WO2019104134A1 - Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide - Google Patents

Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide Download PDF

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WO2019104134A1
WO2019104134A1 PCT/US2018/062197 US2018062197W WO2019104134A1 WO 2019104134 A1 WO2019104134 A1 WO 2019104134A1 US 2018062197 W US2018062197 W US 2018062197W WO 2019104134 A1 WO2019104134 A1 WO 2019104134A1
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crystalline form
crystalline
compound
subject
ray powder
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English (en)
French (fr)
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Jacob P. SIZEMORE
Liting GUO
Mahmoud Mirmehrabi
Yeqing Su
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Agios Pharmaceuticals Inc
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Agios Pharmaceuticals Inc
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Priority to UAA202003680A priority Critical patent/UA127502C2/uk
Priority to SI201830984T priority patent/SI3713919T1/sl
Priority to FIEP18821779.8T priority patent/FI3713919T3/fi
Priority to IL322576A priority patent/IL322576A/en
Priority to KR1020207015018A priority patent/KR102682430B1/ko
Priority to JP2020528129A priority patent/JP7275130B2/ja
Priority to AU2018373122A priority patent/AU2018373122B2/en
Priority to KR1020247022172A priority patent/KR102777452B1/ko
Priority to HRP20230931TT priority patent/HRP20230931T1/hr
Priority to CN202311301795.5A priority patent/CN117551030A/zh
Priority to MA50805A priority patent/MA50805B1/fr
Priority to CA3081945A priority patent/CA3081945A1/en
Priority to CN201880075099.8A priority patent/CN111372920B/zh
Priority to IL305343A priority patent/IL305343B1/en
Priority to KR1020257007025A priority patent/KR20250034202A/ko
Priority to DK18821779.8T priority patent/DK3713919T3/da
Priority to ES18821779T priority patent/ES2959764T3/es
Application filed by Agios Pharmaceuticals Inc filed Critical Agios Pharmaceuticals Inc
Priority to MDE20200988T priority patent/MD3713919T2/ro
Priority to EP23186155.0A priority patent/EP4285904A3/en
Priority to RS20230793A priority patent/RS64592B1/sr
Priority to MX2020005348A priority patent/MX2020005348A/es
Priority to SG11202004587XA priority patent/SG11202004587XA/en
Priority to SM20230327T priority patent/SMT202300327T1/it
Priority to EA202091277A priority patent/EA202091277A1/ru
Priority to EP18821779.8A priority patent/EP3713919B1/en
Priority to PL18821779.8T priority patent/PL3713919T3/pl
Priority to LTEPPCT/US2018/062197T priority patent/LT3713919T/lt
Priority to BR112020010185-0A priority patent/BR112020010185A2/pt
Priority to IL274488A priority patent/IL274488B2/en
Priority to US16/765,456 priority patent/US11254652B2/en
Publication of WO2019104134A1 publication Critical patent/WO2019104134A1/en
Priority to PH12020550644A priority patent/PH12020550644A1/en
Anticipated expiration legal-status Critical
Priority to US17/575,898 priority patent/US20220220093A1/en
Priority to AU2024200724A priority patent/AU2024200724A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • PTD Pyruvate kinase deficiency
  • PKR activators can be beneficial to treat PKD, thalassemia (e.g., beta-thalessemia), abetalipoproteinemia or Bassen-Kornzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, anemia (e.g., congenital anemias (e.g., enzymopathies), hemolytic anemia (e.g. hereditary and/or congenital hemolytic anemia, acquired hemolytic anemia, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency, anemia of chronic diseases, non- spherocytic hemolytic anemia or hereditary spherocytosis).
  • thalassemia e.g., beta-thalessemia
  • abetalipoproteinemia or Bassen-Kornzweig syndrome e.g., enzymopathies
  • hemolytic anemia e.g. hereditary and/or congenital hemolytic
  • N-(4-(4-(cyclopropylmethyl)piperazine-l-carbonyl)phenyl)quinoline-8- sulfonamide herein referred to as Compound 1
  • PLR pyruvate kinase
  • Compound 1 was developed to treat PKD and is currently being investigated in phase 2 clinical trials. See e.g., U.S. clinical trials identifier NCT02476916. Given its therapeutic benefits, there is a need to develop alternative forms of Compound 1 in an effort to facilitate isolation, manufacturing, and formulation development, as well as to enhance storage stability.
  • compositions comprising the amorphous and crystalline hemisulfate salt forms, methods for their manufacture, and uses thereof for treating conditions associated with pyruvate kinase such as e.g., PKD.
  • FIG. 1 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form A.
  • FIG. 2 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form A.
  • FIG. 3 depicts the differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form A
  • FIG. 4 depicts the dynamic vapor sorption (DVS) isotherm for crystalline hemisulfate salt Form A.
  • FIG. 5 (i) depicts X-ray powder diffraction pattern (XRPD) overlay for crystalline hemisulfate salt Form A and after exposure to 11%, 48%, and 75% relative humidity and 40 °C for two weeks. The XRPD remained unchanged aftger two- week test under these three humidity conditions.
  • FIG. 5 (ii) depicts XRPD overlay for crystalline hemisulfate salt Form A and after exposure to phosphorus pentoxide (P2O5) granules at room temperature and 50°C for one week, as well as ambient temperature in a vial for 24hrs.
  • P2O5 phosphorus pentoxide
  • FIG. 6 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form B obtained in MeOH:EtOH (3:7) .
  • FIG. 7(i) depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form B.
  • FIG. 7(ii) depicts the XRPD for crystalline hemisulfate salt Form B before and after dynamic vapor sorption (DVS). After DVS, Form B was converted to a different Form K.
  • FIG. 8 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form D.
  • FIG. 9 depicts the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form D.
  • FIG. 10 depicts the X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form D before and after dynamic vapor sorption (DVS).
  • FIG. 11 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form E.
  • FIG. 12 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form F.
  • FIG. 13 depicts the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form F.
  • FIG. 14 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form G.
  • FIG. 15 depicts the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form G.
  • FIG. 16 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form H.
  • FIG. 17 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form I.
  • FIG. 18 depicts the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemisulfate salt Form I.
  • FIG. 19 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form J.
  • FIG. 20 depicts the X-ray powder diffraction pattern (XRPD) for amorphous hemisulfate salt form of Compound 1.
  • FIG. 21 depicts the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for amorphous hemisulfate salt of Compound 1 dried in vacuum oven at 50 °C for overnight.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • FIG. 23 depicts the X-ray powder diffraction pattern (XRPD) for amorphous free base form of Compound 1.
  • FIG. 24 depicts the TGA and DSC thermograms for amorphous free base form of Compound 1.
  • FIG. 25 depicts the X-ray powder diffraction pattern (XRPD) for crystalline free base form of Compound 1.
  • the terms“Form A”,“Form B”,“Form C”,“Form D”,“Form E”,“Form F”,“Form G”,“Form H”,“Form I”, and“Form J” refer to the crystalline hemisulfate salt forms A, B, C, D, E, F, G, H, I, and J of Compound 1, respectively.
  • Compound 1 are used interchangeably.
  • “Form B”,“crystalline Form B”, and “crystalline hemisulfate salt Form B of Compound 1” are used interchangeably.
  • “Form C”,“crystalline Form C”, and“crystalline hemisulfate salt Form C of Compound 1” are used interchangeably.
  • “Form D”,“crystalline Form D”, and“crystalline hemisulfate salt Form D of Compound 1” are used interchangeably.
  • “Form E”, “crystalline Form E”, and“crystalline hemisulfate salt Form E of Compound 1” are used interchangeably.
  • “Form F”,“crystalline Form F”, and“crystalline hemisulfate salt Form F of Compound 1” are used interchangeably.
  • “Pattern A”,“Pattern B”,“Pattern C”,“Pattern D”,“Pattern E”,“Pattern F”, “Pattern G”,“Pattern H”,“Pattern I”, and“Pattern J” refer to the X-ray powder diffraction pattern (XRPD) for crystalline hemisulfate salt Form A, B, C, D, E, F, G, H, I and J respectively.
  • crystalline free base “free-base crystalline form of Compound 1,” “crystalline free base form of Compound 1,” and“crystalline free base of Compound 1” are used interchangeably and mean the free base or non-salt form of Compound 1, which is present in a crystalline form.
  • anhydrous means that the referenced crystalline form has substantially no water in the crystal lattice e.g., less than 0.1% by weight as determined by Karl Fisher analysis.
  • amorphous means a solid that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • chemical purity refers to extent by which the disclosed form is free from materials having different chemical structures.
  • Chemical purity of the compound in the disclosed crystal forms means the weight of the compound divided by the sum of the weight of the compound plus materials/impurities having different chemical structures multiplied by 100%, i.e., percent by weight.
  • the compound in the disclosed crystalline forms has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.
  • “crystalline” refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms.
  • the crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. If the XRPD shows sharp intensity peaks in the XRPD then the compound is crystalline.
  • solvate refers to a crystalline compound wherein a stoichiometric or non-stoichiometric amount of solvent, or mixture of solvents, is incorporated into the crystal structure.
  • hydrate refers to a crystalline compound where a stoichiometric or non- stoichiometric amount of water is incorporated into the crystal structure.
  • a hydrate is a solvate wherein the solvent incorporated into the crystal structure is water.
  • anhydrous when used with respect to a compound means substantially no solvent incorporated into the crystal structure.
  • a single crystalline form of the disclosed crystalline hemisulfate salt means that N-(4-(4-(cyclopropylmethyl)piperazine-l-carbonyl)phenyl)quinoline-8-sulfonamide hemisulfate salt is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (i.e., Form A, B, C, D, E, F, G, H, I, or J).
  • the crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified.
  • the crystalline form is at least 60% a single crystalline form, at least 70% a single crystalline form, at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
  • the 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, unless otherwise defined, the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ⁇ 0.2 degrees.
  • the 2-theta values provided herein were obtained using Cu Kal radiation.
  • Temperature values e.g., for DSC peaks herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary ⁇ 5 degrees or ⁇ 2 degrees.
  • substantially the same XRPD pattern” or“an X-ray powder diffraction pattern substantially similar to” a defined figure means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ⁇ 0.2 degrees.
  • A“therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • the term“therapeutically effective amount” and“effective amount” are used interchangeably.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for eliciting measurable activation of wild-type or mutant PKR.
  • a therapeutically effective amount is an amount sufficient for regulating 2,3-diphosphoglycerate levels in blood in need thereof or for treating pyruvate kinase deficiency (PKD), hemolytic anemia (e.g., chronic hemolytic anemia, hereditary non-spherocytic anemia), sickle cell disease, thalassemia (e.g., alfa thalassemia, beta-thalassemia or non-transfusion-dependent thalassemia), hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia (or Bassen- Komzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemias (e.g., enzymopathies)), anemia of chronic diseases or treating diseases
  • PTD
  • a therapeutically effective amount is an amount sufficient for eliciting measurable activation of wild-type or mutant PKR and for regulating 2,3-diphosphoglycerate levels in blood in need thereof or for treating pyruvate kinase deficiency (PKD), hemolytic anemia (e.g., chronic hemolytic anemia, hereditary non- spherocytic anemia), sickle cell disease, thalassemia (e.g., alfa thalassemia, beta-thalassemia or non-transfusion-dependent thalassemia), hereditary spherocytosis, hereditary
  • PTD pyruvate kinase deficiency
  • hemolytic anemia e.g., chronic hemolytic anemia, hereditary non- spherocytic anemia
  • sickle cell disease e.g., alfa thalassemia, beta-thalassemia or non-transfusion-dependent thalassemia
  • elliptocytosis elliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemias (e.g., enzymopathies)), anemia of chronic diseases or treating diseases or conditions that are associated with increased 2,3-diphosphoglycerate levels (e.g., liver diseases).
  • abetalipoproteinemia or Bassen-Kornzweig syndrome
  • paroxysmal nocturnal hemoglobinuria e.g., acquired hemolytic anemia (e.g., congenital anemias (e.g., enzymopathies)), anemia of chronic diseases or treating diseases or conditions that are associated with increased 2,3-diphosphoglycerate levels (e.g., liver diseases).
  • acquired hemolytic anemia e.g., congenital anemias (e.g., enzymopathies)
  • therapeutically effective amount is the amount required to generate a subject’s hemoglobin response of >1.0 g/dL (such as >1.5 g/dL or >2.0 g/dL) increase in Hb concentration from baseline.
  • the subject’s baseline Hb concentration is the average of all available Hb concentrations before treatment with a compound described herein.
  • the therapeutically effective amount is the amount required to reduce the patient’s transfusion burden.
  • the therapeutically effective amount is between 0.01 - 100 mg/kg body weight/day of the provided compound, such as e.g., 0.1 - 100 mg/kg body weight/day.
  • reduction in transfusion burden means at least 20% reduction in the number of RBC units transfused within at least 5 weeks of treatment. In certain embodiments, the reduction in transfusion burden is >33% reduction in the number of RBC units transfused within at least 5 weeks of treatment. In certain embodiments, reduction of transfusion burden is >33% reduction in the number of RBC units transfused within at least 10 weeks (e.g., at least 20 weeks or at least 24 weeks) of treatment.
  • sickle cell disease SCD
  • Hemoglobin SS disease SCD
  • sickle cell anemia is used interchangeably.
  • Sickle cell disease SCD is an inherited blood disorder caused by the presence of sickle hemoglobin (HbS).
  • subjects with SCD have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells.
  • people having SCD have at least one abnormal genes causing the body to make hemoglobin S.
  • people having SCD have two hemoglobin S genes, Hemoglobin SS.
  • Thalassemia is an inherited blood disorder in which the normal ratio of a- to b- globin production is disrupted due to a disease-causing variant in 1 or more of the globin genes.
  • Alpha-globin aggregates (as found in b-thalassemia) readily precipitate, which disrupts the red blood cell (RBC) membrane and results in oxidative stress.
  • Beta-globin tetramers (Hb H, found in a-thalassemia) are generally more soluble, but are still unstable and can form precipitates.
  • the imbalance of the globin chain synthesis can lead to a net reduction in Hb concentrations and has dramatic effects on the survival of RBC precursors, ultimately resulting in their premature destruction in the bone marrow and in extramedullary sites (Cappellini et al, 2014).
  • the disorder results in large numbers of red blood cells being destroyed, which leads to anemia.
  • the thalassemia is alpha thalassemia. In certain embodiments, the thalassemia is beta thalassemia. In other embodiments, the thalassemia is non-transfusion- dependent thalassemia. In other embodiments, the thalassemia is beta thalassemia intermedia. In other embodiments, the thalassemia is Hb E beta thalassemia. In other embodiments, the thalassemia is beta thalassemia with mutations of 1 or more alfa genes.
  • activating means an agent that (measurably) increases the activity of wild type pyruvate kinase R (wt PKR) or causes wild type pyruvate kinase R (wt PKR) activity to increase to a level that is greater than wt PKR’s basal levels of activity or an agent that (measurably) increases the activity of a mutant pyruvate kinase R (mPKR) or causes mutant pyruvate kinase R (mPKR) activity to increase to a level that is greater than that mutant PKR’s basal levels of activity, for examples, to a level that is 20%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the activity of wild type PKR.
  • a PRBC unit has a hematocrit of at least about 95%. In certain embodiments, a PRBC unit has a hematocrit of at least about 90%. In certain embodiments, a PRBC unit has a hematocrit of at least about 80%. In certain embodiments, a PRBC unit has a hematocrit of at least about 70%. In certain embodiments, a PRBC unit has a hematocrit of at least about 60%. In certain embodiments, a PRBC unit has a hematocrit of at least about 50%.
  • a PRBC unit has a hematocrit of at least about 40%. In certain embodiments, a PRBC unit has a hematocrit of at least about 30%. In certain embodiments, a PRBC unit has a hematocrit of at least about 20%. In certain embodiments, a PRBC unit has a hematocrit of at least about 10%.
  • treatment refers to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g ., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to reduce the likelihood of or delay their recurrence.
  • the terms“subject” and“patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • the term“subject” refers to a human subject in need of treatment of a disease.
  • the term“subject” refers to a human subject in need of treatment of PKD.
  • the term“subject” refers to a human subject in need of treatment of thalassemia. In certain embodiments, the term“subject” refers to a human subject in need of treatment of sickle cell disease. In certain embodiments, the term“subject” refers to a human adult over 18 years old in need of treatment of a disease. In certain embodiments, the term“subject” refers to a human child no more than 18 years old in need of treatment of a disease. In certain embodiments, the subject is a patient in need of regular blood transfusion. As used here, the regular blood transfusion refers to at least 4 transfusion episodes in a 52- week period prior to the treatment.
  • the regular blood transfusion refers to at least 5 transfusion episodes in a 52- week period prior to the treatment. In certain embodiments, the regular blood transfusion refers to at least 6 transfusion episodes in a 52- week period prior to the treatment. In certain embodiments, the regular blood transfusion refers to at least 7 transfusion episodes in a 52- week period prior to the treatment.
  • the subject with a least one of the indications selected from the sickle cell disease, thalassemia, PKD under regular transfusion, and non-transfusion dependent PKD has not been exposed to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy.
  • such subject is not taking inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin. In certain embodiments, such subject is not receiving chronic cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin. In certain embodiments, such subject is not receiving chronic cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin. In certain embodiments, such subject is not receiving chronic cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin. In certain embodiments, such subject is not receiving chronic cytochrome P450 (CYP)3A4, strong inducers of CYP3
  • anticoagulant therapy anabolic steroids
  • hematopoietic stimulating agents eg, hematopoietic stimulating agents
  • erythropoietins erythropoietins, granulocyte colony stimulating factors, thrombopoietins), or allergic to sulfonamides.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
  • the terms“about” and“approximately” when used in combination with a numeric value or range of values used to characterize a particular crystal form, amorphous form, or mixture thereof of a compound mean the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while describing the particular crystal form, amorphous form, or mixture thereof.
  • hemisulfate salt of the compound in crystalline Form A is a sesquihydrate.
  • crystalline Form A is a hemisulfate sesquihydrate of compound 1, N-(4-(4-(cyclopropylmethyl)piperazine-l-carbonyl)phenyl)quinoline-8-sulfonamide.
  • crystalline Form A can be named“l-(cyclopropylmethyl)-4-(4-(quinoline- 8-sulfonamido)benzoyl)piperazin-l-ium hemisulfate sesquihydrate” having Formula A, or alternatively“l-(cyclopropylmethyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-l- ium sulfate trihydrate” having Formula B as shown below:
  • crystalline Form A can be referred to either Formula A or Formula B interchangeably.
  • hemisulfate means the stoichiometric ratio of compound 1 to H 2 S0 4 is 2:1 in a crystalline form (i.e. a crystalline form contains two molecules of compound 1 per one molecule of H 2 S0 4 ).
  • “sesquihyrate” or“trihydrate” means the stoichiometric ratio of compound 1 to H 2 0 is 2:3 in crystalline Form A (i.e. crystalline Form A contains two molecules of compound 1 per three molecules of water).
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 15.8°, and 22.6°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 15.8°, and 22.6° and at least one additional x-ray powder diffraction peak at 2Q angles ( ⁇ 0.2°) selected from 15.0°, 17.1°, 21.3°, and 21.9°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 15.8°, and 22.6°; and at least two additional x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 15.0°, 17.1°, 21.3°, and 21.9°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 15.8°, and 22.6°; and at least three additional x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 15.0°, 17.1°, 21.3°, and 21.9° .
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 15.0°, 15.8°, 17.1°, 21.3°, 21.9°, and 22.6°. In certain embodiments, crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 11.4°, 15.0°, 15.3°, 15.8°, 17.1°, 17.7°, 21.3°, 21.9°, 22.6°, and 23.5°. In certain embodiments, crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.9°, 9.9°, 11.0°, 11.4°, 11.7°, 12.3°, 12.8°,
  • crystalline Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1.
  • crystalline Form A is characterized by a differential scanning calorimetry (DSC) thermograph comprising endotherm peaks at about 159 °C ⁇ 5 °C and 199 °C ⁇ 5 °C.
  • crystalline Form A is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to the one depicted in FIG. 2.
  • crystalline Form A is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 4.5 ⁇ 0.5 % up to 180 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form A is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to the one depicted in FIG 2.
  • crystalline Form A is characterized by a DSC substantially similar to the one depicted in FIG 3.
  • hemisulfate salt of a compound having the formula (I) was found to have a variety of favorable physicochemical properties, including high crystallinity, stability in multiple solvent systems (e.g. especially containing water), relatively small particle size (e.g. below 20 pm under microscope so as to potentially avoid the subsequent micronization), and stability in humidity (e.g. at least 20% RH or at least a water activity of 0.2), and demonstrate favorable plasma concentration-time profiles and pharmacokinetic parameters.
  • hemisulfate salt of the compound in crystalline Form B is an ethanol solvate.
  • crystalline Form B is characterized by at least three x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 10.6°, 12.7°, 15.7°, 16.9°, 22.0°, and 22.5°.
  • crystalline Form B is characterized by at least four x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 10.6°, 12.7°, 15.7°, 16.9°, 22.0°, and 22.5°.
  • crystalline Form B is characterized by at five three x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 10.6°, 12.7°, 15.7°, 16.9°, 22.0°, and 22.5°.
  • crystalline Form B is characterized by at least six x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 10.6°, 12.7°, 15.7°, 16.9°, 22.0°, and 22.5°.
  • crystalline Form B is characterized by x- ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 10.6°, 12.7°, 15.7°, 16.9°, 22.0°, and 22.5°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 9.9°, 10.6°, 12.7°, 13.9°, 14.6°, 15.7°, 16.9°, 22.0°, 22.5°, and 27.6°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 7.0°, 7.8°, 9.9°, 10.6°, 11.7°, 12.7°, 13.1°, 13.5°, 13.9°, 14.6°, 14.9°, 15.3°, 15.7°, 16.1°, 16.9°, 17.6°, 19.3°, 19.7°, 20.7°, 21.2°, 22.0°, 22.5°, 23.3°, 24.0°, 24.7°, 25.1°, 25.7°, 26.1°, 27.2°, 27.6°, 28.4°, 29.3°, and 29.8°.
  • crystalline Form B is characterized by an X-ray powder diffraction pattern substantially similar to FIG 6.
  • crystalline Form B is characterized by a TGA or DSC pattern substantially similar to FIG 7.
  • crystalline Form B is characterized by a differential scanning calorimetry (DSC) thermograph comprising endotherm peaks at about 154 ⁇ 5 °C.
  • crystalline Form B is characterized by a TGA comprising a weight loss of about 4.3 ⁇ 0.5 % up to 200 °C ⁇ 2 °C.
  • crystalline Form C is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.9°, 10.4°, and 12.0°.
  • crystalline Form D is characterized by at least three x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 5.8°, 10.0°, 10.2°, 19.3°, 22.9°, 23.3°, and 25.2°.
  • crystalline Form D is characterized by at least four x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 5.8°, 10.0°, 10.2°, 19.3°, 22.9°, 23.3°, and 25.2°.
  • crystalline Form D is characterized by at least five x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 5.8°, 10.0°, 10.2°, 19.3°, 22.9°, 23.3°, and 25.2°.
  • crystalline Form D is characterized by at least six x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 5.8°, 10.0°, 10.2°, 19.3°, 22.9°, 23.3°, and 25.2°.
  • crystalline Form D is characterized by x- ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 5.8°, 10.0°, 10.2°, 19.3°, 22.9°, 23.3°, and 25.2°.
  • crystalline Form D is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 5.8°, 10.0°, 10.2°, 12.2°, 17.3°, 17.6°, 19.3°, 22.9°, 23.3°, 23.6°, and 25.2°.
  • crystalline Form D is characterized by x- ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 5.8°, 10.0°, 10.2°, 11.3°, 11.5°, 12.2°, 13.6°, 14.1°, 14.7°, 15.4°, 16.0°, 17.3°, 17.6°, 19.3°, 20.0°, 20.8°, 22.1°, 22.9°, 23.3°, 23.6°, 24.4°, 25.2°, 26.4°, 27.4°, 28.3°, and 29.6°.
  • crystalline Form D is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 8.
  • crystalline Form D is characterized by a differential scanning calorimetry (DSC) pattern having a peak at 239.0 °C ⁇ 2 °C.
  • crystalline Form D is characterized by a DSC substantially similar to FIG. 9.
  • crystalline Form D is characterized by a TGA comprising a weight loss of about 0.62+ 0.5 % up to 220 °C + 2 °C.
  • crystalline Form D is characterized by a TGA substantially similar to FIG. 9.
  • crystalline Form E is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.6°, 9.0°, 13.5°, and 22.5°.
  • crystalline Form E is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.6°, 9.0°, 13.5°, 15.1°, 18.5°, 21.7°, and 22.5°.
  • crystalline Form E is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.6°, 9.0°, 9.9°, 11.0°,
  • crystalline Form E is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 11.
  • crystalline Form F is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 5.0°, 9.9°, and 14.7°.
  • ⁇ 0.2° 2Q angles
  • Form F is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from
  • crystalline Form F is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 5.0°, 9.9°, 11.1°, 14.7°, 16.5°, 19.6°, 21.6°, 22.8°, and 24.4°.
  • crystalline Form F is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 12.
  • crystalline Form F is characterized by a DSC pattern having a peak at 101.0 °C ⁇ 2 °C.
  • crystalline Form F is characterized by a TGA comprising a weight loss of about 8.8 ⁇ 0.5 % up to 182 °C ⁇ 2 °C.
  • crystalline Form F is characterized by a TGA or DSC substantially similar to FIG. 13.
  • crystalline Form G is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.7°, 9.4°, and 14.1°.
  • ⁇ 0.2° 2Q angles
  • crystalline Form G is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.7°, 9.4°, and 14.1°.
  • Form G is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.7°, 9.4°, 11.0°, 14.1°, 18.9°, 21.2°, and 23.8°.
  • crystalline Form G is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.7°, 9.4°, 11.0°, 13.3°, 14.1°, 15.9°, 16.2°, 18.9°, 21.2°, 22.8°, 23.8°, 26.7°, and 28.5°.
  • crystalline Form G is characterized by an X-ray powder diffraction pattern substantially similar to FIG 14.
  • crystalline Form G is
  • crystalline Form G is characterized by a DSC pattern having a peak at 156.7 °C ⁇ 2 °C.
  • crystalline Form G is characterized by a TGA comprising a weight loss of about 2.6 ⁇ 0.5 % up to 176 °C ⁇ 2 °C.
  • crystalline Form G is characterized by a TGA or DSC substantially similar to FIG. 15.
  • crystalline Form H is characterized by at least three x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.6°, 7.4°, 9.2°, 11.1°, 13.5°, 14.9°, and 22.3°.
  • crystalline Form H is characterized by at least four x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.6°, 7.4°, 9.2°, 11.1°, 13.5°, 14.9°, and
  • crystalline Form H is characterized by at least five x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.6°, 7.4°, 9.2°, 11.1°, 13.5°, 14.9°, and 22.3°.
  • crystalline Form H is characterized by at least six x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 4.6°, 7.4°, 9.2°, 11.1°, 13.5°, 14.9°, and 22.3°.
  • crystalline Form H is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.6°, 7.4°, 9.2°, 11.1°, 13.5°, 14.9°, and 22.3°.
  • crystalline Form H is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 4.6°, 5.4°, 7.4°, 9.2°, 10.3°, 11.1°, 13.5°, 13.8°, 14.9°, 16.9°, 17.6°, 18.4°, 19.5°, 20.7°, 22.3°, 22.9°, 23.4°, 24.1°, 24.8°, 26.5°, 27.2°, and 29.5°.
  • crystalline Form H is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 16.
  • hemisulfate salt of the compound in crystalline Form I is an ethanol solvate.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 9.5°, and 19.7°.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 9.5°, and 19.7°; and at least one additional x-ray powder diffraction peak at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 12.6°, 15.8°, 21.9°, and 22.3°.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 9.5°, and 19.7°; and at least two additional x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 12.6°, 15.8°, 21.9°, and 22.3°.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 9.5°, and 19.7°; and at least three additional x-ray powder diffraction peak at 2Q angles ( ⁇ 0.2°) selected from 9.9°, 12.6°, 15.8°, 21.9°, and 22.3°.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 9.5°, 9.9°, 12.6°, 15.8°, 19.7°, 21.9°, and 22.3°.
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.7°, 7.7°, 9.5°, 9.9°, 10.5°, 11.6°, 12.6°, 13.4°, 13.8°, 14.3°, 15.2°, 15.8°, 16.8°, 17.2°, 19.0°, 19.7°, 20.5°, 20.9°, 21.9°, 22.3°, 23.9°, 24.6°, 25.5°, 26.0°, 27.5°, 28.3°, and 29.3°.
  • crystalline Form I is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17.
  • crystalline Form I is characterized by a DSC pattern having a peak at 134.7 °C ⁇ 2 °C.
  • crystalline Form I is characterized by a TGA comprising a weight loss of about 6.9 ⁇ 0.5 % up to 180 °C ⁇ 2 °C.
  • crystalline Form I is characterized by a TGA or DSC substantially similar to FIG. 18.
  • crystalline Form J is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 12.4°, 13.2°, 14.6°, 20.4°, and 23.7°.
  • crystalline Form J is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 12.4°, 13.2°, 14.6°, 15.7°, 20.4°, 23.3°, and 23.7°.
  • crystalline Form J is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 12.4°, 13.2°, 14.6°, 15.7°, 20.4°, 22.0°, 23.3°, 23.7°, and 28.0°.
  • crystalline Form J is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19.
  • the free-base crystalline form of Compound 1 is characterized by x- ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 6.9°, 13.5°, 19.8°, and 20.3°.
  • the free-base crystalline form of Compound 1 is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) selected from 6.9°, 13.5°, 19.8°, 20.3°, and 25.7°.
  • the free-base crystalline form of Compound 1 is characterized by x-ray powder diffraction peaks at 2Q angles ( ⁇ 0.2°) 6.9°, 13.5°, 15.7°, 15.9°, 19.8°, 20.3°, 23.6°, and 25.7°.
  • the free-base crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 25.
  • the compounds described herein are at least 60% a single crystalline form, at least 70% a single crystalline form, at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight.
  • the compounds described herein have a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.
  • the compounds described herein are substantially free of amorphous forms, i.e., less than 10% of the amorphous form is present e.g., less than 5%, less than 3%, less than 2%, or less than 1% of the amorphous form is present.
  • the molar ratio of the compound of Formula 1 to H 2 S0 4 is about 2:1.
  • the alcoholic solution further comprises water.
  • the method of forming crystalline Form A described above further comprises the step of, after the reaction with H 2 S0 4 , adding a sufficient amount of water to precipitate the crystalline form.
  • the alcohol is methanol or ethanol.
  • the solution further comprises an aromatic solvent.
  • the aromatic solvent is toluene.
  • crystalline Form A is prepared by reacting Compound 1 with H 2 S0 4 in a solution comprising acetone and water.
  • the solution is
  • the method comprising reacting the non-crystalline freebase of compound 1 with a solution of sulfuric acid in EtOAc.
  • concentration of sulfuric acid in EtOAc is about 15 wt% to about 30 wt%. In certain embodiments, the concentration of sulfuric acid in EtOAc is about 24 wt%.
  • the hemisulfate salt is prepared by reacting Compound 1 with H 2 S0 4 in a solution comprising water and an alcohol such as MeOH or EtOH.
  • the amorphous form of the hemisulfate salt can be prepared by crystallizing the crystalline Form A of a hemisulfate salt from THF.
  • the evaporative crystallization is performed in methanol or THF at about 50 °C.
  • compositions comprising one or more of the disclosed crystalline forms (e.g. crystalline Form A), or the disclosed amorphous form, together with a pharmaceutically acceptable carrier.
  • the amount of crystalline or amorphous form in a provided composition is such that is effective to measurably modulate PKR in a subject.
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • such preparatory methods include the steps of bringing one or more of the disclosed crystalline forms (e.g. crystalline Form A) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • Pharmaceutically acceptable carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g . acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. bentonite (aluminum silicate) and Veegum (mag
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),
  • polyoxyethylene sorbitan Teween 60
  • polyoxyethylene sorbitan monooleate Teween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g.
  • polyoxyethylene monostearate Myrj 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate polyethoxylated castor oil
  • polyoxymethylene stearate polyethoxylated castor oil
  • Solutol sucrose fatty acid esters
  • polyethylene glycol fatty acid esters e.g. CremophorTM
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-l88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g . cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • SLS sodium lauryl sulfate
  • SLES sodium lauryl ether sulfate
  • sodium bisulfite sodium metabisulfite
  • potassium sulfite potassium metabisulfite
  • Glydant Plus Phenonip
  • methylparaben Germall 115
  • Germaben II Germaben II
  • Neolone Kathon, and Euxyl.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, camauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, transmucosally, or in an ophthalmic preparation.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions provided herewith are orally administered in an orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the amount of provided crystalline or amorphous form that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the subject to be treated and the particular mode of administration. For example, a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • composition will also depend upon the particular form (e.g., Form A, B, C, D, E, F, G, H, I, or J) in the composition.
  • a provided composition may be formulated such that a dosage equivalent to about 0.001 to about 100 mg/kg body weight/day of compound 1 (e.g., about 0.5 to about 100 mg/kg of compound 1) can be administered to a subject receiving these compositions.
  • dosages equivalent to 1 mg/kg and 1000 mg/kg of compound 1 every 4 to 120 hours is also acceptable.
  • the dose refers to the amount of compound 1 in the particular crystalline form. The amount of the particular crystalline form will be calculated based on the equivalence to the free-base form of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose of equivalent to about 2 mg to about 3000 mg of compound 1.
  • the dose is oral dose.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 2 mg to about 3000 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 5 mg to about 350 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 5 mg to about 200 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 5 mg to about 100 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 5 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 10 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 15 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 20 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 30 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 40 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 45 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 50 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 60 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 70 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 80 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 90 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 100 mg of compound 1. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 110 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated equivalent to about 120 mg of compound 1.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of compound 1 per day.
  • crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg to about 500 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg to about 200 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg to about 10 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose of about 15 mg equivalent to compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 20 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 25 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 30 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 35 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 40 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 45 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 50 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 60 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 70 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 80 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 90 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 100 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 110 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 120 mg of compound 1 per day. In certain embodiments, a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated
  • crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 130 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 140 mg of compound 1 per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 150 mg of compound 1 per day. Dosing can be once, twice, or three times daily.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg of compound 1 twice per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 20 mg of compound 1 twice per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 50 mg of compound 1 twice per day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 100 mg of compound 1 twice per day.
  • a disclosed crystalline (e.g.g.) or amorphous form is formulated for administration at a dose equivalent to about 100 mg of compound 1 twice per day.
  • crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 5 mg of compound 1 once every other day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 20 mg of compound 1 once every other day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 50 mg of compound 1 once every other day.
  • a disclosed crystalline (e.g. crystalline Form A) or amorphous form is formulated for administration at a dose equivalent to about 100 mg of compound 1 once every other day.
  • a disclosed form (crystalline Form A, B, C, D, E, F, G, H, I, J, the crystalline free-base, or the amorphous form) is formulated as a tablet composition together with a pharmaceutically acceptable carrier.
  • the carrier is selected from one or more of microcrystalline cellulose, mannitol, Croscarmellose Sodium, and Sodium Stearyl Fumarate.
  • the carrier is microcrystalline cellulose e.g., present in an amount of 50% w/w to 70% w/w ( ⁇ 2%), 55% w/w to 65% w/w ( ⁇ 2%), 58% w/w to 62% w/w ( ⁇ 2%), 59% w/w ( ⁇ 2%), 60% w/w ( ⁇ 2%), 61% w/w ( ⁇ 2%), 62% w/w ( ⁇ 2%), 61% w/w, or 62% w/w.
  • the carrier is mannitol e.g., present in an amount of 15% w/w ( ⁇ 2%) to 35% w/w ( ⁇ 2%), 20% w/w ( ⁇ 2%) to 30% w/w ( ⁇ 2%), 22% w/w ( ⁇ 2%) to 26% w/w ( ⁇ 2%), 22% w/w ( ⁇ 2%), 23% w/w ( ⁇ 2%), 24% w/w ( ⁇ 2%), or 23% w/w.
  • the carrier is croscarmellose sodium e.g., present in an amount of 1% w/w to 5% w/w ( ⁇ 2%), 2% w/w to 4% w/w ( ⁇ 2%), 2% w/w ( ⁇ 2%), 3% w/w ( ⁇ 2%), 4% w/w ( ⁇ 2%) or 3% w/w.
  • the carrier is stearyl fumarate e.g., present in an amount of 1% w/w to 5% w/w ( ⁇ 2%), 2% w/w to 4% w/w ( ⁇ 2%), 1% w/w ( ⁇ 2%), 2% w/w ( ⁇ 2%), 3% w/w ( ⁇ 2%) or 2% w/w.
  • crystalline form A is present in the tablet composition in an amount equivalent to about 1 to about 200 mg of compound 1.
  • crystalline form A is present in the tablet composition in an amount equivalent to about 1 to about 150 mg of compound 1.
  • crystalline form A is present in the tablet composition in an amount equivalent to about 1 to about 100 mg of compound 1.
  • crystalline form A is present in the tablet composition in an amount equivalent to about 5 mg of compound 1. In some embodiments, crystalline form A is present in the tablet composition in an amount equivalent to about 20 mg of compound 1. In some embodiments, crystalline form A is present in the tablet composition in an amount equivalent to about 50 mg of compound 1. In some embodiments, crystalline form A is present in the tablet composition in an amount equivalent to about 75 mg of compound 1. In some embodiments, crystalline form A is present in a tablet composition in an amount equivalent to about 100 mg of compound 1.
  • the dose amount of crystalline Form A, B, C, D, E, F, G, H, I, J, or the amorphous form is based on the equivalence to the free-base form of compound 1.
  • “crystalline form A present in the composition in an amount equivalent to about 1.0 mg of compound 1” means about 1.18 mg of crystalline Form A is present in the composition and is equivalent to about 1.0 mg of free base compound 1.
  • the tablet composition comprises 10% w/w (( ⁇ 1%) of the crystalline free-base; 62% w/w ( ⁇ 2%) microcrystalline cellulose; 23% w/w ( ⁇ 2%) mannitol, 3% w/w ( ⁇ 2%) croscarmellose sodium, and 2% w/w ( ⁇ 2%) stearyl fumarate.
  • the tablet composition comprises 11.78% w/w ( ⁇ 1%) of crystalline Form A; 62% w/w ( ⁇ 2%) microcrystalline cellulose; 23% w/w ( ⁇ 2%) mannitol; 3% w/w ( ⁇ 2%) croscarmellose sodium; and 2% w/w ( ⁇ 2%) stearyl fumarate.
  • a pharmaceutical composition comprising the crystalline Form A is substantially free of Compound IM-l and/or Compound IM-2 (see Exemplification).
  • the pharmaceutical composition comprising Form A is substantially free of other crystal forms of the hemisulfate salt of compound 1.
  • the one or more carriers are processed to generate particles of a consistent size.
  • processing the powder i.e., crystalline Form A
  • processing the powder comprises milling the powder for an amount of time suitable to bring about a desired particle size (“milled powder”).
  • the particle size of the milled powder is less than about 400 pm.
  • the particle size of the milled powder is less than about 300 pm.
  • the particle size of the milled powder is less than about 200 pm.
  • the particle size of the milled powder is less than about 100 pm.
  • the particle size of the milled powder is less than about 90 pm. In some embodiments, the particle size of the milled powder is less than about 80 pm. In some embodiments, the particle size of the milled powder is less than about 70 pm. In some embodiments, the particle size of the milled powder is less than about 60 pm. In some embodiments, the particle size of the milled powder is less than about 50 pm. In some embodiments, the particle size of the milled powder is less than about 40 pm. In some embodiments, the particle size of the milled powder is less than about 30 pm. In some embodiments, the particle size of the milled powder is less than about 20 pm.
  • the particle size of the milled powder ranges from about 10 pm to about 400 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 300 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 200 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 100 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 80 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 70 pm. In some embodiments, the particle size of the milled powder ranges from about 10 pm to about 60 pm.
  • the particle size of the milled powder ranges from about 20 pm to about 60 pm.
  • the term“about,” as used herein with respect to particle size, means +/- 5 pm.
  • at least 90% of a representative sample of the milled powder has a particle size of less than about 100, about 80, about 70, about 60, about 50, about 40, about 30, about 20, or about 10 pm. In some embodiments, at least about 90% of a representative sample of the milled powder has a particle size of less than about 60 pm.
  • the crystalline and amorphous forms described herein and compositions thereof are allosteric activators of PKR, and are generally useful for treating the underlying condition of PKD.
  • PWD Pyruvate Kinase Deficiency
  • methods of treating Pyruvate Kinase Deficiency (PKD) in a subject in need thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof in the manufacture of a medicament for treating Pyruvate Kinase Deficiency (PKD).
  • PPD Pyruvate Kinase Deficiency
  • Exemplified conditions related to PKD include, but are not limited to, anemias, cholecystolithiasis, gallstones, tachycardia, hemochromatosis, icteric sclera, splenomegaly, leg ulcers, jaundice, fatigue, and shortness of breath.
  • anemias cholecystolithiasis
  • gallstones tachycardia
  • hemochromatosis icteric sclera
  • splenomegaly leg ulcers, jaundice, fatigue, and shortness of breath.
  • PKD is a deficiency of PKR.
  • the deficiency of PKR is associated with a PKR mutation.
  • Pyruvate kinase deficiency is a glycolytic enzymopathy that results in life long hemolytic anemia.
  • the subject having PKD is a patient having at least 2 mutant alleles in PKLR gene.
  • the subject having PKD is a patient having at least 2 mutant alleles in PKLR gene and at least one is a missense mutation. See Canu. et.al , Blood Cells, Molecules and Diseases 2016, 57, pp. 100-109.
  • a subject having PKD has an Hb concentration less than or equal to 10.0 g/dL.
  • the subject having PKD is an adult not under regular transfusion (e.g. having had no more than 4 transfusion episodes in the l2-month period up to the treatment). In certain embodiments, the subject having PKD is an adult transfusion independent (e.g. having no more than 3 units of RBCs transfused in the l2-month period prior to the treatment). In certain embodiments, the subject having PKD is an adult under regular transfusion (e.g. having had at least 4 transfusion episodes (e.g., at least 6 transfusion episodes) in the l2-month period prior to the treatment). In certain embodiments, the subject having PKD has a total number of at least 5 transfusion episodes during the subject’s lifetime.
  • the subject having PKD has a total number of at least 10 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 15 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 20 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 25 transfusion episodes during the subject’s lifetime. In certain
  • the subject having PKD has a total number of at least 30 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 40 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 30 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 40 transfusion episodes during the subject’s lifetime. In certain
  • the subject having PKD has a total number of at least 50 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 60 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 50 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD has a total number of at least 60 transfusion episodes during the subject’s lifetime. In certain
  • the subject having PKD has a total number of at least 70 transfusion episodes during the subject’s lifetime. In certain embodiments, the subject having PKD is not homozygous for the R479H mutation or does not have 2 non-missense mutations in the PKLR gene. In certain embodiments, the subject having PKD, under regular transfusion, has hemoglobin (Hb) ⁇ 12.0 g/dL (if male) or ⁇ 11.0 g/dL (if female), prior to the treatment. In certain embodiments, the subject having PKD, under regular transfusion, has transfusion occurring on average less than or equal to once every three weeks. In certain embodiments, the subject having PKD has received at least 0.8 mg (e.g.
  • the subject with PKD under regular transfusion achieves a reduction in transfusion burden (e.g. at least 33% reduction in the number of RBC units transfused) during the 5 weeks, 10 weeks, 15 weeks,
  • the subject having PKD not under regular transfusion (having had no more than 4 transfusion episodes in the l2-month period prior to the treatment and/or no transfusion in the 3 months prior to the treatment), has hemoglobin (Hb) ⁇ 10.0 g/dL regardless of gender prior to the treatment.
  • the subject having PKD has undergone splenectomy.
  • the subject with PKD achieves a hemoglobin response of at least 1.0 g/dL increase in Hb concentration after the treatment compared to the baseline of prior to the treatment. In certain embodiments, the subject with PKD achieves a hemoglobin response of at least 1.5 g/dL increase in Hb concentration from baseline prior to the treatment. In certain embodiments, the subject with PKD achieves a hemoglobin response of at least 2.0 g/dL increase in Hb concentration from baseline prior to the treatment.
  • the mutant PKR is selected from the group consisting of A3 IV, A36G, G37Q, R40W, R40Q, L73P, S80P, P82H, R86P, I90N, T93I, G95R, M107T, G111R, A115P, S120F, H121Q, S130P, S130Y, V134D, R135D, A137T, G143S, I153T, A154T, L155P, G159V, R163C, R163L, T164N, G165V, L167M, G169G, E172Q, W201R, I219T, A221Y, D221N, G222A, I224T, G232C, N253D, G263R, G263W, E266K, V269F, L272V, L272P, G275R, G275R, E277K, V280G, D281N, F287V, F2
  • the mutant PKR is selected from G332S, G364D, T384M, K410E, R479H, R479K, R486W, R532W, R510Q, and R490W.
  • the mutant PKR is selected from A468V, A495V, I90N, T408I, and Q421K, and R498H.
  • the mutant PKR is R532W, K410E, or R510Q.
  • the mutant PKR is R510Q, R486W, or R479H.
  • a disease selected from hemolytic anemia, sickle cell disease, thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, Bassen- Komzweig syndrome, and paroxysmal nocturnal hemoglobinuria in a subject in need thereof, comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof.
  • disease selected from hemolytic anemia, sickle cell disease, thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, Bassen- Komzweig syndrome, and paroxysmal nocturnal hemoglobinuria in a subject.
  • disease selected from hemolytic anemia, sickle cell disease, thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalip
  • the disease to be treated is hemolytic anemia.
  • thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia
  • methods for treating thalassemia comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a
  • thalassemia e.g., beta-thalassemia or non-transfusion-dependent thalassemia
  • thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia
  • methods for treating thalassemia comprising administering to the subject an effective amount of crystalline Form A, or a pharmaceutical composition thereof.
  • crystalline Form A or a pharmaceutical composition thereof for use in treating thalassemia e.g., beta-thalassemia or non-transfusion- dependent thalassemia.
  • thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia.
  • thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia
  • methods for treating thalassemia comprising administering to the subject an effective amount of crystalline Form D, or a pharmaceutical composition thereof.
  • crystalline Form D, or a pharmaceutical composition thereof for use in treating thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia.
  • crystalline Form D, or a pharmaceutical composition thereof for use in treating thalassemia (e.g., beta- thalassemia or non-transfusion-dependent thalassemia).
  • the subject is an adult subject with thalassemia.
  • the subject has thalassemia such as b-thalassemia intermedia, Hb E b- thalassemia, a-thalassemia (Hb H disease), or b-thalassemia with mutations of 1 or more a genes.
  • the subject has beta- thalassemia or non-transfusion-dependent thalassemia.
  • the subject is an adult male subject with thalassemia such as beta-thalassemia or non-transfusion-dependent thalassemia.
  • the subject is a female subject with thalassemia such as beta-thalassemia or non-transfusion- dependent thalassemia. In certain embodiments, the subject is an adult female subject with thalassemia such as beta-thalassemia or non-transfusion-dependent thalassemia. In certain embodiments, the subject has a hemoglobin concentration of less than or equal to 6.0 g/dL. In certain embodiments, the subject has a hemoglobin concentration of less than or equal to 7.0 g/dL. In certain embodiments, the subject has a hemoglobin concentration of less than or equal to 8.0 g/dL. In certain embodiments, the subject has a hemoglobin concentration of less than or equal to 9.0 g/dL.
  • the subject having non-transfusion-dependent thalassemia does not have a known history (e.g., has been diagnosed in the past) of Hb S or Hb C forms of thalassemia.
  • the term“non-transfusion dependent” thalassemia refers to subjects with thalassemia having no more than 4 (e.g. five) units of RBCs transfused during a 24-week period up to the first day of administration of a crystalline or amorphous form described herein and/or no RBC transfusions in the 8 weeks prior to the first day of administration of a crystalline or amorphous form described herein.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof for use in increasing the lifetime of red blood cells (RBCs) in a subject in need thereof.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof in the manufacture of a medicament for increasing the lifetime of red blood cells (RBCs).
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof is added directly to whole blood or packed red blood cells
  • methods for regulating 2,3- diphosphoglycerate levels in blood in a subject in need thereof comprising contacting blood with an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof for use in regulating 2,3- diphosphoglycerate levels in blood in a subject in need thereof.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G,
  • the anemia to be treated is dyserythropoietic anemia.
  • the anemia is a dyserythropoietic anemia such as congenital dyserythropoietic anemia type I, II, III, or IV.
  • the anemia is hemolytic anemia.
  • the hemolytic anemia is a congenital and/or hereditary form of hemolytic anemia such as PKD, sickle cell disease, thalassemias (e.g. alpha or beta or non-transfusion-dependent thalassemia), hereditary spherocytosis, hereditary elliptocytosis), paroxysmal nocturnal hemoglobinuria, abeta-liproteinemia (Bassen- Komzweig syndrome).
  • PKD a dyserythropoietic anemia
  • thalassemias e.g. alpha or beta or non-transfusion-dependent thalassemia
  • hereditary spherocytosis e.g. alpha or beta or non-transfusion-dependent thalassemia
  • the hemolytic anemia is acquired hemolytic anemia such as autoimmune hemolytic anemia, drug-induced hemolytic anemia.
  • the hemolytic anemia is anemia as part of a multi-system disease, such as the anemia of Congenital Erythropoietic Purpura, Fanconi, Diamond-Blackfan.
  • the term“anemia” refers to a deficiency of red blood cells (RBCs) and/or hemoglobin.
  • anemia includes all types of clinical anemia, for example (but not limited to): microcytic anemia, iron deficiency anemia, hemoglobinopathies, heme synthesis defect, globin synthesis defect, sideroblastic defect, normocytic anemia, anemia of chronic disease, aplastic anemia, hemolytic anemia, macrocytic anemia, megaloblastic anemia, pernicious anemia, dimorphic anemia, anemia of prematurity, Fanconi anemia, hereditary spherocytosis, sickle cell disease, warm autoimmune hemolytic anemia, cold agglutinin hemolytic anemia, osteopetrosis, thalassemia, and myelodysplastic syndrome.
  • anemia can be diagnosed on a complete blood count. In certain embodiments, anemia can be diagnosed based on the measurement of one or more markers of hemolysis (e.g. RBC count, hemoglobin, reticulocytes, schistocytes, lactate Dehydrogenase (LDH), haptoglobin, bilirubin, and ferritin) and/or hemosiderinuria mean corpuscular volume (MCV) and/or red cell distribution width (RDW).
  • hemolysis e.g. RBC count, hemoglobin, reticulocytes, schistocytes, lactate Dehydrogenase (LDH), haptoglobin, bilirubin, and ferritin
  • MCV mean corpuscular volume
  • RW red cell distribution width
  • anemia is present if an individual has a hemoglobin (Hb) less than the desired level, for example, the Hb concentration of less than 14 g/dL, more preferably of less than 13 g/dL, more preferably of less than 12 g/dL, more preferably of less than 11 g/dL, or most preferably of less than 10 g/dL.
  • Hb hemoglobin
  • provided herein is a method of increasing the amount of hemoglobin in a subject by administering an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a
  • compositions thereof as described herein are also provided herein.
  • a method of increasing the amount of hemoglobin in a subject having thalassemia comprising administering to the subject an effective amount of crystalline Form
  • a method of increasing the amount of hemoglobin in subjects having non-transfusion- dependent thalassemia comprising administering an effective amount of crystalline Form A,
  • the provided methods increase hemoglobin concentration in the subject.
  • the provided methods increase Hb concentration to a desired level, for example, above 10 g/dL, more preferably above 11 g/dL, more preferably above 12 g/dL, more preferably above 13 g/dL, or most preferably above 14 g/dL.
  • the provided methods increase Hb concentration by at least about 0.5 g/dL.
  • the provided methods increase Hb concentration by at least about 1.0 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 1.5 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 2.0 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 2.5 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 3.0 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 3.5 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 4.0 g/dL. In certain embodiments,
  • the provided methods increase Hb concentration by at least about 4.5 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 5.0 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 5.5 g/dL. In certain embodiments, the provided methods increase Hb concentration by at least about 6.0 g/dL.
  • the increase in Hb concentration is determined from baseline at one or more assessment between week 1 and week 20 (e.g., between week 2 and week 15, between week 3 and week 15, and between week 4 and week 12) of treatment with an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J, or the crystalline free base or amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof as described herein.
  • the provided methods increase Hb concentration as described above in female subjects having thalassemia (e.g., beta- thalassemia or non-transfusion-dependent thalassemia).
  • the provided methods increase Hb concentration from baseline to about 12 g/dL in female subjects having thalassemia (e.g., beta-thalassemia or non-transfusion- dependent thalassemia). In certain embodiments, the provided methods increase Hb concentration as described above in male subjects having thalassemia (e.g., beta-thalassemia or non-transfusion-dependent thalassemia). In certain embodiments, the provided methods increase Hb concentration from baseline to about 13 g/dL in male subjects having thalassemia (e.g., beta-thalassemia or non-transfusion-dependent thalassemia). In certain embodiments, the provided methods increase Hb concentration from baseline to about 13 g/dL in male subjects having
  • thalassemia e.g., beta- thalassemia or non-transfusion-dependent thalassemia.
  • provided herein are methods for treating hemolytic anemia in a subject in need thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof for use in treating hemolytic anemia in a subject in need thereof.
  • the hemolytic anemia to be treated is hereditary and/or congenital hemolytic anemia, acquired hemolytic anemia, or anemia as part of a multi-system disease.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof for use in treating sickle cell disease in a subject in need thereof.
  • kits for treating thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia or Bassen-Kornzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, or anemia of chronic diseases in a subject in need thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof in the manufacture of a medicament for treating thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia or Bassen- Komzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, or anemia.
  • methods for activating wild-type or mutant PKR in red blood cells in a subject in need thereof comprising administering to the subject an effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof. Also provided is crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof for use in activating wild-type or mutant PKR in red blood cells in a subject in need thereof.
  • crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof in the manufacture of a medicament for activating wild-type or mutant PKR in red blood cells.
  • the provided crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), and pharmaceutical compositions described herein are activators of PKR mutants having lower activities compared to the wild type, thus are useful for methods of the present disclosure.
  • Such mutations in PKR can affect enzyme activity (catalytic efficiency), regulatory properties (modulation by fructose bisphosphate
  • thermostability of the enzyme examples include G332S, G364D, T384M, R479H, R479K, R486W, R532W, R510Q, and R490W.
  • the compounds described herein affect the activities of PKR mutants by activating FBP non- responsive PKR mutants, restoring thermostability to mutants with decreased stability, or restoring catalytic efficiency to impaired mutants.
  • the activating activity of the present compounds against PKR mutants may be tested following a method described in the
  • the provided crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), and pharmaceutical compositions described herein increase the affinity of PKR to phosphoenolpyruvate (PEP).
  • the provided crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), and pharmaceutical compositions described herein restore the ability of RBCs to cover PEP and ADP to pyruvate and ATP.
  • transfusion frequency of a subject with PKD comprising administering to the subject crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), and pharmaceutical compositions described herein.
  • crystalline Form A is administered.
  • the transfusion frequency is reduced by at least 5% in the number of RBC units transfused over at least 15 weeks.
  • the transfusion frequency is reduced by at least 10% in the number of RBC units transfused over at least 15 weeks.
  • the transfusion frequency is reduced by at least 15% in the number of RBC units transfused over at least 15 weeks.
  • the transfusion frequency is reduced by at least 20% in the number of RBC units transfused over at least 15 weeks. In certain embodiments, the transfusion frequency is reduced by at least 25% in the number of RBC units transfused over at least 15 weeks. In certain embodiments, the transfusion frequency is reduced by at least 30% in the number of RBC units transfused over at least 15 weeks. In certain embodiments, the transfusion frequency is reduced by at least 35% in the number of RBC units transfused over at least 15 weeks. In certain embodiments, the transfusion frequency is reduced by at least 40% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 5% in the number of RBC units transfused over at least 20 weeks.
  • the transfusion frequency is reduced by at least 10% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 15% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 20% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 25% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 30% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 35% in the number of RBC units transfused over at least 20 weeks. In certain embodiments, the transfusion frequency is reduced by at least 40% in the number of RBC units transfused over at least 20 weeks.
  • a value for the level of the crystalline or amorphous form is acquired by analyzing the plasma concentration of crystalline or amorphous form.
  • the level of 2,3-DPG is acquired by analyzing the blood concentration of 2,3-DPG.
  • the level of ATP is acquired by analyzing the blood concentration of ATP.
  • the activity of PKR is acquired by analyzing the blood concentration of a
  • the analysis is performed by sample analysis of bodily fluid.
  • the bodily fluid is blood.
  • the analysis is performed by mass spectroscopy.
  • the analysis is performed by LC-MS.
  • acquiring comprises receiving a sample from the subject.
  • acquiring comprises transmitting the value to another party.
  • the other party is the party that administered crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof.
  • methods of treating a subject comprising: administering to the subject a therapeutically effective amount of crystalline Form A, B, C, D, E, F, G, H, I, or J or the amorphous Form of the compound of formula (I), or a pharmaceutical composition thereof; and acquiring a value for the level of the crystalline or amorphous form, the level of 2,3-diphosphoglycerate (2,3-DPG), the level of adenosine triphosphate (ATP), or the activity of PKR in the subject, to thereby treat the subject.
  • kits for treating Pyruvate Kinase Deficiency (PKD) in a subject in need thereof comprising administering to the subject an effective amount of crystalline free-base form of Compound 1 or a pharmaceutical composition thereof.
  • the deficiency of PKR is associated with a PKR mutation.
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof for use in treating Pyruvate Kinase Deficiency (PKD) in a subject in need thereof.
  • PTD Pyruvate Kinase Deficiency
  • a disease selected from hemolytic anemia, sickle cell anemia, thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, Bassen- Komzweig syndrome, and paroxysmal nocturnal hemoglobinuria in a subject in need thereof, comprising administering to the subject an effective amount of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof.
  • the disease to be treated is hemolytic anemia.
  • provided herein are methods for treating hemolytic anemia, comprising administering to the subject an effective amount of crystalline free -base form of Compound 1, or a pharmaceutical composition thereof. Also provided is crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, for use in treating hemolytic anemia in a subject in need thereof. Further provided is the use of crystalline free -base form of Compound 1, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating hemolytic anemia.
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof for use in treating sickle cell disease in a subject in need thereof.
  • use of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating sickle cell disease is also provided.
  • thalassemia e.g., beta- thalassemia
  • methods for treating thalassemia comprising administering to the subject an effective amount of crystalline free- base form of Compound 1, or a pharmaceutical composition thereof.
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof for use in treating thalassemia (e.g., beta- thalassemia) in a subject in need thereof.
  • use of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof in the manufacture of a medicament for treating thalassemia (e.g., beta-thalassemia).
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof is added directly to whole blood or packed red blood cells extracorporeally.
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof for use in increasing the lifetime of red blood cells (RBCs) in a subject in need thereof.
  • provided herein are methods for regulating 2,3- diphosphoglycerate levels in blood in a subject in need thereof comprising contacting blood with an effective amount of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof. Also provided is crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, for use in regulating 2,3-diphosphoglycerate levels in blood in a subject in need thereof. Further provided is the use of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, in the manufacture of a medicament for regulating 2,3-diphosphoglycerate levels in blood.
  • provided herein are methods for treating anemia in a subject in need thereof comprising administering to the subject an effective amount of crystalline free- base form of Compound 1, or a pharmaceutical composition thereof.
  • the anemia to be treated is dyserythropoietic anemia.
  • crystalline free-base form of Compound 1, or a pharmaceutical composition thereof for use in treating anemia in blood in a subject in need thereof.
  • provided herein is a method of increasing the amount of hemoglobin in a subject by administering an effective amount of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof. Also provided is crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, for use in increasing the amount of hemoglobin in a subject in need thereof. Further provided is the use of crystalline free-base form of Compound 1, or a pharmaceutical composition thereof, in the manufacture of a medicament for increasing the amount of hemoglobin.
  • a therapeutically effective amount of a disclosed form is a therapeutically effective amount of a disclosed form
  • crystalline Form A, B, C, D, E, F, G, H, I, J, the crystalline free-base, or the amorphous form can be administered to cells in culture, e.g. in vitro or ex vivo , or to a subject, e.g., in vivo , to treat, prevent, and/or diagnose a variety of disorders, including those described herein below.
  • the disclosed compositions, methods of treatment, and uses thereof comprising a disclosed form (crystalline Form A, B, C, D, E, F, G, H, I, J, the crystalline free-base, or the amorphous form) further comprise the administration or use of folic acid.
  • the administration or use of folic acid can be prior to, during, and/or following the administration or use of a crystalline or amorphous form described herein. In one aspect, however, the folic acid is administered or used prior to and/or concurrently with a disclosed form (crystalline Form A, B, C, D, E, F, G, H, I, J, the crystalline free-base, or the amorphous form).
  • a method for treating a condition described herein e.g., PKD, anemia such as hemolytic anemia, acquired hemolytic anemia, and sickle cell anemia, thalassemia (e.g., beta-thalassemia, alpha- thalassemia, non-transfusion dependent thalassemia, etc.), sickle cell disease, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, Bassen- Komzweig syndrome, and paroxysmal nocturnal hemoglobinuria); increasing the lifetime of RBCs; regulating 2,3-diphosphoglycerate levels in blood; activating wild-type or mutant PKR in red blood cells; increasing the amount of hemoglobin; evaluating the level of 2,3-diphosphoglycerate (2,3-DPG), the level of adenosine triphosphate (ATP), or the activity of PKR; evaluating the level of 2,3- di
  • the folic acid may be used at least 5 days, at least 10 days, at least 15 days, at least 20 days, or at least 25 days prior to the administration or use of disclosed form.
  • the folic acid is administered or used at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25 days prior to the administration or use of disclosed form.
  • the folic acid is administered at least 21 days prior to the administration or use of disclosed form.
  • the folic acid is administered or used from 1 to 30 days prior to the administration or use of disclosed form. In another aspect, the folic acid is administered or used from 5 to 25 days prior to the administration or use of disclosed form. In another aspect, the folic acid is administered or used from 10 to 30 days prior to the administration or use of disclosed form. In another aspect, the folic acid is administered or used from 10 to 25 days prior to the administration or use of disclosed form. In another aspect, the folic acid is administered or used from 15 to 25 days prior to the administration or use of disclosed form. In another aspect, the folic acid is administered or used from 20 to 25 days prior to the administration or use of disclosed form.
  • folic acid to be administered or used with a disclosed form will vary depending upon the subject to be treated and the particular mode of administration.
  • the effective amount of folic acid is about 0.1 mg to about 10 mg daily.
  • the effective amount of folic acid is at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,
  • the effective amount of folic acid is at least 0.8 mg daily or at least 1.0 mg daily.
  • a condition described herein e.g., PKD, anemia such as hemolytic anemia, acquired hemolytic anemia, and sickle cell anemia, thalassemia (e.g., beta- thalassemia, alpha- thalassemia, non-transfusion dependent thalassemia, etc.), sickle cell disease, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, Bassen- Komzweig syndrome, and paroxysmal nocturnal hemoglobinuria); increasing the lifetime of RBCs; regulating 2,3- diphosphoglycerate levels in blood; activating wild-type or mutant PKR in red blood cells; increasing the amount of hemoglobin; evaluating the level of 2,3-diphosphoglycerate (2,3- DPG), the level of
  • Powder X-ray diffraction was done using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. A typical scan is from 2Q of 4 to 30 degrees, with step size
  • a high-resolution scan is from 2Q of 4 to 40 degrees, with step size 0.05 degrees over thirty minutes with 40 kV and 15 mA.
  • Typical parameters for XRPD are listed below.
  • Thermogravimetric analysis and differential scanning calorimetry was done using a Mettler Toledo TGA/DSC 3+ .
  • the desired amount of sample is weighed directly in a hermetic aluminum pan with pin-hole.
  • a typical sample mass for the measurement is 5-10 mg.
  • a typical temperature range is 30 °C to 300 °C at a heating rate of 10 °C per minute (total time of 27 minutes).
  • Protective and purge gasses are nitrogen (20 - 30 mL/min and 50 - 100 mL/min). Typical parameters for DSC/TGA are listed below.
  • DVS Dynamic Vapor Sorption
  • the sample is loaded into a sample pan and suspended from a microbalance.
  • a typical sample mass for DVS measurement is 25 mg. Nitrogen gas bubbled through distilled water provides the desired relative humidity.
  • a typical measurement comprises the steps:
  • Karl Fischer titration for water determination was done using a 785 DMP Titrino and 703 Ti Stand equipped with 6.0338.100 double platinum wire electrodes. Samples are dissolved in HPLC grade or anhydrous methanol and titrated with Hydranal-Composite 5. A typical sample mass for the measurement is 0.03 - 0.10 g. Hydranal 1 wt.% water standard is used for calibration.
  • Compound 1 i.e., the non-crystalline free base, can be prepared following the procedures described below.
  • the first impurity is Compound IM- 1 (about 0.11% area percent based on representative HPLC) with the following structure:
  • the second impurity is Compound IM-2 (about 0.07% area percent based on the representative HPLC) with the following structure:
  • Solubility measurements were done by gravimetric method in 20 different solvents at two temperatures (23 °C and 50 °C). About 20-30 mg of Form A, the synthesis of which is described below, was weighed and 0.75 mL solvent was added to form a slurry. The slurry was then stirred for two days at the specified temperature. The vial was centrifuged and the supernatant was collected for solubility measurement through gravimetric method. The saturated supernatant was transferred into pre- weighed 2 mL HPLC vials and weighed again (vial + liquid). The uncapped vial was then left on a 50 °C hot plate to slowly evaporate the solvent overnight.
  • MeOFFwater (1:1) system the room temperature solubility were 208 mg/mL, 118, 39 and 5 for 0 vol%, 1%, 2.5% and 5%, respectively. Therefore, just adding 5 vol% water decreased the solubility 42 fold.
  • Three solvent compositions were used as MeOFFWater (99:lvol), (98:2) and (95:5). About 25mg of Form A was weighed into 2 mL vial and 6 volume solvent was added, then slowly heated to dissolve. For experiment with 5% water, an additional test was conducted with 8 vol solvents. See Table 3. Table 2
  • Pattern A Solids from the slurry of solubility measurement experiments were collected for XRPD analysis, shown in Table 5. Pattern A remained unchanged in most solvent systems over the course of two days slurry. In some cases, it lost its crystallinity indicating that stirring longer would possibly change the form. Three new patterns were observed: Pattern B in EtOH at RT and 50 °C; Pattern A + C in IPA at RT; Pattern D in IPA and acetonitrile at 50 °C. Pattern D + crystalline free-base in IPA:DMSO (8:2) at 50 °C.
  • FB-A refers to the crystalline free base form of Compound 1
  • Anti-solvent experiments were conducted to further study the polymorphic behavior of the Form A.
  • the Anti-solvent was added to a solution of 20-25 mg Form A dissolved in 3 volume MeOH with 25 pL increments every time.
  • the solution was added to 6 volume anti-solvent at once. The experiments were performed at RT. The results are shown in Table 14. Only in MeOH/EtOH system solids were generated during the course of experiments.
  • Salt formation was conducted by slurrying Compound 1, i.e., the non-crystalline free base in various solvents followed by adding sulfuric acid solution in EtOAc.
  • a sulfuric solution in EtOAc was prepared (concentration approximately 24 wt.%).
  • 25 to 30 mg of non-crystalline free base of Compound 1 was weighed in a 2 mL vial, followed by adding 15 vol solvent. The desired number of equivalents of sulfuric acid were then added.
  • the slurries were heated to 45 °C and held for 1 hour and then cooled down to RT over 2 hours, then held overnight.
  • the slurry was filtered and then analyzed by XRPD. The results was shown in Table 16.
  • FB-A refers to the crystalline free-base form of Compound 1
  • the hemisulfate was also formed in MeOAc:MeOH (1:1) mixture with and without water.
  • Hemisulfate salt formation was also conducted by slurrying Compound 1 in methanol followed by adding sulfuric acid solution in water (43 wt% aq.). About 100 mg Compound 1, the non-crystalline free base, was weighed in a 4 mL vial, followed by adding 6 vol solvent. 0.52 equivalents of sulfuric acid solution in water (concentration approximately 43wt.%) was then added which resulted in complete dissolution at room temperature. For experiment 1, one volume water was added dropwise first, tiny amount of Pattern A was added as seeds, then 5 volume water was added over 1 hour; for experiment 2, no water was added, both Patterns A and B were added as seeds; for experiment 3, six volume water was added over 2 hours, no seed. All vials were stirred overnight (O/N). The slurry was filtered and then analyzed by XRPD. Yield was about 80% for the experiment with adding water and about 60% for the experiment without adding water, refer to Table 18.
  • Hemisulfate salt formation was also performed in methanol:water (95:5) by using freebase and sulfuric acid.
  • About 150 mg of Compound 1 was weighed into 4 mL vial and 8 volume solvent was added. The mixture was stirred at 500 rpm and then 0.52 eq. sulfuric acid solution in water (concentration approximately 43 wt.%) was added. This mixture was heated to 45 °C which resulted in complete dissolution followed by adding 0.5 volume water, then cooled to RT and held O/N. This resulted in a flowable slurry. 3.5 vol water was then added and filtered. XRPD analysis showed Pattern A. Yield was about 84%. Refer to Table 19.
  • Hemisulfate salt was produced at 2 gram scale as detailed below.
  • the resulting solid was hemisulfate salt Form A.
  • the yield was about 88%.
  • N-(4-(4-(cyclopropylmethyl)piperazine-l- carbonyl)phenyl)quinoline-8-sulfonamide (5) (111.0 g, 246.4 mmol)
  • a pre-mixed process solvent of ethanol (638.6 g), toluene (266.1 g) and water (159.6 g).
  • the suspension was stirred and heated above 60°C to dissolve the solids, and then the resulting solution was cooled to 50°C.
  • Patterns B, D, E, F were reproducible.
  • Pattern G was reproduced at lower crystallinity.
  • Pattern I was reproduced, although, it was missing a few peaks. Refer to Table 20.
  • Form B can be prepared by slurrying Form A in about 10 volumes ethanol at room temperature for a number of days until Form B is obtained.
  • Form B is typically dried Drying at 50 °C under vacuum.
  • Other methods of forming Form B are described above, e.g., in Tables 5, 6, 12-14, 18, and 20.
  • Form C is formed as a mixture with Form A after slurrying Form A in IPA for 2 days at about 23 °C. See e.g., Table 5.
  • XRPD peaks for Form C are obtained from subtracting the Form A peaks.
  • Form D is formed by adding 15 vol acetonitrile and then 0.52 eq. sulfuric acid to compound 1 and heating the mixture to 50 °C. The mixture is then held at 50 °C for 30 mins and cooled to RT. The resulting product, Form D, is then Filtered and dried.
  • Form A can be slurried in IPA or acetonitrile at more than 50 °C for at least 2 days to convert to Form D. The latter method was not as robust as the first procedure in which freebase is used. Additional methods are described above, e.g., in Tables 5, 6, 9, 16, and 20.
  • Form E can be prepared by adding 24 volume acetonitrile: water (2:1) to Form A and heating the mixture to 50 °C to dissolve the material. The solution is then cooled to -20 °C and left overnight. The resulting product, Form E, is then filtered. See e.g., Table 8 and
  • Form F can be prepared by drying Form E at 50 °C under vacuum. See e.g., Table 20. Additional methods are described above, e.g., in Tables 8 and 12.
  • Form G can be prepared by adding 72 volume acetonitrile: water (8:2) to Form A and then heating the mixture to 50 °C to dissolve the solids. The solution is then rapidly cooled to -20 °C and left overnight to produce Form G. See e.g., Table 20. Additional methods are described above, e.g., in Table 13.
  • Form H can be prepared by dissolved Form A in 40 volume MeOFFEtOAc (1:1) at 50 °C, and then placing the solution in ice to crash cool the solution and then cooling the solution to -20 °C. The resulting precipitate, Form H, is then filtered and analyzed as wet cake. See e.g., Table 20. Reproducing Pattern H resulted in an amorphous like solid which does not have peaks of Form H. Additional methods are described above, e.g., in Tables 13.
  • Form I is a possible solvate that can be prepared by adding 15 volumes of ethanol to compound 1 and heating the mixture to 45 °C to obtain a slurry. 0.52 eq. sulfuric acid in EtOAc is then added and the mixture is held for 1 hr then cooled to room temperature over 2 hours, held for 1 hr and filtered. The product, Form I, is then dried at 50 °C and vacuum. See e.g., Tables 16 and 20.
  • Form J can be formed by adding compound 1 and 6 volume MeOAc:MeOH (1:1) at room temperature. 0.52 eq. of sulfuric acid diluted to 43 wt% in water is then added. The slurry is then heated to 60 °C to dissolve the mixture, and the solution is cooled to RT and filtered. Form J is was obtained as wet cake, which converts to Form A upon drying. See e.g., Table 17.
  • the crystalline free-base form of Compound 1 can be prepared via the following method.
  • Patterns B and D converted to Pattern A after two days slurry.
  • Pattern D also converted to Pattern A within 1 hour slurry in Fasted state simulated gastric fluid (FaSSGF) or water. Only in Fasted State Simulated Intestinal Fluid (FaSSIF), Patterns A and B disproportionated to crystalline free base after two days slurry and showed lower solubility. Pattern D, however, did not disproportionate in FaSSIF and instead converted to Pattern D.
  • the solubility in water and the simulated fluid of the three patterns were not significantly different. This could be because of the conversion of Patterns B and D to Pattern A.
  • the solubility data and the resulting XRPD Pattern after the measurement are reported in Table 21.
  • FB means crystalline free base of compound 1.
  • Pattern A was stable in the solvents that contained water.
  • Pattern D was stable in anhydrous systems especially at higher temperatures. It appears that Pattern D which is anhydrous solid is the most stable solid when anhydrous organic solvents are used. See Table 22.
  • Form A has been formulated into a tablet either through direct compression of the direct blend formulation or via a dry granulation or wet granulation process.
  • Other excipients can be added, such as binders, and/or surfactants, and coating films to aid tablet integrity, taste masking and aesthetics.
  • An exemplified tablet composition is as follows:
  • TGA of Form A showed about 4.5% weight loss up to 180 °C. See FIG. 2.
  • the water content by Karl Fisher was about 5.3%.
  • Two thermal events were observed in DSC thermogram with the first peak at 159.9 °C and the second peak at 199.1 °C. See FIG. 3.
  • the first peak also showed a shoulder.
  • Dynamic vapor sorption of salt Form A at 25 °C showed that the solid picks up about 1.3% moisture from 2% to 95% relative humidity.
  • the DVS showed a rapid weight loss at humidity of less than 10% which was reversible upon sorption cycle.
  • a DVS isotherm taken at 40 °C was essentially the same as the one at 25°C.
  • the XRPD remained unchanged after DVS at both temperatures.
  • Form B tends to hold substantial amount of solvent.
  • TGA data did not correspond to the NMR data for organic solvent, which could be due to hygroscopic nature of Form B. See e.g., FIG. 7.
  • the DVS of Form B showed the solid picks up about 14% moisture between 2% and 95% relative humidity.
  • Form D was determined to be anhydrous with a melting peak at 239 °C. See e.g., FIG. 9.
  • DVS of Pattern D was performed and solid picked up about 2% moisture from 2% to 95% relative humidity. See FIG. 10.
  • the XRPD pattern remained unchanged after DVS and one week exposure to 75% relative humidity at 40 °C also did not change the form.
  • a 1 mg/mL standard solution in DMSO: methanol (20:80, v/v) was diluted in 50 fold and subsequently serial diluted in 50% methanol water. Aliquots (10 m ⁇ ) of the serial dilutions were mixed with 190 ul of control plasma for use as a standard curve. Plasma samples (50 m ⁇ ) and standard samples (non-diluted) were diluted lOx with ice cold
  • LC 7.5 pl of each sample and standard were injected onto a Waters BEH C18 (2.1x50 mm, 1.7 pm, maintained at 60 °C) column at 0.6 mL/min by an UPLC. The column was equilibrated at 10% acetonitrile. Compounds were eluted with a gradient to 95% acetonitrile. All mobile phase contained 0.025% (v/v) formic acid with 1 mM ammonium acetate.
  • MS Colum n eluent was analyzed by electrospray ionization into a triple quadruple mass spectrometer system. Eluent composition was analyzed for ion pair specifics to the internal standard and the analyte respectively.

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PCT/US2018/062197 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide Ceased WO2019104134A1 (en)

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US16/765,456 US11254652B2 (en) 2017-11-22 2018-11-21 Crystalline forms of N-(4-(4-(cyclopropymethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
MDE20200988T MD3713919T2 (ro) 2017-11-22 2018-11-21 Forme cristaline de N-(4-(4-(ciclopropilmetil)piperazin-1-carbonil)fenil)chinolin-8-sulfonamidă
FIEP18821779.8T FI3713919T3 (fi) 2017-11-22 2018-11-21 N-(4-(4-(syklopropyylimetyyli)piperatsiini-1-karbonyyli)fenyyli)kinoliini-8-sulfonamidin kiteisiä muotoja
IL322576A IL322576A (en) 2017-11-22 2018-11-21 Crystalline forms of N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
KR1020207015018A KR102682430B1 (ko) 2017-11-22 2018-11-21 N-(4-(4-(시클로프로필메틸)피페라진-1-카르보닐)페닐)퀴놀린-8-술폰아미드의 결정 형태
RS20230793A RS64592B1 (sr) 2017-11-22 2018-11-21 Kristalne forme n-(4-(4-(ciklopropilmetil)piperazin-1-karbonil)fenil) hinolin-8-sulfonamida
AU2018373122A AU2018373122B2 (en) 2017-11-22 2018-11-21 Crystalline forms of N-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
KR1020247022172A KR102777452B1 (ko) 2017-11-22 2018-11-21 N-(4-(4-(시클로프로필메틸)피페라진-1-카르보닐)페닐)퀴놀린-8-술폰아미드의결정 형태
HRP20230931TT HRP20230931T1 (hr) 2017-11-22 2018-11-21 Kristalični oblici n-(4-(4-(ciklopropilmetil)piperazin-1-karbonil)fenil)kinolin-8-sulfonamida
CN202311301795.5A CN117551030A (zh) 2017-11-22 2018-11-21 N-(4-(4-(环丙基甲基)哌嗪-1-羰基)苯基)喹啉-8-磺酰胺的结晶形式
MA50805A MA50805B1 (fr) 2017-11-22 2018-11-21 Formes cristallines de n-(4-(4-(cyclopropylméthyl) pipérazine-1-carbonyl)phényl)quinoléine-8-sulfonamide
CA3081945A CA3081945A1 (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
CN201880075099.8A CN111372920B (zh) 2017-11-22 2018-11-21 N-(4-(4-(环丙基甲基)哌嗪-1-羰基)苯基)喹啉-8-磺酰胺的结晶形式
IL305343A IL305343B1 (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
KR1020257007025A KR20250034202A (ko) 2017-11-22 2018-11-21 N-(4-(4-(시클로프로필메틸)피페라진-1-카르보닐)페닐)퀴놀린-8-술폰아미드의결정 형태
DK18821779.8T DK3713919T3 (da) 2017-11-22 2018-11-21 Krystallinske former af n-(4-(4-(cyclopropylmethyl)piperazin-1-carbonyl)phenyl)quinolin-8-sulfonamid
ES18821779T ES2959764T3 (es) 2017-11-22 2018-11-21 Formas cristalinas de n-(4-(4-(ciclopropilmetil) piperazina-1-carbonil)fenil)quinolina-8-sulfonamida
UAA202003680A UA127502C2 (uk) 2017-11-22 2018-11-21 Кристалічні форми n-(4-(4-(циклопропілметил)піперазин-1-карбоніл)феніл)хінолін-8-сульфонаміду
EP23186155.0A EP4285904A3 (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
SI201830984T SI3713919T1 (sl) 2017-11-22 2018-11-21 Kristalinične oblike n-(4-(4-(ciklopropilmetil)piperazin-1-karbonil) fenil)kinolin-8-sulfonamida
JP2020528129A JP7275130B2 (ja) 2017-11-22 2018-11-21 Ｎ－（４－（４－（シクロプロピルメチル）ピペラジン－１－カルボニル）フェニル）キノリン－８－スルホンアミドの結晶性形態
MX2020005348A MX2020005348A (es) 2017-11-22 2018-11-21 Formas cristalinas de la n-(4-(4-(ciclopropilmetil)piperazin-1-car bonil)fenil)quinolin-8-sulfonamida.
SG11202004587XA SG11202004587XA (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
SM20230327T SMT202300327T1 (it) 2017-11-22 2018-11-21 Forme cristalline di n-(4-(4-(ciclopropilmetil) piperazin-1-carbonil)fenil)chinolina-8-solfonammide
EA202091277A EA202091277A1 (ru) 2018-06-29 2018-11-21 Кристаллические формы n-(4-(4-(циклопропилметил)пиперазин-1-карбонил)фенил)хинолин-8-сульфонамида
EP18821779.8A EP3713919B1 (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
PL18821779.8T PL3713919T3 (pl) 2017-11-22 2018-11-21 Formy krystaliczne n-(4-(4-(cyklopropylometylo)piperazyno-1-karbonylo)fenylo)chinolino-8-sulfonoamidu
LTEPPCT/US2018/062197T LT3713919T (lt) 2017-11-22 2018-11-21 Kristalinės n-(4-(4-(ciklopropilmetil)piperazin-1-karbonil)fenil)chinolin-8- sulfonamido formos
BR112020010185-0A BR112020010185A2 (pt) 2017-11-22 2018-11-21 Formas cristalinas de n-(4-(4- (ciclopropilmetil)piperazina-1-carbonil)fenil)quinolina-8- sulfonamida
IL274488A IL274488B2 (en) 2017-11-22 2018-11-21 Crystalline forms of n-(4-(4-(cyclopropylmethyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
PH12020550644A PH12020550644A1 (en) 2017-11-22 2020-05-15 Crystalline forms of n-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
US17/575,898 US20220220093A1 (en) 2017-11-22 2022-01-14 Crystalline forms of n-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
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WO2024084501A1 (en) 2022-10-17 2024-04-25 Mylan Laboratories Limited Crystalline polymorphs of mitapivat and mitapivat hemisulfate
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