (VIII) is/are deuterium-enriched. For example, particular

isotopologues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium-enriched atomic position, i.e., a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance:

Table 2

[0089] In certain embodiments, one or more Y atoms on the pyridine portion of a compound of Formula (VIII) is/are deuterium-enriched. For example, particular

Table 3

[0091] In certain embodiments, one or more Y atoms on the heteroatoms of a compound of Formula (VIII) is/are deuterium-enriched. For example, particular isotopologues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium- enriched atomic position, i.e., a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance: Table 5

[0092] In certain embodiments, one or more Y atoms on the phenyl, pyridine, heteroatoms, and/or alkyl portions of a compound of Formula (VIII) is/are deuterium- enriched, i.e., any combination of deuterium-enrichment shown above is encompassed, some embodiments the isotopologue is selected from: Table 6

[0093] In certain more specific embodiments, the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (IX):

Formula (IX)

or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein one or more Y atoms (i.e. , Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, and/or Y¹¹) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s). In particular embodiments, one, two, three, four, five, six, seven, or eight of the indicated Y atoms is/are isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen(s). In one embodiment, all of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, and Y¹¹ are isotopically enriched with deuterium.

[0094] In certain more specific embodiments, all of Y¹, Y⁴, and Y⁵ are hydrogen.

[0095] In certain embodiments, one or more Y atoms on the phenyl portion of a compound of Formula (IX) is/are deuterium-enriched. For example, particular isotopologues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium-enriched atomic position, i.e. , a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance:

Table 7

[0096] In certain embodiments, one or more Y atoms on the pyridine portion of a compound of Formula (IX) is/are deuterium-enriched. For example, particular isotopol ogues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium-enriched atomic position, i.e., a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance: Table 8

[0098] In certain embodiments, one or more Y atoms on the heteroatoms of a compound of Formula (IX) is/are deuterium-enriched. For example, particular isotopologues provided herein include the following listed compounds, wherein the label "D" indicates a deuterium- enriched atomic position, i.e., a sample comprising the given compound has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium, and any atom not designated as a deuterium is present at its natural abundance: Table 10

[0099] In certain embodiments, one or more Y atoms on the phenyl, pyridine,

heteroatoms, and/or alkyl portions of a compound of Formula (IX) is/are deuterium-enriched, i.e., any combination of deuterium-enrichment shown above is encompassed. In some embodiments the isotopologue is selected from: Table 11

[00100] In certain embodiments, a metabolite of a compound has a structure of Formula (VI), Formula (VII), Formula (VIII), or Formula (IX). In certain more specific embodiments, such a metabolite is a phenolic glucuronide having the structure of Metabolite 3 or an acyl -glucuronide having a structure of Metabolite 4:

Metabolite 3 Metabolite 4 or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein

R is selected from:

(i) Y¹⁶; or

(ii) substituted or unsubstituted phenyl;

said substitution selected from:

(i) C(Y^17"19)₃;

(ii) halogen;

(iii) cyano;

(iv) Y²⁰;

(v) Y²¹;

(vi) Y²²;

(vii) Y²³; or

(viii) Y²⁴; wherein one or more Y atoms (i.e., Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, Y¹⁶, Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, Y²¹, Y²², Y²³, and/or Y²⁴) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s). In particular embodiments, one, two, three, four, five, six, seven, or eight of the indicated Y atoms is/are isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen(s). In one embodiment, all of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, Y¹⁶, Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, Y²¹, Y²², Y²³, and Y²⁴ are isotopically enriched with deuterium. [00101] In certain more specific embodiments, all of Y¹, Y⁴, Y⁷, Y¹⁰, Y¹¹, and Y¹⁴ are hydrogen.

[00102] In certain embodiments, a compound selected from Metabolite 3 or Metabolite 4 is isolated.

4.5 Treatment of Hemoglobin Disorders

[00103] The methods provided herein can be used to efficaciously administer to a patient a compound in the form of a HIF prolyl hydroxylase inhibitor to treat a hemoglobin disorder. Such hemoglobin disorders include any disorder associated with an alteration in the amount, structural integrity, or function of adult hemoglobin, specifically adult β globin. Hemoglobin disorders include, but are not limited to, sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle β thalassemia, β thalassemias, including p°-(major) thalassemia and P⁺-(minor) thalassemia, and disorders involving ineffective erythropoiesis.

[00104] In certain embodiments provided herein is a method for treating a hemoglobin disorder, comprising administering to a patient having a hemoglobin disorder a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00105] In certain embodiments provided herein is a method for treating a sickle cell disease, comprising administering to a patient having a sickle cell disease a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00106] In certain embodiments provided herein is a method for treating sickle cell anemia, comprising administering to a patient having sickle cell anemia a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00107] In certain embodiments provided herein is a method for treating hemoglobin SC disease, comprising administering to a patient having hemoglobin SC disease a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. [00108] In certain embodiments provided herein is a method for treating sickle β thalassemia, comprising administering to a patient having β thalassemia a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00109] In certain embodiments provided herein is a method for treating β thalassemia, comprising administering to a patient having β thalassemia a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00110] In certain embodiments provided herein is a method for treating P°-thalassemia, comprising administering to a patient having P°-thalassemia a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

[00111] In certain embodiments provided herein is a method for treating P⁺-thalassemia, comprising administering to a patient having 3⁺-thalassemia a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

[00112] In certain embodiments provided herein is a method for treating ineffective erythropoiesis, comprising administering to a patient having ineffective erythropoiesis a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,

Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00113] In certain embodiments provided herein is a method for reducing or alleviating a symptom of a hemoglobin disoder, comprising administering to a patient having a

hemoglobin disorder a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III),

Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,

Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite,

pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In certain embodiments, the symptom is vasoocclusion. In certain embodiments, the symptom is acute pain. In certain embodiments, the symptom is infection, including but not limited to bacterial infection. In certain embodiments, the symptom is stroke. In certain embodiments, the symptom is acute chest syndrome. In certain embodiments, the symptom is pulmonary hypertension. In certain embodiments, the symptom is heart disease. In certain embodiments, the symptom is a renal complication, including but not limited to renal failure, renal damage, hematuria, renal medullary carcinoma, and nocturnal enuresis. In certain embodiments, the symptom is hemolytic anemia. In certain embodiments, the symptom is cholelithiasis. In certain embodiments, the symptom is brain infarction. In certain embodiments, the symptom is cognitive impairment. In certain embodiments, the symptom is transfusion burden.

[00114] In certain embodiments provided herein is a method for increasing the plasma levels of fetal hemoglobin in a subject, comprising administering to a subject a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00115] In certain embodiments provided herein is a method for increasing the expression of fetal hemoglobin in a subject, comprising administering to a subject a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00116] In certain embodiments provided herein is a method for increasing the plasma levels of γ subunits of hemoglobin in a subject, comprising administering to a subject a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,

[00117] In certain embodiments provided herein is a method for increasing the expression of γ subunits of hemoglobin in a subject, comprising administering to a subject a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

[00118] In certain embodiments provided herein is a method for reducing sickle hemoglobin (HbS) in a subject, comprising administering to a subject a HIF prolyl hydroxylase inhibitor, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98. In a more specific embodiment, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor are administered, wherein the HIF prolyl hydroxylase inhibitor is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a HIF prolyl hydroxylase inhibitor is Compound 1. In embodiments, a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.

4.6 Patient Populations

[00119] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, is unresponsive to treatment with other therapeutic agents. In certain embodiments, the subject is unresponsive to treatment with hydroxyurea. In certain embodiments, the subject is unresponsive to treatment with butyrate. In certain embodiments, the subject is unresponsive to treatment with 5- azacytidine. In certain embodiments, the subject is unresponsive to treatment with nitric oxide. In certain embodiments, the subject is unresponsive to treatment with vitamin B12. In certain embodiments, the subject is unresponsive to treatment with folic acid. In certain embodiments, the subject is unresponsive to treatment with an iron supplement. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98.

[00120] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, is hyporesponsive to treatment with other therapeutic agents. In certain embodiments, the subject is hyporesponsive to treatment with hydroxyurea. In certain embodiments, the subject is hyporesponsive to treatment with butyrate. In certain embodiments, the subject is hyporesponsive to treatment with 5- azacytidine. In certain embodiments, the subject is hyporesponsive to treatment with nitric oxide. In certain embodiments, the subject is hyporesponsive to treatment with vitamin B12. In certain embodiments, the subject is hyporesponsive to treatment with folic acid. In certain embodiments, the subject is hyporesponsive to treatment with an iron supplement. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98.

[00121] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, is undergoing blood transfusion. In certain embodiments, the patient is transfusion independent. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises

administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98. [00122] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, has a genotype for hemoglobin disorder. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In certain embodiments, the genotype is HbS/S. In certain embodiments, the genotype is HbS/ β°. In certain embodiments, the genotype is HbS/S. In certain embodiments, the genotype is Sever HbS/ β⁺ thalassemia. In certain embodiments, the genotype is HbS/ OArab. In certain embodiments, the genotype is HbS/ D Punjab. In certain embodiments, the genotype is HbS/ C Harlem. In certain embodiments, the genotype is HbC/S Antilles. In certain embodiments, the genotype is HbS/ Quebec-CHORI. In certain embodiments, the genotype is HbS/ C. In certain embodiments, the genotype is Moderate HbS/ β⁺ thalassemia. In certain embodiments, the genotype is HbA/ S Oman. In certain embodiments, the genotype is Mild HbS/ β⁺⁺ thalassemia. In certain embodiments, the genotype is HbS/ E. In certain embodiments, the genotype is HbA/ Jamaica Plain. In certain embodiments, the genotype is HbS/ HPFH. In certain embodiments, the genotype is HbS/ other HB variants. In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising

administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,

Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, has or is at risk of developing chronic organ damage secondary to a hemoglobin disorder. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98. In certain embodiments, the chronic organ damage is of the lungs, kidney, liver, skeleton, and skin. [00123] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, has or is at risk of developing a complication secondary to a hemoglobin disorder. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt,

isotopologue, solvate or hydrate thereof. In embodiments, a method comprises

administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98. In certain embodiments, the

complication is acute chest syndrome. In certain embodiments, the complication is cerebrovascular disease. In certain embodiments, the complication is kidney failure. In certain embodiments, the complication is pulmonary hypertension. In certain embodiments, the complication is blindness. In certain embodiments, the complication is skin ulcers. In certain embodiments, the complication is gallstones. In certain embodiments, the

complication is hand-foot syndrome. In certain embodiments, the complication is renal insufficiency. In certain embodiments, the complication is retinitis. In certain embodiments, the complication is osteonecrosis. In certain embodiments, the complication is osteomyelitis. In certain embodiments, the complication is aplastic crises. In certain embodiments, the complication is functional asplenism. In certain embodiments, the complication is stroke. In certain embodiments, the complication is priapism.

[00124] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, has or is at risk of developing a deficiency in vitamin B 12, folic acid, or iron. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt,

isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98.

[00125] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, is less than 18 years old. In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98. In certain embodiments, the subject is less than 12 years old. In certain embodiments, the subject is less than 6 years old.

[00126] In certain embodiments, a subject being treated with a method provided herein, e.g., a method comprising administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, can be homozygous or

heterozygous for one of the following haplotypes: the Benin ("BEN") haplotype, the Bantu ("BAN") haplotype, the Senegal ("SEN") haplotype, the Cameroon ("CAM") haplotype, the Arabian-Indian ("ARAB") haplotype, and the Central African Republic ("CAR") haplotype. The distribution of haplotypes among different patient populations has been well studied in the art (See Gabriel, A., et al., 2010, Nature Education 3 :2, and Loggetto, S. R., 2013, Rev. Bras. Hematol. Hemoter. 3 : 155-157). In embodiments, a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98. 4.7 Combination Therapy

[00127] In certain embodiments, a compound as disclosed herein, such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,

Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof, may be administered in combination with a second pharmaceutically active agent. In

embodiments, a combination therapy comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a combination therapy comprises administration of Compound 1. Such combination therapy may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Additionally, when administered as a component of such combination therapy, the compound provided herein (see Section 4.2) and the second pharmaceutically active agent may be synergistic, such that the daily dose of either or both of the components may be reduced as compared to the dose of either component that would normally be given as a monotherapy. Alternatively, when

administered as a component of such combination therapy, the compound provided herein (see Section 4.2) and the second pharmaceutically active agent may be additive, such that the daily dose of each of the components is similar or the same as the dose of either component that would normally be given as a monotherapy.

[00128] In certain embodiments, a compound as disclosed herein, such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,

Compound 11, Compound 12, and Compound 13, or a metabolite, e.g., Metabolite 1 or Metabolite 2, pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof is administered at the same time as a second pharmaceutically active agent. In embodiments, a compound is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a compound is Compound 1. In certain embodiments, the compound provided herein (see Section 4.2) is administered on the same day as a second pharmaceutically active agent. In certain embodiments, the compound provided herein (see Section 4.2) is administered one, two, three, or more days before a second pharmaceutically active agent. In certain embodiments, the compound provided herein (see Section 4.2) is administered one, two, three or more days after a second pharmaceutically active agent. In certain embodiments, the compound provided herein (see Section 4.2) is administered within one, two, three or more weeks of a second

pharmaceutically active agent. In certain embodiments, the compound is Compound 1. In certain embodiments, the compound is Compound 7. In certain embodiments, the compound is any one of Compounds 14-98.

[00129] In certain embodiments, the second pharmaceutically active agent is hydroxyurea. In certain embodiments, the second pharmaceutically active agent is butyrate. In certain embodiments, the second pharmaceutically active agent is 5-azacytidine. In certain embodiments, the second pharmaceutically active agent is nitric oxide. In certain

embodiments, the second pharmaceutically active agent is vitamin B12. In certain

embodiments, the second pharmaceutically active agent is folic acid.

[00130] In certain embodiments, the second pharmaceutically active agent is an iron supplement, such as ferrous sulfate, ferrous gluconate, or ferrous fumarate. In certain such embodiments, the iron supplement is administered at least one hour, at least two hours, at least three hours, at least four hours, or even at least six hours following administration of a compound provided herein (see Section 4.2). In certain embodiments, the iron supplement is administered in an amount such that ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL. In certain embodiments, the iron supplement is administered orally at a daily dose of at least about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered orally at a dose of about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered intravenously. In certain embodiments, the iron supplement is administered continuously and/or indefinitely, such as for more than 42 consecutive days. In certain alternative embodiments, the iron supplement is administered on an as needed basis such ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL.

[00131] In certain embodiments, the second pharmaceutically active agent is an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic. In certain such embodiments, the ESA is an rhEPO product, including, but not limited to, epoetin alfa, epoetin beta, darbepoetin, or peginesatide. In certain such embodiments, the ESA is administered as a rescue therapy. In certain alternative embodiments, the ESA is

administered continuously and/or indefinitely, such as for more than 42 days. [00132] In certain embodiments, the second pharmaceutically active agent is a compound that prevents or inhibits polymerization of hemoglobin S. In certain embodiments, the compound is selected from GBT440, vanillin, pentosan polysulfate, sulodexide, xylan sulfates, dextran sulfates, chitin sulfates, di-, tri-, or oligomers and polymers of

iduronic/uronic acids, keratan sulfates, and hyaluronic acid.

[00133] In certain embodiments, the second pharmaceutically active agent is a compound that effects allosteric modulation of hemoglobin S. Compounds that effect allosteric modulation of hemoglobin S are known in the art and described in, for example, International Publication No. WO2014/150256. Specifically, in certain embodiments the compound is selected from 2-methoxy-5-[[2-(lH-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[5-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[2-(l-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[2-(2H-tetrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[2-(4-methyl-lH-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[(2-pyrazol-l-ylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde, 5-[[2-(l,5-dimethylpyrazol-4-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-(2-ethylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2- methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2- methoxy-5-[(2-phenylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[3-(2- propap-2-ylpyrazol-3-yl)pyridin-4-yl]methoxy]pyridine-4-carbaldehyde, 2-hydroxy-6-[[2-(2- propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde, 2-methoxy-5-[(2-pyridin-3- ylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-[2-(2- methoxyethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 5-[[2-[2-(2- hydroxyethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2- methoxy-5-[[2-(2-propylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2- methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4- carbaldehyde,5-[[2-(2-cyclobutylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4- carbaldehyde, 5-[[2-(2-cyclohexylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4- carbaldehyde, 5-[[2-[2-(cyclohexylmethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2- methoxypyridine-4-carbaldehyde, 5-[[2-(2-cyclopentylpyrazol-3-yl)pyridin-3-yl]methoxy]-2- methoxypyridine-4-carbaldehyde, 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2-methoxy-5-[[2-(2-methylphenyl)pyridin- 3-yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-(2-methoxypyridin-3-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[3-(2-propan-2-ylpyrazol-3-yl)pyrazin-2- yl]methoxy]pyridine-4-carbaldehyde, 2-(difluoromethoxy)-5-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-(2-methoxyethoxy)-5-[[2-(2-propan-2- ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 5-[5-[3-[(4-formyl-6- methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]acetic acid, 3-[[2-(2-propan-2- ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 6-methyl-3-[[2-(2-propan-2- ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 5-[[2-(2-hydroxypropan-2- yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2-(2-methoxyethoxy)-5-[[2-(2- methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, methyl 3-[5-[3-[(4- formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]propanoate, 3-[5-[3-[(4- formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]propanoic acid, 3- hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 3- methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2- methoxy-5-[[2-(4-methyl-2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]benzaldehyde, 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3- yl]methoxy]benzaldehyde, 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-(2- methoxyethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine- 4-carbaldehyde, 6-methyl-3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]pyridine-2-carbaldehyde, 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 2-fluoro-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]benzaldehyde, 2-fluoro-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]benzaldehyde, 3-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 3-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 3-chloro-5-[[2- (2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-fluoro-6-[[2-(2- propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde, 3-methyl-5-[[2-(2-propan-2- ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, and 3-methyl-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde. 4.8 Formulations and Routes of Administration

[00134] Exemplary formulations comprising a HIF prolyl hydroxylase inhibitor, or pharmaceutically acceptable addition salts or hydrates thereof (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) include those described in US Patent Application Publication No. 2018/0092892, which is incorporated by reference in its entirety, as well as the further exemplary formulations described herein.

[00135] A HIF prolyl hydroxylase inhibitor, or pharmaceutically acceptable addition salts or hydrates thereof (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal, and parenteral administration, including intramuscular, subcutaneous and intravenous injections.

[00136] For any mode of administration, the actual amount of HIF prolyl hydroxylase inhibitor (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) delivered will depend, in part, on such factors as the

bioavailability of HIF prolyl hydroxylase inhibitor, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The actual amounts delivered and dosing schedules can be readily determined by those of skill without undue experimentation. Dosing regimens of HIF prolyl hydroxylase inhibitor according to the methods are described in Section 4.8.

[00137] HIF prolyl hydroxylase inhibitors, their metabolites or pharmaceutically acceptable salts and/or hydrates thereof (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) may be administered in combination with other compounds, and/or in combination with other therapeutic agents. HIF prolyl hydroxylase inhibitors may be administered in the form of a pharmaceutical composition, wherein the HIF prolyl hydroxylase inhibitor is in admixture with one or more

pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical compositions for use in accordance with the methods described herein may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the HIF prolyl hydroxylase inhibitor into

preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. [00138] For injection, the agents of the methods described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer' s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[00139] Pharmaceutical compositions may be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise a compound as provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., the parent compound). Pharmaceutical compositions and dosage forms can further comprise one or more excipients.

[00140] In certain embodiments, pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided are pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or disaccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.

[00141] Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25 F20 (2002). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In one embodiment, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.

[00142] Also provided are anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long- term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[00143] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers {e.g., vials), blister packs, and strip packs.

[00144] Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[00145] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.

[00146] Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets {e.g., chewable tablets), caplets, capsules, and liquids {e.g., flavored syrups). Such dosage forms contain

predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

[00147] Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms {e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. [00148] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[00149] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free- flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00150] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, insoluble diluents, binders, fillers, disintegrants, glidants, carriers, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methylcellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[00151] Examples of insoluble diluents and carriers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, dibasic calcium phosphate and microcrystalline cellulose. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL- PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM. Other suitable forms of microcrystalline cellulose include, but are not limited to, silicified microcrystalline cellulose, such as the materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof.

[00152] Examples of diluents / fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, hydroxypropyl methylcellulose (e.g., Methocel E5 Premium LV) and mixtures thereof.

[00153] In certain embodiments, fillers may include, but are not limited to block copolymers of ethylene oxide and propylene oxide. Such block copolymers may be sold as POLOXAMER or PLURONIC, and include, but are not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof.

[00154] In certain embodiments, fillers may include, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.

[00155] Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[00156] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate (e.g., Explotab®), potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[00157] Glidants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to fumed silica, magnesium carbonate, magnesium stearate, colloidal silicon dioxide (e.g., Aerosil, Cab-O-Sil), starch and talc.

[00158] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate (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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof.

[00159] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

[00160] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[00161] Suspensions, in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00162] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[00163] For administration by inhalation, HIF prolyl hydroxylase inhibitor for use according to the methods described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[00164] The HIF prolyl hydroxylase inhibitors (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. For example, the HIF prolyl hydroxylase inhibitor may be administered by continuous infusion subcutaneously over a period of 15 minutes to 24 hours. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. HIF prolyl hydroxylase inhibitors may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

[00165] Pharmaceutical formulations for parenteral administration include aqueous solutions of HIF prolyl hydroxylase inhibitor (e.g., Compound 1, or a metabolite,

pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) in water soluble form. Additionally, suspensions of HIF prolyl hydroxylase inhibitor may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[00166] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00167] The HIF prolyl hydroxylase inhibitor (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[00168] In addition to the formulations described previously, HIF prolyl hydroxylase inhibitors (e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[00169] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[00170] For topical applications according to the methods described herein, the HIF prolyl hydroxylase inhibitor may be formulated with suitable excipients, carriers and diluents well known to those skilled in the pharmaceutical arts that are suitable for formulating topical preparations. When the tissues to be treated are mucosal tissues, including oral mucosa, suitable excipients, carriers and diluents must also be safe for application to oral and related mucosal tissue. These are well known to the skilled artisan.

[00171] Examples of excipients, carriers and diluents include, for example, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. The skilled artisan can readily select the particular excipients, carriers and diluents appropriate to the type and location of the tissue to be treated.

[00172] Additionally, moisturizers or humectants can be added to the present composition if desired. Examples of such additional ingredients can be found in Remington's

Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990).

[00173] In addition to these and other vehicles which are known to those of ordinary skill in the art, it will be understood that the topical pharmaceutical compositions for the methods described herein may optionally include other ingredients such as analgesics, anesthetics, antibacterial, antiyeast agents, antifungal agents, antiviral agents, anti dermatitis agents, antipruritic agents, other anti-inflammatory agents, antihyperkeratolytic agents, anti-dry skin agents, antipsoriatic agents, antisebborrheic agents, antihistamine agents, vitamins, corticosteroids, hormones, retinoids, topical cardiovascular agents, clotrimazole,

ketoconazole, miconozole, griseofulvin, hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine, monobenzone, erythromycin, tetracycline, clindamycin, meclocyline, hydroquinone, minocycline, naproxen, ibuprofen, theophylline, cromolyn, albuterol, retinoic acid, 13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasone valerate,

betamethasone diproprionate, triamcinolone acetonide, fluocinonide, clobetasol, proprionate, benzoyl peroxide, crotamiton, propranolol, promethazine, vitamin A palmitate, vitamin E acetate and mixtures thereof.

[00174] Depending upon the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with the active component(s). For example, penetration enhancers may be used to assist in delivering the active component to the tissue. Suitable penetration enhancers include acetone, various alcohols (e.g., ethanol, oleyl, tetrahydrofuryl, etc.), allcyl sulfoxides such as dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, polyethylene glycol, pyrrolidones such as polyvinylpyrrolidone, Kollidon grades (Povidone, Polyvidone), urea, and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate). [00175] The pH of the composition, or of the tissue to which the compound(s) is applied, may also be adjusted to improve delivery of the compound. Preferably, the pH is somewhat basic, as a basic pH is believed to enhance the stability of the active compounds. A pH of about 8 to 9 is preferred. Similarly, the polarity of the solvent, its ionic strength or tonicity may be adjusted to improve delivery. In addition, compounds such as stearates may be added to compositions comprising the active compound(s) to advantageously alter the

hydrophilicity or lipophilicity of the compound(s) and improve skin delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Also, different salts, hydrates or solvates of the active compounds may be used to further adjust the properties of the resulting composition.

[00176] The compounds can be formulated in compositions such as creams, lotions, ointments, gels, solutions, suspensions, or other forms known to one of skill in the art and described in, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990), and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Most compositions to be used with the methods described herein may be formulated as a solution, gel, lotion, cream, or ointment in a pharmaceutically acceptable form. Actual methods for preparing pharmaceutical

compositions are known or apparent to those skilled in the art and are described in detail in, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990).

[00177] In a specific embodiment for use in treating mucosal tissues within the oral cavity, the active ingredient is formulated into a solution suitable for use as a mouthwash or as an oral gel.

4.8.1 Compound 1 Formulations

[00178] In embodiments, provided herein are formulations comprising Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a formulation comprises Compound 1.

[00179] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise Compound 1, an insoluble diluent or carrier, a disintegrant, and a diluent, or filler; wherein the extra-granular components comprise a disintegrant, a glidant, and/or a lubricant; and wherein the film coating components comprise a tablet coating.

[00180] In certain embodiments, provided herein are oral dosage formulations that comprise about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%), about 85%), or about 90% by weight of Compound 1, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00181] In certain embodiments, provided herein are oral dosage formulations that comprise about 5%, about 10%>, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%), about 45%, or about 50%, by weight of an insoluble diluent or carrier, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00182] In certain embodiments, provided herein are oral dosage formulations that comprise about 1%, about 1.5%, about 2.0%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8%), about 8.5%), about 9.0%, about 9.5%, or about 10%, by weight of a disintegrant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00183] In certain embodiments, provided herein are oral dosage formulations that comprise about 0.05%, 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 0.55%, about 0.6%, about 0.65%, about 0.7%), about 0.75%, or about 0.8%, by weight of a glidant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00184] In certain embodiments, provided herein are oral dosage formulations that comprise 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 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 1.45%, or about 1.5%, by weight of a lubricant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00185] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 50% to about 80% by weight of Compound 1, about 10%) to about 40% by weight of an insoluble diluent 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; wherein the extra-granular component comprises about 1.5% to about 4.5% by weight of a disintegrant, about 0.1% to about 0.4% by weight of a glidant, and about 0.15% to about 1.35%) by weight of a lubricant; and wherein the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00186] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 55% to about 75% by weight of Compound 1, about 15%) to about 35% by weight of an insoluble diluent 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 filler; wherein the extra-granular component comprises about 2.0%> to about 4.0% by weight of a disintegrant, about 0.15% to about 0.35% by weight of a glidant, and about 0.35% to about 1.15% by weight of a lubricant; and wherein the film coating component comprises about 1.0% to about 8% by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00187] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% to about 70% by weight of Compound 1, about 20%) to about 30% by weight of an insoluble diluent 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 filler; wherein the extra-granular component comprises about 2.5% to about 3.5% by weight of a disintegrant, about 0.2% to about 0.3% by weight of a glidant, about 0.55% to about 0.95%) by weight of a lubricant; and

wherein the film coating component comprises about 1.0% to about 8% by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00188] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 65% by weight of Compound 1, about 25% by weight of an insoluble diluent or carrier, about 3% by weight of a disintegrant, and about 2.8%) by weight of a diluent or filler; wherein the extra-granular 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 wherein the film coating component comprises about 2.0% to about 6.0% by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components. [00189] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise Compound 1, microcrystalline cellulose, sodium starch glycolate, and hydroxypropyl methylcellulose, wherein the extra-granular components comprise sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate; and wherein the film-coating components comprise Opadry®.

[00190] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 50% to about 80%> by weight of Compound 1, about 10%) to about 40%> by weight of microcrystalline cellulose, about 1.5% to about 4.5% by weight of sodium starch glycolate, and about 1%> to about 5% by weight of a

hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 1.5% to about 4.5%) by weight of a sodium starch glycolate, about 0.1% to about 0.4% by weight of colloidal silicon dioxide, and about 0.15% to about 1.35% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of

Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00191] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 55% to about 75% by weight of Compound 1, about 15%) to about 35% by weight of microcrystalline cellulose, about 2.0% to about 4.0% by weight of sodium starch glycolate, and about 1.8% to about 3.8% by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 2.0%> to about 4.0%) by weight of a sodium starch glycolate, about 0.15% to about 0.35% by weight of colloidal silicon dioxide, and about 0.35% to about 1.15% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00192] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% to about 70% by weight of Compound 1, about 20%) to about 30% by weight of microcrystalline cellulose, about 2.5% to about 3.5% by weight of sodium starch glycolate, and about 2.3% to about 3.3% by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 2.5% to about 3.5% by weight of a sodium starch glycolate, about 0.2% to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00193] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% by weight of Compound 1, about 30% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate;

wherein the film coating component comprises about 2.0% to about 6.0% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00194] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 65% by weight of Compound 1, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate;

wherein the film coating component comprises about 2.0%> to about 6.0%> by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00195] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 70% by weight of Compound 1, about 20% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate;

[00196] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 75% by weight of Compound 1, about 15% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate; wherein the film coating component comprises about 2.0% to about 6.0% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00197] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 80% by weight of Compound 1, about 10% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate; wherein the film coating component comprises about 2.0%> to about 6.0%> by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00198] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises 150 mg of Compound 1, 158.4 mg of microcrystalline cellulose, 9.53 mg of isomalt, 10.70 mg of sodium starch glycolate, 3.57 mg sodium lauryl sulfate, and 8.92 mg of povidone, and wherein the extra-granular components comprises 14.28 mg of sodium starch glycolate, 0.89 mg of colloidal silicon dioxide, and 0.71 mg of magnesium stearate.

[00199] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises 150 mg of Compound 1, 57.46 mg of microcrystalline cellulose, 6.90 mg of sodium starch glycolate, and 6.44 mg of hydroxypropyl

methylcellulose, and wherein the extra-granular components comprises 6.90 mg of sodium starch glycolate, 0.575 mg of colloidal silicon dioxide, and 1.725 mg of magnesium stearate, and a film coating component of about 2.0% to about 6.0% by weight of Opadry®.

[00200] In certain other embodiments, provided herein are unit dosage forms that comprise between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue (e.g., any one of Compounds 14-98), 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 certain other embodiments, provided herein are unit dosage forms that comprise between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of Compound 1.

[00201] In certain other embodiments, provided herein are unit dosage forms that comprise about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1, 100 mg, 1, 150, or even about 1,200 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue (e.g., any one of Compounds 14-98), 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 certain other embodiments, provided herein are unit dosage forms that comprise about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1, 100 mg, 1, 150, or even about 1,200 mg of Compound 1.

[00202] In certain embodiments, the unit dosage form comprises 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),

Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, isotopologue (e.g., any one of Compounds 14-98), 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 certain embodiments, the unit dosage form comprises 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 Compound 1. In certain such embodiments, the unit dosage form is a capsule comprising about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of the compound (e.g., Compound 1). In certain such embodiments, the unit dosage form is a tablet comprising about 150 mg of the compound (e.g., Compound 1). In certain such embodiments, the unit dosage form is a tablet comprising about 315 mg of the compound (e.g., Compound 1).

4.8.2 Compound 7 Formulations

[00203] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise Compound 7, an insoluble diluent or carrier, a disintegrant, and a diluent or filler; wherein the extra-granular components comprise a disintegrant, a glidant, and/or a lubricant; and wherein the film coating components comprise a tablet coating.

[00204] In certain embodiments, provided herein are oral dosage formulations that comprise about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%), about 85%), or about 90% by weight of Compound 7, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00205] In certain embodiments, provided herein are oral dosage formulations that comprise about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, by weight of an insoluble diluent or carrier, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00206] In certain embodiments, provided herein are oral dosage formulations that comprise about 1%, about 1.5%, about 2.0%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9.0%, about 9.5%, or about 10%>, by weight of a disintegrant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00207] In certain embodiments, provided herein are oral dosage formulations that comprise about 0.05%, 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 0.55%, about 0.6%, about 0.65%, about 0.7%), about 0.75%, or about 0.8%>, by weight of a glidant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00208] In certain embodiments, provided herein are oral dosage formulations that comprise 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 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 1.45%, or about 1.5%, by weight of a lubricant, wherein the weight is the total weight of all intra-granular and extra-granular components of a tablet.

[00209] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 50% to about 80% by weight of Compound 7, about 10%) to about 40% by weight of an insoluble diluent 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; wherein the extra-granular component comprises about 1.5% to about 4.5% by weight of a disintegrant, about 0.1% to about 0.4% by weight of a glidant, and about 0.15% to about 1.35%) by weight of a lubricant; and wherein the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00210] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 55% to about 75% by weight of Compound 7, about 15%) to about 35% by weight of an insoluble diluent 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 filler; wherein the extra-granular component comprises about 2.0%> to about 4.0% by weight of a disintegrant, about 0.15% to about 0.35% by weight of a glidant, and about 0.35% to about 1.15% by weight of a lubricant; and wherein the film coating component comprises about 1.0%) to about 8% by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components. [00211] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% to about 70% by weight of Compound 7, about 20%) to about 30%> by weight of an insoluble diluent 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 filler; wherein the extra-granular component comprises about 2.5% to about 3.5% by weight of a disintegrant, about 0.2% to about 0.3% by weight of a glidant, about 0.55% to about 0.95%) by weight of a lubricant; and wherein the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00212] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 65% by weight of Compound 7, about 25% by weight of an insoluble diluent or carrier, about 3% by weight of a disintegrant, and about 2.8%) by weight of a diluent or filler; wherein the extra-granular 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 wherein the film coating component comprises about 2.0%> to about 6.0% by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00213] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise Compound 7, microcrystalline cellulose, sodium starch glycolate, and hydroxypropyl methylcellulose, wherein the extra-granular components comprise sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate; and wherein the film-coating components comprise Opadry®.

[00214] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 50% to about 80% by weight of Compound 7, about 10%) to about 40% by weight of microcrystalline cellulose, about 1.5% to about 4.5% by weight of sodium starch glycolate, and about 1% to about 5% by weight of a

hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 1.5% to about 4.5%) by weight of a sodium starch glycolate, about 0.1% to about 0.4% by weight of colloidal silicon dioxide, and about 0.15% to about 1.35% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00215] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 55% to about 75% by weight of Compound 7, about 15%) to about 35% by weight of microcrystalline cellulose, about 2.0% to about 4.0% by weight of sodium starch glycolate, and about 1.8% to about 3.8% by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 2.0%> to about 4.0% by weight of a sodium starch glycolate, about 0.15% to about 0.35% by weight of colloidal silicon dioxide, and about 0.35% to about 1.15% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00216] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% to about 70% by weight of Compound 7, about 20%) to about 30% by weight of microcrystalline cellulose, about 2.5% to about 3.5% by weight of sodium starch glycolate, and about 2.3% to about 3.3% by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 2.5%) to about 3.5% by weight of a sodium starch glycolate, about 0.2% to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight of magnesium stearate; wherein the film coating component comprises about 1.0% to about 8% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00217] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 60% by weight of Compound 7, about 30% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate;

wherein the film coating component comprises about 2.0% to about 6.0%> by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components. [00218] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 65% by weight of Compound 7, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate; wherein the film coating component comprises about 2.0% to about 6.0% by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00219] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 70% by weight of Compound 7, about 20% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate; wherein the film coating component comprises about 2.0%> to about 6.0%> by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00220] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 75% by weight of Compound 7, about 15% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8%) by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate; wherein the film coating component comprises about 2.0%> to about 6.0%> by weight of Opadry®; and wherein the weight is the total weight of all intra-granular and extra-granular components.

[00221] In certain embodiments, provided herein are formulations comprising intra- granular components, extra-granular components, and film coating components, wherein the intra-granular component comprises about 80% by weight of Compound 7, about 10% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, and about 2.8% by weight of a hydroxypropyl methylcellulose; wherein the extra-granular component comprises about 3% by weight of a sodium starch glycolate, about 0.25% by weight of colloidal silicon dioxide, and about 0.75% by weight of magnesium stearate;

[00222] In certain other embodiments, provided herein are unit dosage forms that comprise between about 25 mg and about 2000 mg, about 50 mg and about 1500 mg, about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from

Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-fluorophenyl)-3- hydroxypyridine-2-carbonyl]amino}acetic acid.

[00223] In certain other embodiments, provided herein are unit dosage forms that comprise about 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1, 100 mg, 1,150, or even about 1,200 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain

embodiments, the unit dosage form comprises about 25 mg, 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 of Formula (V), or a compound selected from Compound 1, Compound 2,

Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,

Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue (e.g., any one of

Compounds 14-98), solvate, or hydrate thereof (specifically, {[5-(3-fluorophenyl)-3- hydroxypyridine-2-carbonyl]amino}acetic acid). In certain such embodiments, the unit dosage form is a capsule comprising about 25 mg, about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of the compound. In certain such embodiments, the unit dosage form is a tablet comprising about 150 mg of the compound. In certain such embodiments, the unit dosage form is a tablet comprising about 315 mg of the compound. In certain such embodiments, the unit dosage form is a tablet comprising about 25 mg of the compound. In certain such embodiments, the unit dosage form is a free acid in form of a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir, comprising about 25 mg, about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of the compound. In certain such embodiments, the unit dosage form is a free acid in form of a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir, comprising about 150 mg of the compound. In certain such embodiments, the unit dosage form is a free acid in form of a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir, comprising about 315 mg of the compound. In certain such embodiments, the unit dosage form is a free acid in form of a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir, comprising about 25 mg of the compound.

4.9 Doses and Dosing Regimens

[00224] Exemplary dosage forms and dosing regimens include those described in U.S. Patent Application Publication No. 2016/0143891, which is incorporated by reference in its entirety, as well as the still further exemplary doses and dosing regimens described herein.

[00225] Various parameters are described herein to guide the dosing regimen of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer for the prevention and/or treatment of various diseases and disorders as described in Section 4.4, such as sickle cell diseases and β thalassemias. This section provides several specific doses for such uses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. In certain embodiments, such a dose is the initial dose at the beginning of a treatment. In other embodiments, such a dose is the adjusted dose at a later time during the course of treatment. In certain embodiments, the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In a specific embodiment, the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In an embodiment, the compound is Compound 1. In a specific embodiment, the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98.

[00226] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) which is between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg, or about 300 mg and about 600 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid) is between about 150 mg and about 600 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In certain embodiments, the daily dose of the compound is between about 150 mg and about 300 mg, about 300 and about 600 mg, or between about 600 mg and about 750 mg. In certain embodiments, the daily dose is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1, 100 mg, 1, 150 mg, or even about 1,200 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is

Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In certain embodiments, the daily dose is at least about 300 mg, at least about 450 mg, or even at least about 600 mg of a compound (e.g., of Compound 1). In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98.

[00227] In certain 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 a structure of Formula (I),

Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In certain embodiments, the daily dose is not 240 mg, 370 mg, 500 mg, or 630 mg of Compound 1. In certain embodiments, the daily dose is about 240 mg, 370 mg, 500 mg or about 630 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98.

[00228] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein the compound is administered continuously and/or indefinitely. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98.

[00229] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein the daily dose is about 450 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, a daily dose of about 450 mg comprises three unit dosage forms, such as three tablets, each comprising about 150 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, a daily dose of about 450 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be increased by about 150 mg such that the daily dose of the compound is about 600 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, a daily dose of 450 mg of a compound having a structure of Formula (I), Formula (II), Formula (III),

Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5- (3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be decreased by about 150 mg, such that the daily dose of the compound is about 300 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be decreased by about 300 mg, such that the daily dose of the compound is about 150 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the daily dose may be increased or decreased by 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, or about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain such embodiments, the daily dose does not exceed about 600 mg or about 750 mg.

[00230] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein the compound may be administered continuously and/or indefinitely, such as for more than 42 consecutive days. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,

Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

[00231] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein hemoglobin levels of a patient are maintained at a level of at least about 10.0 g/dL and at or below about 13.0 g/dL. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, the hemoglobin levels are maintained at a level of at least about 11.0 g/dL and at or below about 13.0 g/dL. In certain such embodiments, the hemoglobin levels are maintained at a level of at least about 11.0 g/dL and at or below about 12.0 g/dL. In certain such embodiments, a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I),

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, 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 embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

[00232] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein level of hemoglobin of a patient are increased at least about 1.2 g/dL relative to a baseline hemoglobin level. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III),

[00233] In certain embodiments, administration of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) may be suspended if the level of hemoglobin is at or above 13.0 g/dL. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, administration of the compound may be resumed once the level of hemoglobin is at or below 12.5 g/dL.

[00234] In certain embodiments, hemoglobin levels are monitored and the dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,

Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be adjusted based on the level of hemoglobin and/or the change in level of hemoglobin. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the dose may be adjusted by either increasing or reducing the amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) by 150 mg or even by 300 mg. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. [00235] In certain embodiments, the daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) may be increased after a period of time, beginning on the day a patient is given a daily dose of the compound. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.

[00236] In certain embodiments, the daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) may be adjusted once in a period of time. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.

[00237] In certain embodiments, the daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,

Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) is not increased if the level of hemoglobin has increased by more than 1.2 g/dL relative to a baseline hemoglobin level. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98.

[00238] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid); measuring the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is less than about 10.0 g/dL and the level of hemoglobin has decreased by less than about 0.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is less than about 10.0 g/dL and the level of hemoglobin has changed by up to about 0.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 10.0 and about 10.9 g/dL and the level of hemoglobin has decreased by less than about 0.5 g/dL as compared to the level measured the period of time earlier;

administering an adjusted daily dose of the compound that is about 150 mg greater than the daily dose. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In certain such embodiments, the compound is administered once daily and may be administered orally. In certain embodiments, the daily dose is about 450 mg, such that when the daily dose is increased by about 150 mg, the adjusted daily dose is about 600 mg. In certain embodiments, the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks. In certain embodiments, the daily dose may be increased or decreased by 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, or about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.

[00239] In certain embodiments, provided herein are methods for treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl] amino} acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid); measuring the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is less than about 10.0 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 10.0 and about 10.9 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 11.0 and about 12.2 g/dL and the level of hemoglobin has increased by between about 1.0 and about 1.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has decreased by up to about 0.4 g/dL or increased by up to about 0.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by about 0.5 to about 0.9 g/dL as compared to the level measured the period of time earlier administering an adjusted daily dose of the compound that is 150 mg less than the daily dose. In embodiments, a compound is

Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain such embodiments, the compound is administered once daily and may be administered orally. In certain

embodiments, the daily dose is about 450 mg, such that when the daily dose is decreased by about 150 mg, the adjusted daily dose is about 300 mg. In certain embodiments, the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks. In certain embodiments, the daily dose may be increased or decreased by 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, or about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.

[00240] In certain embodiments, provided herein are methods of treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid); measuring the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is between about 11.0 and about 12.2 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by between about 1.0 and about 1.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier administering an adjusted daily dose of the compound that is about 300 mg less than the daily dose. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the compound is administered once daily and may be administered orally. In certain embodiments, the daily dose is 450 mg, such that when the initial daily dose is decreased by about 300 mg, the adjusted daily dose is about 150 mg. In certain embodiments, the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks. In certain embodiments, the daily dose may be increased or decreased by 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, or about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.

[00241] In certain embodiments, a method provided herein further comprises a monitoring step wherein the serum concentration of a metabolite of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from 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 an isotopologue thereof is determined. In embodiments, a compound is Compound 1, or an isotopologue thereof. In embodiments, a compound is Compound 1. In more specific embodiments, the serum concentration of the phenolic-glucuronide and/or the acyl-glucuronide of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from 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 an isotopologue thereof is determined. In embodiments, a compound is Compound 1, or an isotopologue thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In even more specific embodiments, the serum concentration of the phenolic-glucuronide and/or the acyl-glucuronide of Compound 1, i.e., Metabolite 1 or Metabolite 2 {see Section 5.2) or an isotopologue thereof is determined. In certain even more specific embodiments, the daily dose is adjusted in accordance with the serum concentration of the metabolite.

[00242] In certain embodiments, provided herein are methods of treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), as described herein, in combination with effective doses of a second pharmaceutical agent. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the second pharmaceutically active agent is a compound that prevents or inhibits polymerization of hemoglobin S. In certain embodiments, the compound is selected from GBT440, vanillin, pentosan polysulfate, sulodexide, xylan sulfates, dextran sulfates, chitin sulfates, di-, tri-, or oligomers and polymers of iduronic/uronic acids, keratan sulfates, and hyaluronic acid.

[00243] In certain embodiments, provided herein are methods of treating a hemoglobin disorder, including those described in Section 4.4, comprising administering to a patient having a hemoglobin disorder a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), as described herein, in combination with effective doses of a second pharmaceutical agent. In embodiments, a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof. In embodiments, a compound is Compound 1. In an embodiment, the compound is an isotopologue that is any one of Compounds 14-98. In certain embodiments, the second pharmaceutically active agent is a compound that effects allosteric modulation of hemoglobin S. Compounds that effect allosteric modulation of hemoglobin S are known in the art and described in, for example, International Publication No. WO2014/150256. Specifically, in certain embodiments the compound is selected from 2-methoxy-5-[[2-(lH-pyrazol-5-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[5-(2-methylpyrazol-3-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-(l-methylpyrazol-3-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-(2H-tetrazol-5-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-(4-methyl-lH-pyrazol-5-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[(2-pyrazol-l-ylpyridin-3- yl)methoxy]pyridine-4-carbaldehyde, 5-[[2-(l,5-dimethylpyrazol-4-yl)pyridin-3- yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-(2-ethylpyrazol-3-yl)pyridin-3- yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[(2-phenylpyridin-3- yl)methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[3-(2-propap-2-ylpyrazol-3-yl)pyridin-4- yl]methoxy]pyridine-4-carbaldehyde, 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3- yl]methoxy]benzaldehyde, 2-methoxy-5-[(2-pyridin-3-ylpyridin-3-yl)methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[2-[2-(2-methoxyethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 5-[[2-[2-(2-hydroxyethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2-methoxy-5-[[2-(2-propylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde,5-[[2-(2- cyclobutylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-(2- cyclohexylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-[2- (cyclohexylmethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-(2-cyclopentylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2-methoxypyridine-4- carbaldehyde, 2-methoxy-5-[[2-(2-methylphenyl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[2-(2-methoxypyridin-3-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-methoxy-5-[[3-(2-propan-2-ylpyrazol-3-yl)pyrazin-2-yl]methoxy]pyridine-4- carbaldehyde, 2-(difluoromethoxy)-5-[f2-(2-propan-2-ylpyrazol-3-yl)pyridin-3- yl]methoxy]pyridine-4-carbaldehyde, 2-(2-methoxyethoxy)-5-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 5-[5-[3-[(4-formyl-6-methoxypyridin-3- yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]acetic acid, 3-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3- yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 5-[[2-(2-hydroxypropan-2-yl)pyridin-3- yl]methoxy]-2-methoxypyridine-4-carbaldehyde, 2-(2-methoxyethoxy)-5-[[2-(2- methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, methyl 3-[5-[3-[(4- formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]propanoate, 3-[5-[3-[(4- formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-l-yl]propanoic acid, 3- hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 3- methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2- methoxy-5-[[2-(4-methyl-2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4- carbaldehyde, 2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]benzaldehyde, 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3- yl]methoxy]benzaldehyde, 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-(2- methoxyethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine- 4-carbaldehyde, 6-methyl-3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3- yl]methoxy]pyridine-2-carbaldehyde, 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 2-fluoro-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]benzaldehyde, 2-fluoro-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]benzaldehyde, 3-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 3-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde, 3-chloro-5-[[2- (2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, 2-fluoro-6-[[2-(2- propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde, 3-methyl-5-[[2-(2-propan-2- ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde, and 3-methyl-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde. 5 EXAMPLES

5.1 EXAMPLE 1

[00244] The use of HIF prolyl hydroxylase inhibitors for the treatment of hemoglobin disorders can be demonstrated in a mouse model. Transgenic mice that exclusively express human HbS ("SCD mice") are used in the art to examine the efficacy of potential treatments for hemoglobin disorders and symptoms thereof (See Barazia et al, 2015, Blood 22:2511- 2517, and Wu et al, 2006, Blood 108: 1183-1188). For example, Berkeley mice can be generated by transplantation of bone marrow cells isolated from Berkeley mice into lethally irradiated WT mice as described previously. (See Chang et al, 2010, Blood 116: 1779-1786.)

[00245] In some experiments, HIF prolyl hydroxylase inhibitor is administered to SCD mice as a continuous treatment, while control mice are injected appropriately with vehicle. The treatment Groups are

Group 1 : 9, 18, or 36 mg/Kg of Compound 1 or vehicle are administered on day 1 and then continuously once per day, over a period of 2-4 weeks; and

Group 2: 9, 18 or 36 mg/Kg of Compound 7 or vehicle are administered on day 1 and then continuously once per day, over a period of 2-4 weeks

[00246] The effect of the HIF prolyl hydroxylase inhibitors on disease pathology in the SCD mice is then assessed using known techniques (See Cui et al, 2015, Blood 16:386-396). Fetal hemoglobin induction is quantified by high-performance liquid chromatography (HPLC). The ratio of fetal hemoglobin to total hemoglobin is then compared among treated and untreated SCD mice after one, two, three, and four weeks.

[00247] The levels of γ-globin mRNA abundance in SCD mice treated with HIF prolyl hydoxylase inhibitor are quantified by real-time reverse transcription polymerase chain reaction ("QRT-PCR"), and the γ-globin mRNA levels are normalized to toal human β-type globin transcripts. These relative γ-globin mRNA levels are determined and compared over the course of four weeks.

[00248] Fetal hemoglobin-high cell population induction in SCD mice treated with HIF prolyl hydroxylase inhibitor is measured using flow cytometric analysis with an anti-fetal hemoglobin antibody. These induction rates are compared across varying dosages of the HIF prolyl hydroxlyase inhibitors. The lifespan of red blood cells is also measured after treatment, and compared across different treatment groups.

[00249] After 4 weeks of treatment with the HIF prolyl hydroxylase inhibitor, the livers and spleens of the SCD mice are weighed. The spleen and liver size of treated and untreated SCD mice are then compared. The spleen and liver size of SCD mice treated with different dosages of HIF prolyl hydroxylase inhibitors are also compared.

[00250] In order to examine the pathophysiologic characteristics of SCD mice treated with HIF prolyl hydroxylase inhibitor, the livers, spleens, and femurs from the SCD mice are removed and processed for histological analyses. The livers, spleens, and femurs are inspected for signs of tissue necrosis.

[00251] Red blood cell morphology of SCD mice treated with HIF prolyl hydroxylase inhibitor is evaluated using staining blood smears. The levels of sickled red blood cells of treated and untreated SCD mice are then compared.

5.2 EXAMPLE 2

[00252] In some experiments, HIF prolyl hydroxylase inhibitor is administered to SCD mice as a continuous treatment, while control mice are injected appropriately with vehicle. The treatment Groups are

Group 1 : 18 or 36 mg/Kg of Compound 1 or vehicle are administered on day 1 and then continuously once per day; and

Group 2: 18 or 36 mg/Kg of Compound 7 or vehicle are administered on day 1 and then continuously once per day.

[00253] The therapeutic effects of the HIF prolyl hydroxylase inhibitors are assessed using known techniques (See Barazia et al, 2015, Blood 22:2511-2517). During the course of treatment, real-time fluorescence intravital microscopy is used to monitor neutrophil adhesion and platelet-neutrophil aggregation in the venules of the mice. Survival rates are also examined.

5.3 EXAMPLE 3

[00254] An exemplary synthesis of a HIF-prolyl hydroxylase inhibitor (Compound 98) is illustrated in Scheme I and further described below.

Scheme I. Exemplary Synthesis of Compound 98

Step 1:

Step 3:

Step 4:

Step 5:

98

Exemplary Synthetic Protocol for Preparing Methyl {[5-(S-chloro-2,4,6-di-phenyl)-S- hydroxypyridin-2-ylJaminojacetic acid (Compound 98)

Step 1: Preparation of l-bromo-3-chloro-2,4,6-d3-benzene (Compound b)

[00255] To a mixture of 48% HBr (170.6 g, 1.0 mol, 3.3 eq) and water (80 mL) at room temperature was added NaBr (31.5 g, 306.3 mmol, 1.0 eq). After the solid was dissolved, 3- chloro-2,4,6-i¾-aniline (Compound a) (40.0 g, 306.3 mmol, 1.0 eq) was added dropwise to the reaction solution over 10 min. After addition, the suspension was warmed to 40 °C and stirred for 10 min., followed by warming to 60 °C. CuBr (4.4 g, 30.6 mmol, 0.1 eq) was added and the mixture was stirred for 10 min at 60 °C. To the suspension, an aqueous solution of NaNCte (23.2 g of NaNCte in 76 mL of water, 336.9 mmol, 1.1 eq) was added dropwise to the reaction mixture over 1.5 h. After addition, the mixture was stirred at 60 °C for 0.5 ~ 1.0 h. After Compound a was consumed as indicated by GCMS analysis, the mixture was cooled to room temperature and extracted with hexane (125 mL ^χ 2). The combined organic layer was washed with water (200 mL x 2) and dried over anhydrous sodium sulfate. The organic solution was further filtrated through a pad of silica gel (50.0 g, 60-80 mesh) and the filter cake was rinsed by hexane (~ 400 mL). The combined filtrate was concentrated under reduced pressure and 54.2 g of crude Compound b was obtained as brown oil. This product was used for the next step without further purification. Yield: 91.0%.

[00256] HPLC: 78.6% (220 nm); GCMS (EI): m/z 193, 195; ¾-NMR (300 MHz, CDCh) 5 7.18 (s, 1H).

Step 2: Preparation of 3-chloro-2,4,6-d3-phenylboronic acid pinacol ester (Compound c)

[00257] A mixture of Compound b (66.6 g, 342.5 mmol, 1.0 eq), bis(pinacolato)diboron (86.9 g, 342.2 mmol, 1.0 eq), KOAc (100.1 g, 1.0 mol, 3.0 eq), DMSO (13.3 g, 170.2 mmol, 0.5 eq) and dioxane (660 mL) was purged with nitrogen 3 times, followed by the addition of Pd(dppf)Cl2 (7.5 g, 10.2 mmol, 3% eq). After addition, the mixture was purged again with nitrogen 3 times, and then warmed to 90 °C. The reaction mixture was stirred at 90 °C for 2 ~ 3 h. After Compound b was consumed as indicated by GCMS or HPLC analysis, the mixture was cooled to room temperature, followed by concentration under reduced pressure. CH2CI2 (500 mL) and water (500 mL) were added to the residue. The resulting mixture was filtered through a pad of Celite. The filter cake was washed with CH2CI2 (500 mL). The combined filtrate was transferred to a separately funnel and the aqueous layer was separated. The organic layer was washed with water (500 mL x 2), and dried over anhydrous sodium sulfate. After filtration and concentration, 132.0 g of crude product was obtained as dark brown mixture.

[00258] Hexane (700 mL) was added to the crude product. The resulting suspension was stirred at room temperature for 10 min., followed by filtration. The filter cake was washed with hexane (200 mL). The hexane solution was further filtered through a pad of silica gel (90.0 g, 60 ~ 80 mesh) and the filter cake was rinsed with hexane (~ 1.0L). The combined filtrate was concentrated under reduced pressure, and 84.4 g of Compound c was obtained as brown oil. This crude product was used for the next step without further purification.

[00259] HPLC: 88.7% (220 nm); GCMS (EI): m/z 241; ¹H- MR (300 MHz, CDCh) δ 7.30 (s, 1H), 1.36 (s, 12H).

Step 3: Preparation of 3-chloro-2,4,6-d3-phenylboronic acid (Compound d)

[00260] To a solution of Compound c (84.4 g, 349.4 mmol, 1.0 eq) in THF (840 mL) at room temperature was added IN HC1 (870 mL, 870.0 mmol, 2.5 eq) slowly over 10 min. After addition, NaI0₄ (112.3 g, 525.0 mmol, 1.5 eq) was added portion-wise over 10 min. The resulting mixture was stirred at room temperature for 1 ~ 2h. After Compound c was consumed as indicated by GCMS or HPLC analysis, the mixture was concentrated under reduced pressure until the most of THF was evaporated. The resulting mixture was extracted with ethyl acetate 2 times (500 mL + 300 mL). The combined organic layer was washed with water twice (500 mL x 2) and dried over anhydrous sodium sulfate. After filtration and concentration, 62.9 g of the crude product was obtained as brown solid.

[00261] The crude product was slurried in hexane (156 mL) at room temperature overnight, followed by filtration. The filter cake was washed with hexane (120 mL). After air drying, 31.3 g of Compound d was obtained as pale yellow solid. Yield: 56.2%.

[00262] HPLC: 96.8% (220 nm); ¾-NMR (300 MHz, CDCh) δ 7.47 (s, 1H).

[00263] An additional 4.0 g of the product was recovered from mother liquor after multiple purifications (HPLC purity: 80% (220 nm)). Step 4: Preparation of ethyl {[5-(3-chloro-2,4,6-d3-phenyl)-3-hydroxypyridin-2- yl] amino} acetate (Compound A)

[00264] To a mixture of Compound d (30.0 g, 188.2 mmol, 1.2 eq), Compound e (61.8 g, 156.8 mmol, 1.0 eq), and K3PO4 (10.0 g, 47.0 mmol, 0.3 eq) in dioxane (600 mL) and water (24 mL) was purged with nitrogen 3 times, followed by the addition of Pd(dppf)Ch (11.5 g, 15.7 mmol, 0.1 eq). After addition, the mixture was purged again with nitrogen 3 times, and then warmed to 90 °C. The reaction mixture was stirred at 90 °C overnight under nitrogen atmosphere. After Compound e was consumed as indicated by HPLC analysis, the mixture was cooled to room temperature and concentrated under reduced pressure. Generally, the residual amount of Compound e was less than 5% by HPLC analysis.

[00265] To the residue was added ethyl acetate (400 mL) and 0. IN HC1 (400 mL), followed by filtration through a pad of Celite. The filter cake was washed with ethyl acetate (150 mL x 3). The combined filtrate was transferred to a separately funnel and aqueous layer was separated. The organic layer was washed with 0.1N HC1 (500 mL ^χ 2), brine (500 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, 75.0 g of the crude product was obtained as brown solid.

[00266] The crude product was dissolved with CH2CI2 (350 mL) and hexane (350 mL). The solution was filtered through a pad of silica gel (150.0 g, 60 ~ 80 mesh) and the filter cake was rinsed with CHiCh/hexane (1/1, ~ 250 mL; 2/1, ~ 1.0 L, 100/0, -500 mL). The combined filtrate was concentrated under reduced pressure and 50.6 g of the product was obtained as brown solid.

[00267] The product was slurried in hexane (150 mL) at room temperature overnight, followed by filtration. The filter cake was washed with hexane (30 mL x 3). After drying,

44.9 g of Compound A was obtained as pale brown solid. Yield: 84.8%.

HPLC: 97.8% (220 nm); ¾-NMR (300 MHz, CDC13) δ 11.87 (s, 1H), 8.43 (s, 1H), 8.31 (d,

J = 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.43 (s, 1H), 4.32-4.24 (m, 4H), 1.33 (t, J = 7.0 Hz,

3H).

Step 5: Preparation of ethyl {[5-(3-chloro-2,4,6-d3-phenyl)-3-hydroxypyridin-2- yl] amino} acetic acid (Compound 98)

[00268] To a solution of Compound A (44.5 g, 131.7 mmol, 1.0 eq) in THF (445 mL) at room temperature was added 4% NaOH aqueous (445 mL, 445.0 mmol, 3.3 eq) slowly over 5 min. After addition, the mixture was stirred at room temperature for 15 ~ 30 min. After Compound A was consumed as indicated by HPLC analysis, water (~ 400 mL) was added to the reaction mixture. The resulting mixture was washed with MTBE (500 mL and 250 mL x 2). The organic layer was separated and the aqueous layer was filtered. To the filtrate was added IN HC1 (~ 450 mL) dropwise at room temperature until pH = 2 ~ 3. After addition, the suspension was stirred at room temperature for 0.5 h, followed by filtration. The filter cake was rinsed with water (100 mL x 3) and hexane (50 mL x 3). After vacuum drying, 39.5 g of Compound 98 was obtained as pale yellow solid. Yield: 96.8%.

[00269] HPLC: 97.9% (254 nm), 97.9% (263 nm); LCMS (ESI): m/z 310; ¾-NMR (300 MHz, OMSO-de) δ 12.45 (brs, 1H), 9.31(t, J= 5.8 Hz, 1H), 8.56 (d, J= 1.8 Hz, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 3.93 (d, J= 5.7 Hz, 2H).

Claims

CLAIMS WHAT IS CLAIMED:

1. A method for treating a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from 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, and any one of Compounds 14-98, or a pharmaceutically acceptable salt thereof.

2. A method for reducing the frequency of a symptom of a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from 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, and any one of Compounds 14- 98, or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the compound is a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13.

4. The method of claim 1 or 2, wherein the compound is selected from any one of compounds 14-98.

5. The method of claim 1 or 2, wherein the compound is Compound 1.

6. The method of claim 1 or 2, wherein the compound is Compound 7.

7. The method of any one of claims 1-6, wherein the hemoglobin disorder is a sickle cell disease.

8. The method of any one of claims 1-6, wherein the hemoglobin disorder is sickle cell anemia.

9. The method of any one of claims 1-6, wherein the hemoglobin disorder is hemoglobin SC disease.

10. The method of any one of claims 1-6, wherein the hemoglobin disorder is sickle β thalassemia.

11. The method of any one of claims 1-6, wherein the hemoglobin disorder is a β thalassemia.

12. The method of any one of claims 1-6, wherein the hemoglobin disorder is β°- thalassemia.

13. The method of any one of claims 1-6, wherein the hemoglobin disorder is β⁺- thalassemia.

14. The method of any one of claims 1-6, wherein the hemoglobin disorder involves ineffective erythropoiesis.

15. The method of any one of claims 1-14, wherein the subject is unresponsive to treatment with other therapeutic agents.

16. The method of claim 15, wherein the other therapeutic agent is hydroxyurea, butyrate, 5-azacytidine, nitric oxide, vitamin B 12, folic acid, iron, or a combination thereof.

17. The method of any one of claims 1-14, wherein the subject is hyporesponsive to treatment with other therapeutic agents.

18. The method of claim 17, wherein the other therapeutic agent is hydroxyurea, butyrate, 5-azacytidine, nitric oxide, vitamin B 12, folic acid, iron, or a combination thereof.

19. The method of any one of claims 1-18, wherein the subject has or is at risk of developing a complication secondary to the hemoglobin disorder.

20. The method of claim 19, wherein the complication is acute chest syndrome, cerebrovascular disease, kidney failure, pulmonary hypertension, blindness, skin ulcers, gallstones, hand-foot syndrome, renal insufficiency, retinitis, osteonecrosis, osteomyelitis, aplastic crises, functional asplenism, stroke, priapism, or a combination thereof.

21. The method of any one of claims 1-20, wherein the subject has or is at risk of developing a deficiency in vitamin B12, folic acid, iron, or a combination thereof.

22. The method of any one of claims 1-21, wherein the subject is transfusion- dependent.

23. A method for treating a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of

(i) a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a

pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof; and

(ii) a second pharmaceutically active agent.

24. A method for reducing the frequency of a symptom of a hemoglobin disorder in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of

(ii) a second pharmaceutically active agent.

25. The method of claim 23 or 24, wherein the compound is an isotopologue seleted from any one of Compounds 14-98.

26. The method of claim 23 or 24, wherein the compound is Compound 1.

27. The method of claim 23 or 24, wherein the compound is Compound 7.

28. The method of any one of claims 23-27, wherein the second pharmaceutically active agent is hydroxyurea, butyrate, 5-azacytidine, nitric oxide, vitamin B12, folic acid, an iron supplement, or a combination thereof.

29. The method of claim 28, wherein the iron supplement is ferrous sulfate, ferrous gluconate, ferrous fumarate, or a combination thereof.

30. The method of any one of claims 23-27, wherein the second pharmaceutically active agent is an erythropoiesis stimulating agent (ESA).

31. The method of claim 30, wherein the ESA is an rhEPO product.

32. The method of claim 31, wherein the rhEPO product is epoetin alfa, epoetin beta, darbepoetin, or peginesatide.

33. A method for treating a hemoglobin disorder, comprising administering to a patient a formulation comprising intra-granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,

Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, and any one of Compounds 14-98, or a pharmaceutically acceptable salt thereof; an insoluble diluent or carrier, a disintegrant, and a diluent or filler; wherein the extra-granular components comprise a disintegrant, a glidant, and/or a lubricant; and wherein the film coating components comprise a tablet coating.

34. The method of claim 33, wherein the compound is a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13.

35. The method of claim 33, wherein the compound is seleted from any one of Compounds 14-98.

36. The method of claim 33, wherein the compound is Compound 1.

37. The method of claim 33, wherein the compound is Compound 7.

38. The method of claim 33,

wherein the intra-granular component comprises

about 50% to about 80% by weight of Compound 1,

about 10%) to about 40%> by weight of an insoluble diluent 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;

wherein the extra-granular component comprises

about 1.5%) to about 4.5%> by weight of a disintegrant,

about 0.1%) to about 0.4%> by weight of a glidant, and

about 0.15%) to about 1.35% by weight of a lubricant;

wherein the film coating component comprises about 1.0% to about 8%> by weight of a tablet coating; and wherein the weight is the total weight of all intra-granular and extra-granular components.

39. The method of claim 33,

wherein the intra-granular component comprises

about 60%) to about 70% by weight of Compound 1,

about 20%) to about 30%> by weight of an insoluble diluent or carrier, about 2.5%o to about 3.5% by weight of a disintegrant, and

about 2.3%o to about 3.3%> by weight of a diluent or filler;

wherein the extra-granular component comprises

about 2.5%o to about 3.5% by weight of a disintegrant,

about 0.2% to about 0.3% by weight of a glidant, and about 0.55% to about .95% by weight of a lubricant;

40. The method of any one of claims 33-39, wherein the hemoglobin disorder is a sickle cell disease.

41. The method of any one of claims 33-39, wherein the hemoglobin disorder is sickle cell anemia

42. The method of any one of claims 33-39, wherein the hemoglobin disorder is hemoglobin SC disease.

43. The method of any one of claims 33-39, wherein the hemoglobin disorder is sickle β thalassemia.

44. The method of any one of claims 33-39, wherein the hemoglobin disorder is a β thalassemia.

45. The method of any one of claims 33-39, wherein the hemoglobin disorder is P°-thalassemia.

46. The method of any one of claims 33-39, wherein the hemoglobin disorder is P⁺-thalassemia.

47. The method of any one of claims 33-39, wherein the hemoglobin disorder involves ineffective erythropoiesis.

48. A method for increasing the plasma levels of fetal hemoglobin in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from 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, and any one of Compounds 14- 98, or a pharmaceutically acceptable salt thereof.

49. The method of claim 48, wherein the compound is a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

50. The method of claim 48, wherein the compound is selected from any one of Compounds 14-98.

51. The method of claim 48, wherein the compound is Compound 1.

52. The method of claim 48, wherein the compound is Compound 7.

53. A method for increasing the plasma levels of γ subunits of hemoglobin in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9,

54. The method of claim 53, wherein the compound is a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

55. The method of claim 53, wherein the compound is selected from any one of Compounds 14-98.

56. The method of claim 53, wherein the compound is Compound 1.

57. The method of claim 53, wherein the compound is Compound 7.

58. A method for reducing sickle hemoglobin (HbS) in a subject, wherein the method comprises administering to the subject a pharmaceutically effective amount of a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, and any one of Compounds 14-98, or a pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein the compound is a compound of Formula (I) Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,

60. The method of claim 58, wherein the compound is selected from any one of Compounds 14-98.

61. The method of claim 58, wherein the compound is Compound 1.

62. The method of claim 58, wherein the compound is Compound 7.