WO2019028150A1 - Compositions destinées à être utilisées dans des méthodes de traitement des hémoglobinopathies - Google Patents

Compositions destinées à être utilisées dans des méthodes de traitement des hémoglobinopathies Download PDF

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WO2019028150A1
WO2019028150A1 PCT/US2018/044825 US2018044825W WO2019028150A1 WO 2019028150 A1 WO2019028150 A1 WO 2019028150A1 US 2018044825 W US2018044825 W US 2018044825W WO 2019028150 A1 WO2019028150 A1 WO 2019028150A1
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compound
formula
weight
isotopologue
metabolite
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Ramin FARZANEH-FAR
Anna Zuk
Emil Morada DEGOMA
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Akebia Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present disclosure relates to hypoxia inducible factor (HIF) prolyl
  • hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin disease, and sickle ⁇ thalassemia, and ⁇ thalassemias, including ⁇ °- (major) thalassemia and P + -(minor) thalassemia.
  • 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 ⁇ thalassemia, and ⁇ thalassemias, including ⁇ °-( ⁇ 0 ⁇ ) thalassemia and ⁇ + - (minor) thalassemia.
  • hemoglobin disorders such as sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle ⁇ thalassemia, and ⁇ thalassemias, including ⁇ °-( ⁇ 0 ⁇ ) thalassemia and ⁇ + - (minor) thalassemia.
  • Hemoglobin disorders such as ⁇ 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.
  • ⁇ thalassemias which are also inherited blood disorders, produce a deficiency of ⁇ globin chains. In ⁇ 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.
  • 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 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.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • Compound 8 Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • hemoglobin disorders include any disorder associated with an alteration in the amount, structural integrity, or function of adult hemoglobin, specifically adult ⁇ globin.
  • Hemoglobin disorders include, but are not limited to, sickle cell diseases, including sickle cell anemia, hemoglobin SC disease; sickle ⁇ thalassemia, ⁇ thalassemias, including p°-(major) thalassemia and P + -(minor) thalassemia; and disorders involving ineffective erythropoiesis,
  • 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.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • Described herein is a method for increasing the plasma levels of ⁇ 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.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • 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 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.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • the compound is Compound 1 or
  • a compound is an isotopologue such as any one of
  • 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.
  • the compound is Compound 1 or Compound 7.
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • the compound is Compound 1 or Compound 7.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • the compound is
  • a compound is an isotopologue such as any one of Compounds 14-98.
  • kits for treating hemoglobin disorders in a subject 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • suitable non-toxic acid salts include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic,
  • 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.
  • 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.
  • 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.
  • 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.
  • an “isotopologue” is an isotopically enriched compound. Isotopologues of the compounds provided herein are provided in Section 4.4.
  • 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.
  • 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%.
  • a “deuterium” group is a stable isotope of hydrogen having one proton and one neutron.
  • 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.
  • 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.
  • “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.
  • the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations.
  • 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.
  • ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value.
  • the term "subject” includes mammal, which includes human.
  • the term subject or patient can refer to a mammal, such as a human, mouse, dog, donkey, horse, rat, guinea pig, bird, or monkey.
  • a subject or a patient is a human subject or patient.
  • topical 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.
  • 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.
  • 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.
  • 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%.
  • a compound provided herein for use with the methods provided herein preferentially stabilizes HIF-2-alpha over HIF- 1 -alpha. To determine preferential
  • 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).
  • a compound used in the methods described herein which is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, is a heterocyclic carboxamide.
  • the heterocyclic carboxamide is selected from a pyridyl carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (I):
  • R and R 1 are each independently:
  • said substitution selected from:
  • R 4 is a C1-C4 alkyl or C3-C4 cycloalkyl
  • R 5a and R 5b are each independently selected from:
  • R 2 is selected from:
  • R 6 is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl
  • R 7a and R 7b are each independently selected from:
  • R 7a and R 7b are taken together to form a ring having from 3 to 7 atoms;
  • R 3 is selected from hydrogen, methyl, and ethyl;
  • L is a linking unit having a structure -[C(R 8a R 8b )]n-
  • R 8a and R 8b are each independently selected from hydrogen, methyl and ethyl
  • n is an integer from 1 to 3;
  • R 9 is selected from hydrogen and methyl.
  • R and R 1 are not both hydrogen.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (II):
  • R' is selected from the group consisting of H, Ci-C 6 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) 2 R", S(0) HR", S(0) 2 HR", S(0) R" 2 , S(0) 2 R" 2 , C(0)R", CO2H, CO2R", C(0) H 2 , 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-C 6 alkyl, C3-C6
  • Ci-Ce alkyl, C 3 -C 6 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) 2 R", S(0)NHR", S(0) 2 NHR", S(0)NR" 2 ,
  • R 2 is selected from:
  • R 6 is selected from hydrogen and C1-C4 alkyl or C 3 -C 4 cycloalkyl
  • R 7a and R 7b are each independently selected from:
  • R 7a and R 7b are taken together to form a ring having from 3 to 7 atoms.
  • the HIF stabilizer is a compound having a structure of Formula (III)
  • R 2 and R 3 are each independently selected from:
  • R 2 and R 3 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 R 2 and R 3 are bonded;
  • M 1 is a cation
  • R 4 is:
  • M 2 is a cation.
  • the HIF stabilizer is a compound having a structure of Formula (IV)
  • R is chosen from
  • R 2 and R 3 are each independently selected from:
  • R 2 and R 3 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 R 2 and R 3 are bonded;
  • M 1 is a cation
  • R 4 is:
  • M 2 is a cation.
  • HIF prolyl hydroxylase inhibitor compounds described herein are unsubstituted or substituted 3-hydroxy-pyridine-2-carboxamides, having the structure shown in Formula (V) below:
  • 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.
  • the HIF stabilizer is Compound 2 having the structure:
  • Compound 2 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 3 having a structure
  • Compound 3 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 4 having a structure
  • Compound 4 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 5 having the structure
  • Compound 5 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 6 having the structure
  • Compound 6 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • 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.
  • the HIF stabilizer is Compound 8 having the structure:
  • the HIF stabilizer is Compound 9 having a structure
  • the HIF stabilizer is Compound 10 having a structure
  • the HIF stabilizer is Compound 11 having the structure
  • the HIF stabilizer is Compound 12 having the structure
  • Compound 12 or a pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 13 having the structure
  • Tautomers of Compound 13 include the following:
  • the HIF stabilizer is Compound 98 having the structure:
  • 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.
  • a metabolite is a phenolic glucuronide or an acyl-glucuronide.
  • 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.
  • 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.
  • 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.
  • Ci-6 alkyl units include the following non-limiting examples: methyl (Ci), ethyl (C2), 7-propyl (C3), zso-propyl (C3), /7-butyl (C 4 ), sec-butyl (C 4 ), zso-butyl (C 4 ), tert-butyl (C 4 ), /7-pentyl (C5), tert-pentyl (C5), «eo-pentyl (C5), zso-pentyl (C5), sec-pentyl (C5), 3-pentyl (C5), /7-hexyl (C 6 ), zso-hexyl (C 6 ), «eo-hexyl (C 6 ), 3-methylpentyl (C 6 ), 4-methylpentyl (C 6 ), 3-methylpentan-2-yl (C 6 ), 4-methylpentan-2-yl (C 6 ), 4-methyl
  • alkenyl 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a "cycloalkoxy" group is a cycloalkyl-O- group in which the cycloalkyl group is as defined herein.
  • Representative cycloalkoxy groups include
  • haloalkyl 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 CF 3 , CHF 2 , CH 2 F, CC1 3 , CF 3 CH 2 CH 2 and CF 3 CF 2 .
  • halocycloalkyl 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 .
  • 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.
  • heterocycloalkyl groups are piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3- dioxolanyl, 1,4-dioxanyl, oxazolinyl, tetrahydrofuranyl, tetrahydrothiophenyl and
  • 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.
  • 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,
  • benzofused heteroaryl groups include indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thianaphthenyl),
  • benzofurazanyl All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4- pyridyl.
  • 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.
  • 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.
  • 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.
  • a therapeutic effect of a HIF prolyl hydroxylase inhibitor can be assessed using known techniques (See Barazia et ⁇ , 2015, Blood 22:251 1-2517).
  • a HIF prolyl hydroxylase inhibitor e.g., any of the compounds described herein
  • 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.
  • 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 NaH 2 P0 4 , 1 mM MgCl 2 , 1 mM CaCl 2 , 5 mM glucose, and 0.1% BSA) at a concentration of 3 x 108 cells/ml.
  • HEPESTyrode buffer (20 mM HEPES, pH 7.3, 136 mM NaCl, 2.7 mM KC1, 3.3 mM NaH 2 P0 4 , 1 mM MgCl 2 , 1 mM CaCl 2 , 5
  • 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 ⁇ 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 ⁇ g) in cell lysates are immunoblotted with antibodies against phosphoAKTl or AKT2 or total AKT, followed by densitometry.
  • mice 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.
  • Cultured human umbilical vein ECs are pretreated with 1 - 100 ⁇ SNP 5 minutes prior to stimulation with 20 ng/ml TNF-a.
  • TNF-a and SNP 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.
  • 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 ⁇ 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
  • a deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VI):
  • R and R 1 are each independently selected from:
  • said substitution selected from:
  • R 4 is a C1-C4 alkyl or C3-C4 cycloalkyl
  • R 5a and R 5b are each independently selected from: (i) hydrogen;
  • R 3a and R 5b are taken together to form a ring having from 3 to 7 atoms;
  • R 2 is selected from:
  • R 6 is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl
  • R 7a and R 7b are each independently selected from:
  • R 7a and R 7 are taken together to form a ring having from 3 to 7 atoms;
  • R 3 is selected from hydrogen, methyl, and ethyl
  • L is a linking unit having a structure -[C(R 8a R 8b )]n-
  • R 8a and R 8b are each independently selected from hydrogen, methyl and ethyl
  • n is an integer from 1 to 3;
  • R 9 is selected from hydrogen and methyl
  • the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VII):
  • R is selected from:
  • Y 16 ; wherein one or more Y atoms (i.e., Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , and/or Y 16 ) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s).
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , and/or Y 16 is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s
  • 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).
  • all of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , and Y are isotopically enriched with deuterium.
  • all of Y 1 , Y 4 , and Y 5 are hydrogen.
  • one or more Y atoms of a compound of Formula (VII) is/are deuterium-enriched.
  • 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:
  • the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (VIII):
  • one or more Y atoms i.e., Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and/or Y 11
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and/or Y 11 is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s).
  • all of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are isotopically enriched with deuterium.
  • all of Y 1 , Y 4 , and Y 5 are hydrogen.
  • one or more Y atoms on the phenyl portion of a compound of Formula (VIII) is/are deuterium-enriched.
  • a compound of Formula (VIII) is/are deuterium-enriched.
  • 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:
  • one or more Y atoms on the pyridine portion of a compound of Formula (VIII) is/are deuterium-enriched.
  • a compound of Formula (VIII) is/are deuterium-enriched.
  • 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:
  • one or more Y atoms on the heteroatoms of a compound of Formula (VIII) is/are deuterium-enriched.
  • 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
  • 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
  • the deuterium-enriched HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer isotopologue has a structure of Formula (IX):
  • Y atoms i.e. , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and/or Y 11
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and/or Y 11 is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s).
  • 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).
  • all of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are isotopically enriched with deuterium.
  • all of Y 1 , Y 4 , and Y 5 are hydrogen.
  • one or more Y atoms on the phenyl portion of a compound of Formula (IX) is/are deuterium-enriched.
  • 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:
  • one or more Y atoms on the pyridine portion of a compound of Formula (IX) is/are deuterium-enriched.
  • 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
  • one or more Y atoms on the heteroatoms of a compound of Formula (IX) is/are deuterium-enriched.
  • 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
  • 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.
  • the isotopologue is selected from: Table 11
  • a metabolite of a compound has a structure of Formula (VI), Formula (VII), Formula (VIII), or Formula (IX).
  • 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:
  • said substitution selected from:
  • Y 24 wherein one or more Y atoms (i.e., Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , Y 23 , and/or Y 24 ) is/are hydrogen(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s).
  • 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).
  • all of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , Y 23 , and Y 24 are isotopically enriched with deuterium.
  • all of Y 1 , Y 4 , Y 7 , Y 10 , Y 11 , and Y 14 are hydrogen.
  • a compound selected from Metabolite 3 or Metabolite 4 is isolated.
  • hemoglobin disorders include any disorder associated with an alteration in the amount, structural integrity, or function of adult hemoglobin, specifically adult ⁇ globin.
  • Hemoglobin disorders include, but are not limited to, sickle cell diseases, including sickle cell anemia, hemoglobin SC disease, and sickle ⁇ thalassemia, ⁇ thalassemias, including p°-(major) thalassemia and P + -(minor) thalassemia, and disorders involving ineffective erythropoiesis.
  • 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.
  • 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, Com
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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, Com
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • a method for treating sickle ⁇ thalassemia comprising administering to a patient having ⁇ 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • a method for treating ⁇ thalassemia comprising administering to a patient having ⁇ 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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),
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • the symptom is vasoocclusion.
  • the symptom is acute pain.
  • the symptom is infection, including but not limited to bacterial infection.
  • the symptom is stroke.
  • the symptom is acute chest syndrome.
  • 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.
  • 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.
  • 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
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • a method for increasing the plasma levels of ⁇ 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • a method for increasing the expression of ⁇ 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • HbS sickle hemoglobin
  • 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.
  • 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, Com
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • 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,
  • a HIF prolyl hydroxylase inhibitor is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a HIF prolyl hydroxylase inhibitor is Compound 1.
  • a HIF prolyl hydroxylase inhibitor is an isotopologue such as any one of Compounds 14-98.
  • 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.
  • the subject is unresponsive to treatment with hydroxyurea.
  • the subject is unresponsive to treatment with butyrate.
  • the subject is unresponsive to treatment with 5- azacytidine.
  • the subject is unresponsive to treatment with nitric oxide.
  • the subject is unresponsive to treatment with vitamin B12.
  • the subject is unresponsive to treatment with folic acid.
  • 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.
  • 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.
  • the subject is hyporesponsive to treatment with hydroxyurea.
  • the subject is hyporesponsive to treatment with butyrate.
  • the subject is hyporesponsive to treatment with 5- azacytidine.
  • the subject is hyporesponsive to treatment with nitric oxide.
  • the subject is hyporesponsive to treatment with vitamin B12.
  • the subject is hyporesponsive to treatment with folic acid.
  • 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.
  • 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,
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof. In embodiments, a method comprises
  • a method comprises administration of an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a method comprises administration of Compound 1.
  • the genotype is HbS/S.
  • the genotype is HbS/ ⁇ °.
  • the genotype is HbS/S.
  • the genotype is Sever HbS/ ⁇ + 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/ ⁇ + thalassemia. In certain embodiments, the genotype is HbA/ S Oman. In certain embodiments, the genotype is Mild HbS/ ⁇ ++ thalassemia.
  • 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
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a method comprises administration of Compound 1.
  • a method comprises administration of an isotopologue such as any one of Compounds 14-98.
  • the chronic organ damage is of the lungs, kidney, liver, skeleton, and skin.
  • 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,
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt,
  • a method comprises
  • a method comprises administration of an isotopologue such as any one of Compounds 14-98.
  • an isotopologue such as any one of Compounds 14-98.
  • 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
  • the complication is hand-foot syndrome.
  • the complication is renal insufficiency.
  • the complication is retinitis.
  • the complication is osteonecrosis.
  • the complication is osteomyelitis.
  • the complication is aplastic crises.
  • the complication is functional asplenism.
  • the complication is stroke.
  • the complication is priapism.
  • 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,
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt,
  • a method comprises administration of Compound 1. In embodiments, a method comprises administration of an isotopologue such as any one of Compounds 14-98.
  • 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,
  • a method comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a method comprises administration of Compound 1.
  • a method comprises administration of an isotopologue such as any one of Compounds 14-98.
  • the subject is less than 12 years old. In certain embodiments, the subject is less than 6 years old.
  • 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
  • haplotypes 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.
  • BEN Benin
  • BAN Bantu
  • SEN Senegal
  • CAM Cameroon
  • ARAB Arabian-Indian
  • CAR Central African Republic
  • 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
  • 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.
  • 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.
  • a combination therapy comprises administration of Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • 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.
  • 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.
  • the compound provided herein see Section 4.2
  • 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.
  • 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.
  • 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,
  • a compound is Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a compound is Compound 1.
  • the compound provided herein is administered on the same day as a second pharmaceutically active agent.
  • the compound provided herein is administered one, two, three, or more days before a second pharmaceutically active agent.
  • the compound provided herein 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
  • 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.
  • 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 vitamin B12.
  • the second pharmaceutically active agent is folic acid.
  • the second pharmaceutically active agent is an iron supplement, such as ferrous sulfate, ferrous gluconate, or ferrous fumarate.
  • 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).
  • 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.
  • the iron supplement is administered orally at a daily dose of at least about 50 mg of elemental iron.
  • the iron supplement is administered orally at a dose of about 50 mg of elemental iron.
  • 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.
  • the second pharmaceutically active agent is an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic.
  • ESA erythropoiesis stimulating agent
  • the ESA is an rhEPO product, including, but not limited to, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the ESA is administered as a rescue therapy.
  • the ESA is
  • the second pharmaceutically active agent is a compound that prevents or inhibits polymerization of hemoglobin S.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • HIF prolyl hydroxylase inhibitor e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof
  • the actual amount of HIF prolyl hydroxylase inhibitor will depend, in part, on such factors as the
  • HIF prolyl hydroxylase inhibitor 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.
  • 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
  • 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
  • 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.
  • physiologically compatible buffers such as Hanks' solution, Ringer' s solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • 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.
  • compositions and dosage forms comprise one or more excipients.
  • 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.
  • 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.
  • 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.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • 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).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water 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.
  • water and heat accelerate the decomposition of some compounds.
  • 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.
  • 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.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • 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.
  • 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).
  • dosage forms contain
  • predetermined amounts of active ingredients 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).
  • 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.
  • 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.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • oral dosage forms are tablets or capsules, in which case solid excipients are employed.
  • 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.
  • 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.
  • 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.
  • 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-103TM 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.
  • 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.
  • fillers may include, but are not limited to block copolymers of ethylene oxide and propylene oxide.
  • 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.
  • fillers may include, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • calcium stearate e.g. Hyqual® 5712
  • mineral oil e.g. Hyqual® 5712
  • mineral oil e.g. Hyqual® 5712
  • light mineral oil glycerin
  • sorbitol sorbitol
  • 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.
  • AEROSIL200 syloid silica gel
  • 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
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • 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.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and e
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • 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.
  • 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.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • 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.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • 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.
  • the HIF prolyl hydroxylase inhibitors may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • 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.
  • compositions for parenteral administration include aqueous solutions of HIF prolyl hydroxylase inhibitor (e.g., Compound 1, or a metabolite,
  • HIF prolyl hydroxylase inhibitor e.g., Compound 1, or a metabolite
  • 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.
  • 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.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the HIF prolyl hydroxylase inhibitor e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof
  • rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • HIF prolyl hydroxylase inhibitors e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof
  • a depot preparation e.g., Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • 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.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase 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.
  • 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.
  • suitable excipients, carriers and diluents must also be safe for application to oral and related mucosal tissue.
  • 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.
  • 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
  • moisturizers or humectants can be added to the present composition if desired. Examples of such additional ingredients can be found in Remington's
  • 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,
  • 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.
  • 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).
  • 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.
  • 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.
  • the polarity of the solvent, its ionic strength or tonicity may be adjusted to improve delivery.
  • compounds such as stearates may be added to compositions comprising the active compound(s) to advantageously alter the
  • 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.
  • different salts, hydrates or solvates of the active compounds may be used to further adjust the properties of the resulting composition.
  • 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.
  • 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).
  • the active ingredient is formulated into a solution suitable for use as a mouthwash or as an oral gel.
  • formulations comprising Compound 1, or a metabolite, pharmaceutically acceptable salt, isotopologue, solvate or hydrate thereof.
  • a formulation comprises Compound 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating
  • the weight is the total weight of all intra-granular and extra-granular components.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • the film coating component comprises about 1.0% to about 8% by weight of a tablet coating
  • the weight is the total weight of all intra-granular and extra-granular components.
  • 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
  • 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.
  • 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.
  • 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®.
  • 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
  • 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® wherein the weight is the total weight of all intra-granular and extra-granular components.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • 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;
  • 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.
  • 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;
  • 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.
  • 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;
  • 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.
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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®.
  • 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 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).
  • 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.
  • 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,
  • 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.
  • 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),
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating
  • the weight is the total weight of all intra-granular and extra-granular components.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • the film coating component comprises about 1.0%) to about 8% by weight of a tablet coating
  • the weight is the total weight of all intra-granular and extra-granular components.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • the film coating component comprises about 1.0% to about 8%) by weight of a tablet coating
  • the weight is the total weight of all intra-granular and extra-granular components.
  • 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.
  • 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®.
  • 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
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • 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;
  • 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.
  • 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.
  • formulations comprising intra- granular components, extra-granular components, and film coating components
  • 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
  • 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
  • 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.
  • 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.
  • 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;
  • 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.
  • 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
  • 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 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.
  • a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof specifically, ⁇ [5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • 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,
  • 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.
  • the unit dosage form is a tablet comprising about 150 mg of the compound.
  • the unit dosage form is a tablet comprising about 315 mg of the compound.
  • the unit dosage form is a tablet comprising about 25 mg of the compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ thalassemias.
  • This section provides several specific doses for such uses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer.
  • such a dose is the initial dose at the beginning of a treatment.
  • such a dose is the adjusted dose at a later time during the course of treatment.
  • 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.
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 1.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • kits for treating a hemoglobin disorder 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • 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,
  • a compound is 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).
  • a compound is 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).
  • a compound is a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof (specifically, ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-
  • a compound is Compound 1.
  • 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).
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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),
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III),
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • kits for treating a hemoglobin disorder 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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 may be decreased by about 150 mg, such that the daily dose of the compound is about 300 mg.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • 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.
  • 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.
  • 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • kits for treating a hemoglobin disorder 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • 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),
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • kits for treating a hemoglobin disorder 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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),
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • administration of the compound may be resumed once the level of hemoglobin is at or below 12.5 g/dL.
  • 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 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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,
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is administered once daily and may be administered orally.
  • 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.
  • 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.
  • 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.
  • 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
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the compound is administered once daily and may be administered orally.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the compound is administered once daily and may be administered orally.
  • 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.
  • 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.
  • 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.
  • 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,
  • a compound is Compound 1, or an isotopologue thereof.
  • a compound is Compound 1.
  • 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.
  • a compound is Compound 1, or an isotopologue thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • the daily dose is adjusted in accordance with the serum concentration of the metabolite.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • the second pharmaceutically active agent is a compound that prevents or inhibits polymerization of hemoglobin S.
  • 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.
  • 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.
  • a compound is Compound 1, or a pharmaceutically acceptable salt, isotopologue, solvate, or hydrate thereof.
  • a compound is Compound 1.
  • the compound is an isotopologue that is any one of Compounds 14-98.
  • 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.
  • 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-[(2-pyrazol
  • 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).
  • SCD mice human HbS
  • 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.)
  • 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;
  • 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
  • HIF prolyl hydroxylase inhibitors 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.
  • ⁇ -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 ⁇ -globin mRNA levels are normalized to toal human ⁇ -type globin transcripts. These relative ⁇ -globin mRNA levels are determined and compared over the course of four weeks.
  • QRT-PCR real-time reverse transcription polymerase chain reaction
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • Group 2 18 or 36 mg/Kg of Compound 7 or vehicle are administered on day 1 and then continuously once per day.
  • 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.
  • 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.
  • Step 5 Preparation of ethyl ⁇ [5-(3-chloro-2,4,6-d3-phenyl)-3-hydroxypyridin-2- yl] amino ⁇ acetic acid (Compound 98)

Abstract

La présente invention concerne des composés inhibiteurs de la prolyl hydroxylase du facteur induit par l'hypoxie (HIF) et des sels de qualité pharmaceutique de ces derniers, des compositions comprenant les composés inhibiteurs de la prolyl hydroxylase de HIF (par exemple<i /> le composé 1), et des méthodes de traitement ou de prévention des hémoglobinopathies telles que les maladies drépanocytaires, qui comprennent l'anémie falciforme, l'hémoglobinopathie SC et la β-thalasso-drépanocytose, et les β-thalassémies, qui comprennent la thalassémie à βo (majeure) et la thalassémie à β+ (mineure). De plus, la présente invention concerne des doses spécifiques de l'inhibiteur de la prolyl hydroxylase de HIF dans le traitement ou la prévention d'hémoglobinopathies telles que les maladies drépanocytaires, qui comprennent l'anémie falciforme, l'hémoglobinopathie SC et la β-thalasso-drépanocytose, et les β-thalassémies, qui comprennent la thalassémie à βo (majeure) et la thalassémie à β+ (mineure).
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US11883386B2 (en) 2006-06-26 2024-01-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
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WO2021117767A1 (fr) * 2019-12-10 2021-06-17 田辺三菱製薬株式会社 Procédé de production d'un dérivé d'acide hétéroarylcarboxamide acétique contenant de l'azote
EP3888684A1 (fr) * 2020-03-31 2021-10-06 Bayer Animal Health GmbH Composition ayant une acceptation volontaire améliorée
WO2021198256A1 (fr) * 2020-03-31 2021-10-07 Bayer Animal Health Gmbh Composition présentant une acceptation volontaire améliorée
WO2022078428A1 (fr) * 2020-10-16 2022-04-21 江苏苏中药业集团股份有限公司 Composé en tant qu'inhibiteur de la prolyl hydroxylase et son procédé de préparation
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WO2022195532A1 (fr) * 2021-03-19 2022-09-22 Zydus Lifesciences Ltd. Traitement de la drépanocytose

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