Use of a PK activator in the treatment of sickle cell disease

Abstract

Provided herein are methods of treating sickle cell disease comprising orally administering Compound 1: or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, at specific doses.

Description

USE OF A PK ACTIVATOR IN THE TREATMENT OF SICKLE CELL DISEASERELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 570,365, filed on March 27, 2024 and U.S. Provisional Application No. 63 / 684,515, filed on August 19, 2024. The entire contents of the foregoing applications are expressly incorporated herein by referenceBACKGROUND

[0002] Sickle cell disease (SCD) is a monogenetic red blood disorder that is characterized by hemolytic anemia and vaso-occlusive crises (VOCs), which may also be referred to as sickle cell pain crises (SCPCs). Among the many factors that contribute to disease pathophysiology is stiffening and sickling of red blood cells (RBCs), which is the direct result of the formation of abnormal hemoglobin S. Sickling is one of the core factors that cause vaso-occlusion and sickling is modulated by glycolytic intermediates such as 2,3- diphosphoglycerate (2,3 -DPG) and adenosine triphosphate (ATP). It has been shown that red blood cell pyruvate kinase (PKR), an isoform of Pyruvate Kinase (PK) and one of the key regulatory enzymes of glycolysis, is impaired in SCD and that ex -vivo treatment with allosteric activators of PK increases enzymatic activity and thermostability, reduces 2,3 -DPG levels, decreases hemoglobin oxygen affinity (p50,) and subsequently reduced sickling (See, Rab et al., Blood, volume 138, supplement 1, 23 November 2021, page 2029).

[0003] 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4,6- dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one, herein referred to as Compound 1 or AG-946, is a potent activator of PK and is currently in Phase 2 clinical studies for its use in subjects with anemia due to Lower-Risk Myelodysplastic Syndromes (LR-MDS). AG-946 was also investigated in a Phase 1 study to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers, and then subsequently tested in the same Phase 1 trial to determine its safety, tolerability, pharmacokinetics and pharmacodynamics in subjects with sickle cell disease. See e.g., U.S. clinical trials identifiers NCT05490446 and NCT04536792, respectively. It is important to note that the Phase 1 trial of AG-946 in healthy volunteers and the Phase lb study in SCD patients, like most Phase 1 trials, were designed to determine the safety not the efficacy of AG-946. The efficacy of AG-946 in patients with SCD will be investigated in a future Phase 2 clinical trial.SUMMARY

[0004] Provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 to treat sickle cell disease in a subject.

[0005] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for increasing hemoglobin concentration in subjects with sickle cell disease.

[0006] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing hemolysis in subjects with sickle cell disease.

[0007] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing one or more markers of hemolysis in subjects with sickle cell disease.

[0008] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing lactate dehydrogenase (LDH) in subjects with sickle cell disease.

[0009] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing cell-free heme concentration in subjects with sickle cell disease.

[0010] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing indirect bilirubin in subjects with sickle cell disease.

[0011] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing the percentage of reticulocytes (% reticulocyte) in subjects with sickle cell disease.

[0012] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing the number or frequency of VOC (vaso-occlusive crisis) events in subjects with sickle cell disease.

[0013] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing the number or frequency of sickle cell pain crisis (SCPC) events in subjects with sickle cell disease.

[0014] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for treating anemia in subjects with sickle cell disease.

[0015] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for improving the quality of life (QoL) in subjects with sickle cell disease.

[0016] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing fatigue in subjects with sickle cell disease.

[0017] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing at least one marker of erythropoiesis in subjects with sickle cell disease.

[0018] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing hemolysis in subjects with sickle cell disease.

[0019] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for reducing erythropoietin in subjects with sickle cell disease.

[0020] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for increasing adenosine triphosphate (ATP) concentration in subjects with sickle cell disease.

[0021] Also provided herein are methods of using a dose of about 1 mg to about 30 mg of Compound 1 for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration in subjects with sickle cell disease.

[0022] In some aspects, a pharmaceutical composition comprising Compound 1 is used in any of the provided methods and / or uses described herein.

[0023] In some aspects, a solvate of Compound 1, a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1, a pharmaceutically acceptable salt of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is used in any of the provided methods and / or uses described herein.

[0024] In some aspects, the amount of a solvate of Compound 1, the amount of a pharmaceutically acceptable salt of Compound 1 or the amount of a solvate of a pharmaceutically acceptable salt of Compound 1 used in any of the provided methods and / or uses described herein is a dose that is equivalent to a dose of about 1 mg to about 30 mg of Compound 1.BRIEF DESCRIPTION OF THE FIGURES

[0025] FIG. 1A depicts the hemoglobin change in patients (cohort 1) after a 2 mg daily dose of Compound 1.

[0026] FIG. IB depicts the hemoglobin change in patients (cohort 2) after a 5 mg daily dose of Compound 1.

[0027] FIG. 2A depicts the percent (%) change in lactate dehydrogenase (LDH), indirect bilirubin, reticulocytes, and erythropoietin in patients (cohort 1) after a 2 mg daily dose of Compound 1.

[0028] FIG. 2B depicts the percent change in lactate dehydrogenase (LDH), indirect bilirubin, reticulocytes, and erythropoietin in patients (cohort 2) after a 5 mg daily dose of Compound 1.

[0029] FIG. 3 shows the change in hemoglobin in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.

[0030] FIG. 4 shows the percent (%) change in the % of reticulocytes (% reticulocyte) in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.

[0031] FIG. 5 shows the percent (%) reduction in LDH in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.

[0032] FIG. 6A depicts the change in Pyruvate Kinase R (PKR) activation after ex vivo treatment with Compound 1 or another PK activator (mitapivat).

[0033] FIG. 6B depicts the change in PKR thermostability after ex vivo treatment with Compound 1 or mitapivat.

[0034] FIG. 7A depicts the reduction in 2,3 diphosphoglyceric acid (2,3 DPG) after ex vivo treatment with Compound 1 or mitapivat.

[0035] FIG. 7B depicts the change in adenosine triphosphate (ATP) / 2,3 DPG ratio after ex vivo treatment with Compound 1 or mitapivat.

[0036] FIG. 8A depicts the reduction in p50 after ex vivo treatment with Compound 1 or mitapivat.

[0037] FIG. 8B depicts the reduction in PoS after ex vivo treatment with Compound 1 or mitapivat.DETAILED DESCRIPTION

[0038] In one aspect, provided herein are methods of treating sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising a dose of about 1 mg to about 30 mg of Compound 1) to a subject. In other aspects, provided herein are methods of treating sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to a subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. Inother aspects, provided herein are methods of treating sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to a subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods of treating sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to a subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods of treating sickle cell disease in a subject comprise orally administering a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for treating sickle cell disease in a subject comprise orally administering a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). When used in this context, and as further recited below, “or a pharmaceutical composition comprising any of the foregoing refers to a pharmaceutical composition comprising the recited dosage amount of Compound 1, or a pharmaceutical composition comprising an amount of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising an amount of a solvate of Compound 1, or a pharmaceutical composition comprising an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to the recited dosage amount of Compound 1.

[0039] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for treating sickle cell disease in a subject. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt ofCompound 1) for treating sickle cell disease in a subject, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for treating sickle cell disease in a subject, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for treating sickle cell disease in a subject, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the dose used for treating sickle cell disease in a subject is about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the dose used for treating sickle cell disease in a subject is about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound that is equivalent to a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0040] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of anoral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1.

[0041] In one aspect, provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orallyadministering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the dose for increasing hemoglobin concentration in a subject with sickle cell disease is about 1 mg to about 10 mg of Compound 1, or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the dose for increasing hemoglobin concentration in a subject with sickle cell disease is about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the concentration of hemoglobin in a subject prior to orally administering any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the any of the foregoing).

[0042] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. Inother aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the dose for increasing the concentration of hemoglobin in a subject is about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the dose for increasing the concentration of hemoglobin in a subject is about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the concentration of hemoglobin in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0043] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound1) for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the concentration of hemoglobin in a subject prior to the oral administration or oral use of any amount of Compound 1 or any amount of a pharmaceutically acceptable salt of Compound 1, or any amount of a solvate of Compound 1, or any amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0044] In one aspect, provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1) to the subject. In other aspects, provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1)to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing hemolysis in a subject comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing hemolysis in a subject comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of hemolysis in a subject prior to orally administering any dose of Compound 1, or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0045] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical compositioncomprising a pharmaceutically acceptable salt of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use of a dose for reducing hemolysis in a subject comprises about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use of a dose for reducing hemolysis in a subject comprises about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of hemolysis in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0046] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable saltof Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of hemolysis in a subject prior to the oral administration or oral use of any dose of Compound 1, or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0047] In one aspect, provided herein are methods for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceuticalcomposition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing lactate dehydrogenase (LDH) in a subject comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing lactate dehydrogenase (LDH) in a subject comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of LDH in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0048] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a solvate of Compound 1) for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, reducing lactate dehydrogenase (LDH) in a subject comprises the use of a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising the any of the foregoing). In another aspect, reducing lactate dehydrogenase (LDH) in a subject comprises the use of a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of LDH in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceuticallyacceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0049] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament for reducing lactate dehydrogenase (LDH) is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament for reducing lactate dehydrogenase (LDH) is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that isequivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of LDH in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0050] In one aspect, provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing cell-free heme comprises administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing cell -free heme comprises administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or anamount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of cell-free heme in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0051] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, reducing cell-free heme in a subject comprises the use of a dose of about 1 mg to about 10 mg of Compound 1, or the use of an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, reducing cell-free heme in a subject comprises the use of a doseof about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or the use of an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of cell-free heme in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0052] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing cell- free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament for reducing cell-free heme in a subject is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate ofCompound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament for reducing cell-free heme in a subject is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of cell-free heme in a subject prior to the oral administration or oral use of any dose of Compound 1, or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the any of the foregoing).

[0053] In one aspect, provided herein are methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalentto about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events in a subject comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing the number or frequency of VOC (vaso-occlusive crisis) events in a subject comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of VOC events in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0054] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of apharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for reducing the number or frequency of VOC (vasoocclusive crisis) events comprises a dose of about 1 mg to about 10 mg of Compound 1, or the use of an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for reducing the number or frequency of VOC (vaso-occlusive crisis) events comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or the use of an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of VOC events in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0055] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the number or frequency of VOC events in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0056] In one aspect, provided herein are methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptablesalt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of SCPC events in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0057] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of sickle cell pain (SCPC) crisis events as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect the use for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect the use for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of SCPC events in a subject prior to the oral use ofany dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0058] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or anamount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the number or frequency of SCPC events in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0059] In one aspect, provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that isequivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year or for reducing the number of prescriptions for opioids or other pain medications per year or for reducing the number of days of opioid use or use of other pain medications per year comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year or for reducing the number of prescriptions for opioids or other pain medications per year or for reducing the number of days of opioid use or use of other pain medications per year comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of hospital visits for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). Additionally, as used inthis paragraph, baseline refers to the number of prescriptions for opioids or other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). Furthermore, as used in this paragraph, baseline refers to the number of days of opioid use or use of other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0060] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of otherpain medications per year as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for reducing the number or frequency of hospitalization visits for treatment of VOCs (vasoocclusive crisis) or sickle cell pain crisis (SCPC) events per year or for reducing the number of prescriptions for opioids or other pain medications per year or for reducing the number of days of opioid use or use of other pain medications per year comprise the administration of a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year or for reducing the number of prescriptions for opioids or other pain medications per year or for reducing the number of days of opioid use or use of other pain medications per year comprise the administration of a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the number or frequency of hospitalization visits for treatment of VOCs or SCPC events per year in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of apharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). Additionally, as used in this paragraph, baseline refers to the number of prescriptions for opioids or other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). Furthermore, as used in this paragraph, baseline refers to the number of days of opioid use or use of other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0061] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of hospitalization visits for treatment of VOCs (vasoocclusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of anoral medicament for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the number or frequency of hospitalization visits for treatment of VOCs or SCPC events per year in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).Additionally, as used in this paragraph, baseline refers to the number of prescriptions for opioids or other pain medications for the treatment of VOCs or SCPC events per year in asubject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). Furthermore, as used in this paragraph, baseline refers to the number of days of opioid use or use of other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0062] In one aspect, provided herein are methods for treating anemia in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for treating anemia in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for treating anemia in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for treating anemia in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for treating anemia in a subject with sickle cell disease comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or apharmaceutical composition comprising any of the foregoing). In another aspect, the methods for treating anemia in a subject with sickle cell disease comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0063] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for treating anemia in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for treating anemia in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for treating anemia in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for treating anemia in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for treating anemia in a subject with sickle cell disease comprises administration of a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for treating anemia in a subject with sickle cell disease comprises administration of a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that isequivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0064] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for treating anemia in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for treating anemia in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for treating anemia in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for treating anemia in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.

[0065] In one aspect, provided herein are methods for improving the quality of life (QoL) as compared to baseline in a subject with sickle cell disease comprising orally administering adose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for improving the quality of life as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for improving the quality of life as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for improving the quality of life as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for improving the quality of life (QoL) comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for improving the quality of life (QoL) comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the quality of life (QoL) in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of apharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0066] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for improving the quality of life (QoL) as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for improving the quality of life in a subject comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for improving the quality of life in a subject comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the quality of life (QoL) in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any doseof a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0067] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for improving the quality of life as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the quality of life (QoL) in a subject prior to the oraladministration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0068] In one aspect, provided herein are methods for reducing fatigue in a subject with sickle cell disease as compared to baseline comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing fatigue in a subject with sickle cell disease as compared to baseline comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing fatigue in a subject with sickle cell disease as compared to baseline comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing fatigue in a subject with sickle cell disease as compared to baseline comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing fatigue comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing fatigue comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg orabout 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of fatigue in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0069] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing fatigue as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for reducing fatigue comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for reducing fatigue comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg orabout 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of fatigue in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0070] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceuticallyacceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of fatigue in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0071] In one aspect, provided herein are methods for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing one or more markers of hemolysis comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or apharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing one or more markers of hemolysis comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0072] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for reducing one or more markers of hemolysis comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvateof Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for reducing one or more markers of hemolysis comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0073] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein themedicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0074] In one aspect, provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceuticalcomposition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for reducing erythropoietin comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for reducing erythropoietin comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of erythropoietin in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0075] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or apharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for reducing erythropoietin comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for reducing erythropoietin comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the level of erythropoietin in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0076] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of asolvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the level of erythropoietin in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0077] In one aspect, provided herein are methods for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering adose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for increasing adenosine triphosphate (ATP) concentration comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for increasing adenosine triphosphate (ATP) concentration comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the ATP concentration in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0078] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sicklecell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for increasing adenosine triphosphate (ATP) concentration is a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for increasing adenosine triphosphate (ATP) concentration is a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the ATP concentration in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0079] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical compositioncomprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the ATP concentration in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0080] In one aspect, provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell diseasecomprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject. In other aspects, provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the 2,3 DPG concentration in a subject prior to the oral administration of any dose of Compound 1 or any dose of apharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0081] In one aspect, provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease. In other aspects, provided herein is the oral use of a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising an amount of a solvate of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the use for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing). In another aspect, the use for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or apharmaceutical composition comprising any of the foregoing). As used in this paragraph, baseline refers to the 2,3 DPG concentration in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0082] In one aspect, provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In other aspects, provided herein is the use of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1. In another aspect, the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1. In another aspect, themedicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1. As used in this paragraph, baseline refers to the concentration of 2,3 DPG in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).

[0083] As described in certain aspects, the provided methods and uses comprise increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease. In some aspects, the subject’s hemoglobin concentration increases about 1.0 g / dL (grams per deciliter) or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In other aspects, the subject’s hemoglobin concentration increases about 1.5 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 2.0 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 2.5 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical compositioncomprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 3.0 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 3.5 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases by an amount of about 1.0 g / dL to about 3.5 g / dL as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 45 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). As used herein, “after about x days to about y days” refers to the time period between (and including) day x and day y of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 30 days of administration of Compound 1, ora pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 1.0 g / dL or more as compared to baseline after about 1 day to about 45 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 1.0 g / dL or more as compared to baseline after about 8 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 1.5 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 2.0 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvateof Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 2.5 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 3.0 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s hemoglobin concentration increases about 3.5 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject has a baseline hemoglobin concentration of at least about 5.5 g / dL. In some aspects, subject has a baseline hemoglobin concentration of about 10.5 g / dL. In some aspects, the subject has a baseline hemoglobin concentration of about 5.0 g / dL to about 11.0 g / dL. In some aspects, the subject has a baseline hemoglobin concentration of about 5.5 g / dL to about 10.5 g / dL. In some aspects, the subject has a baseline hemoglobin concentration of about 5.0 g / dL to about 9.0 g / dL.

[0084] As used herein, the term “baseline” refers to a level or concentration of a particular analyte or marker that is measured or established prior to treatment with, or prior to administration of, or at a specific time-point or over a certain period of time (e.g., an average of measurements over a certain period of time) during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In someaspects, a baseline may be a single measurement that is taken prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a baseline may be based on an average of two or more measurements that are taken over a certain period of time, for example, such as one or more weeks apart, prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). For example, when used in connection with a subject’s hemoglobin (Hb) concentration, the subject’s baseline hemoglobin (Hb) concentration is measured or established prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject’s baseline hemoglobin concentration is based on an average of at least 2 Hb concentration measurements (separated by >7 days) prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject’s baseline hemoglobin concentration may be measured or established during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). Other analytes or markers that may involve determining, measuring and / or establishing a baseline include, but are not limited to, adenosine triphosphate (ATP), 2,3 diphosphoglyceric acid (2,3-DPG), lactate dehydrogenase(LDH), cell-free heme, VOC or sickle cell pain crisis (SCPC) events, hemolysis (and various markers of hemolysis, such as, indirect bilirubin, % reticulocyte, and / or erythropoietin), erythropoiesis or markers of erythropoiesis, quality of life (QoL), fatigue and the six minute walking test (6MWT).

[0085] In some aspects, the hemoglobin concentration of the subject being treated increases as compared to baseline over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In other aspects, the hemoglobin concentration of the subject being treated increases as compared to baseline over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0086] As described in certain aspects, the provided methods and uses comprise reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease. In some aspects, the one or more markers of hemolysis are selected from lactate dehydrogenase (LDH), indirect bilirubin, and percent reticulocyte (% reticulocyte). As used herein, a reduction in one or more hemolysis markers (i.e., lactate dehydrogenase, indirect bilirubin, and % reticulocyte) is a reduction of the amounts of one or more of these analytes in the blood of the subject as compared to baseline. In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvateof Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 30% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In someaspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 20% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 40% to about 55% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis ischaracterized by a reduction in the subject’s % reticulocyte of about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, one or more markers of hemolysis is reduced in the subject by about 30% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, one or more markers of hemolysis is reduced in the subject by about 30% to about 40% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, one or more markers of hemolysis is reduced in the subject by about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the one or more hemolysis markers are measured in the blood of the subject.

[0087] As described in certain aspects, the provided methods and uses comprise reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease. In some aspects, the subject’s lactate dehydrogenase is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s lactate dehydrogenase is reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s lactate dehydrogenase is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s lactate dehydrogenase is reduced by about 30% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s lactate dehydrogenase is reduced by about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0088] As described in certain aspects, the provided methods and uses comprise reducing cell-free heme as compared to baseline in a subject with sickle cell disease. As used herein,“free heme” or “free hemoglobin” or “naked hemoglobin” are used interchangeably herein and refer to unbound hemoglobin that is not enclosed in a red blood cell. Free heme may be generated by hemolysis as a pathological feature of sickle cell disease. Generated in sufficient enough quantity, free heme can overwhelm protective mechanisms such as haptoglobin and hemopexin. Free heme in excess of what can be scavenged by the body’s protective mechanisms can have serious and deleterious effects on health and well-being (See, Gbotosho et al., Front. Immunol., 26 January 2021, vol. 11).

[0089] In some aspects, the subject’s cell-free heme concentration is reduced by about 10% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s cell-free heme concentration is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s cell-free heme concentration is reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s cell-free heme concentration is reduced by about 10% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s cell-free heme concentration is reduced by about 30% to about 40% as compared to baseline following administration of Compound 1, or a pharmaceuticallyacceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s cell-free heme concentration is reduced to less than or equal to about 5 mg / dL following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the concentration of cell-free heme in a subject’s plasma may be determined as described in Exp Biol Med (Maywood). 2023 May; 248(10): 897-907.

[0090] As described in certain aspects, the provided methods and uses comprise reducing the number or frequency of VOCs (vaso-occlusive crises) events as compared to baseline in a subject with sickle cell disease following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). The terms “vaso-occlusive crisis” or “VOC” or “vaso-occlusive crises” or “VOCs” or “vasoocclusive crisis event (VOC event)” or “vaso-occlusive crisis events (VOC events)” are used interchangeably herein and refer to acute episodes of pain with no cause other than a vasoocclusive event that requires a medical facility visit (including a hospital, an emergency room, or clinic) and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and / or priapism requiring a visit to a medical facility for treatment are also considered VOCs. In some aspects, the number or frequency of VOCs are reduced by about 30% or more as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of VOCs are reduced by about 40% or more as compared to baseline in a subjectfollowing administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of VOCs are reduced by about 50% or more as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of VOCs are reduced by about 30% to about 80% as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of VOCs are reduced by about 50% to about 90% as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of the subject’s VOCs are reduced by about 30% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the measurement of the number or frequency of VOC events is measured over the course of one year. In some aspects, a subject may have a VOC baseline of zero (0) VOCs per year. In some aspects, a subject may have a VOC baseline of at least one (1) VOC per year. In some aspects, a subject may have a VOC baseline of zero (0) to three (3) VOCs per year. In some aspects, a subjectmay have a VOC baseline of one (1) to three (3) VOCs per year. In some aspects, a subject may have a VOC baseline of less than six (6) VOCs per year. In some aspects, a subject may have a VOC baseline of at least six (6) VOCs per year. In some aspects, a subject may have a VOC baseline of less than ten (10) VOCs per year. In some aspects, a subject may have a VOC baseline of two (2) VOCs to ten (10) VOCs per year. In some aspects, a subject may have a VOC baseline of at least ten (10) VOCs per year. In some aspects, a subject may have a VOC baseline of ten (10) VOCs to twelve (12) VOCs per year. In some aspects, a subject may have a VOC baseline of less than twelve (12) VOCs per year. In some aspects, a subject may have a VOC baseline of twelve (12) VOCs or more per year. In certain aspects, the VOC baseline is an average of the VOC events per year over a two-year period. In another aspect, the VOC baseline is an average of the VOC events per year over a three-year period. In another aspect, the VOC baseline is an average of the VOC events per year over a five-year period. In another aspect, the VOC baseline is an average of the VOC events per year over a ten-year period.

[0091] As used herein, “at least x”, “x or more”, and “less than x” means “x and values greater than x”, “x and values greater than x”, and “x and values less than x”, respectively.

[0092] As described in certain aspects, the provided methods and uses comprise reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease. The terms “sickle cell pain crisis” or “(SCPC)” or “sickle cell pain crises” or “(SCPCs)” or “sickle cell pain crisis events” or “(SCPC) events” or “pain crisis events” or “sickle cell pain crisis event” or “(SCPC) event” are used interchangeably herein and refer to an acute and / or sudden episode of pain caused when sickle-shaped red blood cells impede or block the body’s blood vessels and slows or prevents blood and oxygen from flowing. In some aspects, the subject experiences acute pain, chronic pain or both. In some aspects, acute pain comes on suddenly and lasts for a relatively short period of time. In some aspects, chronic pain is daily on-going pain lasting up to six months. In some aspects, the pain persists for up to several hours. In some aspects, the pain persists for up to several weeks. In some aspects, the pain persists for up to a month. In some aspects, the pain persists for a month or longer. In some aspects, a sickle cell pain crisis event requires a visit to a medical facility (including a hospital, an emergency room, or clinic) and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and / or priapism (requiring a visit to a medical facility) are also considered sickle cell pain crisis events. In some aspects, the subject has a reduction in thenumber or frequency of hospitalization visits per annum (per year) for treatment of sickle cell pain crisis events. In some aspects, a sickle cell pain crisis event comprises pain in one or more of the hands, feet, chest, arms, backjoints, or legs of the subject. In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 50% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptablesalt of Compound 1). In some aspects, the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 30% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the measurement of the number or frequency of SCPC events is measured over the course of one year. In some aspects, a subject may have a SCPC events baseline of zero (0) SCPC events per year. In some aspects, a subject may have a SCPC events baseline of zero (0) or one (1) SCPC events per year (e.g., zero (0) or one (1) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a SCPC events baseline of at least one (1) SCPC event per year (e.g., at least one (1) SCPC in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a SCPC events baseline of at least two (2) SCPC events per year (e.g., at least two (2) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a SCPC events baseline of zero (0) to three (3) SCPC events per year (e.g., zero (0) to three (3) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a SCPC events baseline of one (1) to three (3) SCPC events per year (e.g., one (1) to three (3) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of less than six (6) sickle cell pain crisis events per year (e.g., less than six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of at least six (6)sickle cell pain crisis events per year (e.g., at least six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of less than ten (10) sickle cell pain crisis events per year (e.g., less than ten (10) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of no more than six (6) sickle cell pain crisis events per year (e.g., no more than six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of no more than eight (8) sickle cell pain crisis events per year (e.g., no more than eight (8) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of no more than ten (10) sickle cell pain crisis events per year (e.g., no more than ten (10) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of no more than twelve (12) sickle cell pain crisis events per year (e.g., no more than twelve (12) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of between two (2) sickle cell pain crisis events to ten (10) sickle cell pain crisis events per year (e.g., between two (2) sickle cell pain crisis events to ten (10) sickle cell pain crisis in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of at least ten (10) sickle cell pain crisis events per year (e.g., at least ten (10) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate ofCompound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of between ten (10) sickle cell pain crisis events to twelve (12) sickle cell pain crisis events per year (e.g., between ten (10) sickle cell pain crisis events to twelve (12) sickle cell pain crisis in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of at least twelve (12) sickle cell pain crisis events per year (e.g., at least twelve (12) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject may have a sickle cell pain crisis events baseline of twelve (12) sickle cell pain crisis events or more per year (e.g., twelve (12) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In certain aspects, the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a two-year period. In another aspect, the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a three-year period. In another aspect the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a five-year period. In another aspect the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a ten-year period.

[0093] In some aspects, a subject has a reduction in the number or frequency of opioid prescriptions requested or filled per year as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, a subject has a reduction in the number of days taking an opioid medication per year as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable saltof Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). As used herein, every permutation of the terms listed above to denote vaso-occlusive crisis events or VOC(s) and / or sickle cell pain crisis events or SCPC(s) are all used interchangeably herein and any of these terms may be freely substituted for any of the others.

[0094] As described in certain aspects, the provided methods and uses comprise treating anemia in a subject with sickle cell disease comprising administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0095] As used herein, the term “anemia” refers to a deficiency of red blood cells (RBCs) and / or hemoglobin. In some aspects, anemia may be diagnosed using a complete blood count (CBC). In some aspects, anemia may be diagnosed by measuring the amount of red blood cells in the blood, called hematocrit, and the level of hemoglobin in the blood. In some aspects, anemia may be diagnosed by measuring and / or analyzing one or more of the following: red blood cell count, hemoglobin concentration, iron, ferritin, reticulocytes and a blood smear. In certain aspects, anemia may be diagnosed based on the measurement of one or more markers of hemolysis (e.g., RBC count, hemoglobin, reticulocytes, schistocytes, Lactate Dehydrogenase (LDH), haptoglobin, indirect bilirubin, erythropoietin and ferritin) and / or via hemosiderinuria (the presence of hemosiderin in urine), mean corpuscular volume (MCV) and / or red cell distribution width (RDW). In some aspects, the anemia treated by the described methods and uses is dyserythropoietic anemia. In some aspects, the anemia treated by the described methods and uses is hemolytic anemia. In some aspects, the reduction of or improvement in a subject’s anemia following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is compared to baseline.

[0096] As described in certain aspects, the provided methods and uses comprise improving the quality of life (QoL) of a subject with sickle cell disease as compared to baseline following treatment with or administration of Compound 1, or a pharmaceuticallyacceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, improving the quality of life of a subject comprises improving the overall feeling and function of the subject as compared to baseline. In some aspects, improving the quality of life of a subject comprises a reduction of one or more symptoms such as shortness of breath, fatigue, tiredness, dizziness, pain, rapid heartbeat, eyesight problems, fussiness, and weakness as compared to baseline. In some aspects, a subject’s quality of life can be measured using one or more of the following assessments: the six minute walking test (6MWT), Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F), Adult Sickle Cell Quality of Life Measurement (ASCQ-Me-), Patient-Reported Outcome Measurement Information System® (PROMIS), Patient-Reported Outcomes Measurements Information System (PROMIS) Pain Intensity, Adult Sickle Cell Quality of Life Measurements Information System (ASCQ-Me-) Pain Impact, Patient-Reported Outcomes Measurements Information System (PROMIS) Physical Function, Patient Global Impressions of Severity and Change (PGIS and PGIC), and European Quality of Life (EuroQoL) Group 5- level EQ-5D. In certain aspects, improving the quality of life of a subject may include improvements in the six minute walking test (6MWT) as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). The 6MWT is one method available in clinical practice to assess physical capacity of a patient or subject with SCD. The main response variable of the 6MWT is the maximum walking distance (6MWD), and cardiopulmonary stress test. The 6MWT is a simple and inexpensive test that is widely used in chronic diseases such as chronic obstructive pulmonary disease and heart failure as well as SCD.

[0097] As described in certain aspects, the provided methods and uses comprise reducing fatigue as compared to baseline in a subject with sickle cell disease as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceuticallyacceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, fatigue in a subject is measured by a baseline Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F). As used herein “Functional Assessment of Chronic Illness Therapy - Fatigue Scale” or “FACIT-F” refers to 13 -item measure that assesses self-reported fatigue and its impact upon daily activities and function. The questionnaire comprises 13 questions rated on a scale of zero to four points that measures a subject’s level of fatigue during usual daily activity over the course of one week. A score of less than 22 indicates “normal” levels of fatigue. A score of between 22 and 34 indicates mild-to-moderate fatigue. A score of 35 or more indicates severe fatigue. FACIT-F has been shown to be a reliable and valid measure of fatigue in patients suffering from iron deficiency anemia (See, Acaster et al., Health and Quality of Life Outcomes (2015) 13:60).

[0098] In some aspects, fatigue in a subject is measured by a Patient Reported Outcomes Measurement Information System® (PROMIS) Fatigue assessment (e.g., PROMIS Fatigue 13a short form or “PROMIS Fatigue”). PROMIS Fatigue is a universal person-centered assessment resource and evaluates ten different factors (pain impact, pain behavior, physical functioning, anxiety, depression, fatigue, satisfaction with discretionary social activities, satisfaction with social roles, sleep disturbance, and sleep related impairment). PROMIS Fatigue scores have a mean of 50 and standard deviation (SD) of 10 in a referent population. The referent population is usually the US General Population. A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population.

[0099] In some aspects, fatigue in a subject is measured by the Adult Sickle Cell Quality of Life Measurement (ASCQ-Me-). ASCQ-Me- is a sickle cell disease specific personcentered assessment resource and evaluates six different factors (emotional impact, sleep impact, social impact, stiffness impact, pain impact, sickle cell disease pain episode frequency and severity). ASQC-Me- was designed to be a stand-alone system that could be complementary to PROMIS Fatigue (ASQC-ME USER’S MANUAL, December 2017). ASQC-Me- scores have a mean of 50 and standard deviation (SD) of 10 in a referent population. The reference population is usually the US General Population. A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population.

[0100] In some aspects, a reduction in fatigue is characterized by at least at 5-point change in a subject’s fatigue score as compared to baseline. In some aspects, a reduction in fatigue is characterized by at least at 8-point change in a subject’s fatigue score as compared to baseline. In some aspects, a reduction in fatigue is characterized by at least at 10-point change in a subject’s fatigue score as compared to baseline. In some aspects, a reduction in fatigue is characterized by a change of between 5- and 10-points in a subject’s fatigue score as compared to baseline. In some aspects, fatigue in a subject is measured using one or more of the aforementioned tests.

[0101] As described in certain aspects, the provided methods and uses comprise reducing at least one marker of erythropoiesis as compared to baseline in a subject with sickle cell disease. In some aspects, at least one marker of erythropoiesis is selected from absolute reticulocyte count, percent reticulocyte (% reticulocyte) and erythropoietin. In some aspects, the subject’s % reticulocyte is reduced about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s % reticulocyte is reduced about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s % reticulocyte is reduced about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s % reticulocyte is reduced about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable saltof Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s % reticulocyte baseline is about 5%. In some other aspects, the subject’s % reticulocyte baseline is about 10%. In some other aspects, the subject’s % reticulocyte baseline is about 15%. In some other aspects, the subject’s % reticulocyte baseline is about 20%. In some other aspects, the subject’s % reticulocyte baseline is about 25%. In some other aspects, the subject’s % reticulocyte baseline is about 5% to about 20%. In some other aspects, the subject’s % reticulocyte baseline is about 5% to about 15%. In some aspects, the subject’s erythropoietin is reduced about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s erythropoietin is reduced about 20% to about 65% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s erythropoietin is reduced about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the markers of erythropoiesis described above are measured in the blood of the subject.

[0102] As described in certain aspects, the provided methods and uses comprise reducing erythropoietin as compared to baseline in a subject with sickle cell disease. In some aspects, the subject’s erythropoietin is reduced about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptablesalt of Compound 1). In some aspects, the subject’s erythropoietin is reduced about 20% to about 65% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s erythropoietin is reduced about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0103] As described in certain aspects, the provided methods and uses comprise increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease. In some aspects, the subject’s ATP concentration is increased by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s ATP concentration is increased by about 60% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s ATP concentration is increased by about 70% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s ATP concentration is increased by about 50% to about 90% as compared to baseline following administration of Compound 1, or apharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s ATP concentration is increased by about 60% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s ATP concentration is increased by about 70% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0104] As described in certain aspects, the provided methods and uses comprise decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease. In some aspects, the subject’s 2,3 DPG concentration is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s 2,3 DPG concentration is reduced by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s 2,3 DPG concentration is reduced by about 60% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable saltof Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s 2,3 DPG concentration is reduced by about 40% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s 2,3 DPG concentration is reduced by about 50% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject’s 2,3 DPG concentration is reduced by about 60% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0105] As used herein the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, reducing the likelihood of developing, or inhibiting the progress of a condition (e.g., anemia and / or sickle cell disease) or one or more symptoms or complications of a condition or one or more complications of a condition described herein. As used herein, the terms “treatment”, “treat”, and “treating” are used interchangeably with “administer”, “administration”, and “administering.” In some aspects, treatment comprises administering Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) to the subject. Also as used herein “following treatment” or “following administration” are used interchangeably and mean the period after administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same). In some aspects,such administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) is continuous and uninterrupted, for example, once daily, every day for a period of time. In other aspects, such administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) is continuous, for example, once daily, every day for a period of time, and then such administration is discontinued for some period of time or permanently. In some aspects, symptoms of sickle cell disease may include one or more of anemia, pain, swelling of hands and feet, infections, and vision problems. In some aspects, complications of sickle cell disease may include one or more of stroke, acute chest syndrome, avascular necrosis, pulmonary hypertension, organ damage, splenic sequestration, hepatic sequestration, leg ulcers, gallstones, priapism, and deep vein thrombosis. In some aspects, treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) may be administered after one or more signs or symptoms or complications of the sickle cell disease have developed or have been observed (i.e., therapeutic treatment) or after the subject has been diagnosed with sickle cell disease by a competent medical professional. Treatment may also be continued after symptoms or complications of sickle cell disease have improved, resolved, abated or stabilized. In some aspects, treatment includes delaying the onset of at least one symptom or complication of sickle cell disease for a period of time.

[0106] As used herein, the terms “subject” and “patient” are used interchangeably and refer to a human that is 18 years of age or older. In some aspects, the terms “subject” and “patient” refer to a human that is 16 years of age or older. In some aspects, the terms “subject” and “patient” refer to a human that is 12 years of age or older.

[0107] As used herein, “2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4- methyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one” and “Compound 1” and AG-946 are used interchangeably and refer to the compound having the following chemical structure:See e.g., WO 2019 / 035865 and WO 2019 / 035864, the contents of which are incorporated herein by reference.

[0108] As described herein, the present methods and uses comprises administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1 in the same amount) or administering a dose of an amount of a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in the same amount) that is equivalent to about 1 mg to about 30 mg of Compound 1. In some aspects, a dose of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in the same amount) is administered once or twice daily. In some aspects, a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1 in the same amount) is administered once daily, or a dose of a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in the same amount) that is equivalent to about 1 mg to about 30 mg of Compound 1 is administered once daily.

[0109] In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg to about 15 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg to about 15 mg of Compound 1, once daily. In some aspects,Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at adose of about 1 mg to about 10 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg to about 10 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2.5 mg or about 5 mg or about 7.5 mg, once daily; or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg to about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), is administered at a dose that is equivalent to about 1 mg to about 5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2 mg to about 3 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2 mg to about 3 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 4 mg to about 6 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 4 mg to about 6 mg of Compound 1, oncedaily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 7 mg to about 8 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 7 mg to about 8 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical compositioncomprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2.5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2.5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 5 mg of Compound 1, once daily. In some aspects, Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 7.5 mg, once daily; or apharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 7.5 mg of Compound 1, once daily.

[0110] In some aspects, the subject is administered at least one of hydroxyurea (HU), L- glutamine and crizanlizumab for the treatment of sickle cell disease in addition to Compound 1, or a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0111] In some aspects, the subject is administered folic acid in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject is administered folic acid in an amount that is equivalent to at least about 0.8 mg / day of folic acid in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1). In some aspects, the subject is administered one or more of folic acid, hydroxyurea (HU), L-glutamine and crizanlizumab, in addition to Compound 1, or a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0112] In some aspects, the subject of the described methods and uses has been previously treated with a pyruvate kinase (PK) activator other than Compound 1 and has discontinued treatment with said PK activator prior to administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate ofa pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).

[0113] In some aspects, the present methods and uses comprise administering Compound 1 (or a pharmaceutical composition comprising Compound 1). As used herein, unless expressly stated otherwise, the term “Compound 1” refers to the non-solvated, non-salt, free base form of Compound 1.

[0114] In some aspects, the present methods and uses comprise administering a pharmaceutically acceptable salt or a solvate of a pharmaceutically acceptable salt of Compound 1. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. In some aspects, a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a stoichiometric or non-stoichiometric salt. In certain aspects, a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a stoichiometric salt. In some aspects, a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a non-stoichiometric salt. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4~ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0115] A solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 refers to Compound 1 or a pharmaceutically acceptable salt of Compound 1 comprising a stoichiometric or non-stoichiometric amount of solvent, or mixture of solvents, including organic or non-organic solvents (e.g., water). As used herein, the term “solvate” should be understood to refer to water (i.e., a hydrate) or an organic solvent. In some aspects, a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a hydrate of Compound 1 or a hydrate of a pharmaceutically acceptable salt of Compound 1. As used herein, the term “hydrate” refers to solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprising a stoichiometric or non- stoichiometric amount of water. In some aspects, a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a stoichiometric amount of solvent. In some aspects, a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a non-stoichiometric amount of solvent. In some aspects, a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a stoichiometric or non-stoichiometric amount of water. In still other aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric or stoichiometric salt and a non-stoichiometric or stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric salt and a non-stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric salt and a non-stoichiometric amount of water. In some aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a stoichiometric amount of water. In some aspects, a solvate of a pharmaceutically acceptable salt ofCompound 1 is comprised of a stoichiometric salt and a non-stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a non-stoichiometric amount of water. As used herein “anhydrous” refers to the solvate or non-solvate form of Compound 1 that is free (or substantially free) of water and may also be referred to as an “anhydrate”.

[0116] In some aspects, the present methods and uses comprise administering a sulfate salt of Compound 1 or a hydrate of a sulfate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a hemi sulfate salt of Compound 1 or a hydrate of a hemisulfate salt in the described amount, e.g., in an amount that is equivalent to the described amount of Compound 1. In some aspects, the present methods and uses comprise administering a hemisulfate hemihydrate salt of Compound 1 in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a phosphate salt of Compound 1 or a hydrate of a phosphate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a DL-tartrate salt of Compound 1 or a hydrate of a DL-tartrate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a hydrochloride salt of Compound 1 or a hydrate of a hydrochloride salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering an oxalate salt of Compound 1 or a hydrate of a oxalate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a glycolate salt of Compound 1 or a hydrate of a glycolate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a tosylate salt of Compound 1 or a hydrate of a tosylate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). The present methods and uses also comprise administering pharmaceutical compositions comprising each of the salts of Compound 1 as described herein. The present methods and uses also comprise administering pharmaceutical compositions comprising the solvated salts of Compound 1 as described herein.

[0117] Polymorphic and / or crystalline forms of Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of pharmaceutically acceptable salts of Compound 1 (and pharmaceutical compositions comprising polymorphic and / or crystalline forms of Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of pharmaceutically acceptable salts of Compound 1) are also included as part of the present methods and uses. For example, such forms include those described in US 63 / 466,552 and include crystalline Form A hemisulfate hemihydrate salt characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 (2 theta) angles selected from 9.8° (± 0.2°), 11.3° (± 0.2°), 13.6° (± 0.2°), 18.4° (± 0.2°), 22.8 ° (± 0.2°), 23.3 ° (± 0.2°), and 28.6° (± 0.2°); crystalline Form B phosphate salt characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 angles selected from 10.2°(± 0.2°), 13.4°(± 0.2°), 13.6°(± 0.2°), 14.3°(± 0.2°), 16.8 °(± 0.2°), 20.3 °(± 0.2°), and 21.4°(± 0.2°); crystalline Form C DL-tartrate salt characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 angles selected from 8.1°(± 0.2°), 13.3°(± 0.2°), 15.0°(± 0.2°), 20.4°(± 0.2°), 20.6 °(± 0.2°), 22.6 °(± 0.2°), and 25.3°(± 0.2°); crystalline Form D hydrochloride salt characterized by at least two, at least three, at least four, at least five, or six x-ray powder diffraction peaks at 20 angles selected from 10.6°(± 0.2°), 14.4°(± 0.2°), 24.6(± 0.2°), 24.8°(± 0.2°), 25.2 °(± 0.2°), and 27.0°(± 0.2°); crystalline Form E monohydrate characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 angles selected from 11.6°(± 0.2°), 16.0°(± 0.2°), 16.8°(± 0.2°), 20.6°(± 0.2°), 23.8 °(± 0.2°), 26.0 °(± 0.2°), and 27.4°(± 0.2°).

[0118] Amorphous (e.g., non-crystalline) forms of Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of pharmaceutically acceptable salts of Compound 1 (or pharmaceutical compositions comprising amorphous forms of Compound 1, or pharmaceutically acceptable salts of Compound 1, or solvates of Compound 1, or solvates of pharmaceutically acceptable salts of Compound 1) are also included in the methods and uses described herein.

[0119] Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of a pharmaceutically acceptable salts of Compound 1 may also be formulated as part of a pharmaceutical composition. In some aspects, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. As usedherein the term “pharmaceutically acceptable excipient” or “excipient” refers to an inert substance, such as a carrier, adjuvant, additive, diluent or vehicle that does not adversely affect the pharmacological activity of the compound (including the crystalline or amorphous forms described herein) with which it is formulated. In some aspects, the pharmaceutical formulations of the disclosure are comprised of crystalline Compound 1, or a crystalline pharmaceutically acceptable salt of Compound 1, or a crystalline solvate of Compound 1, or a crystalline solvate of a pharmaceutically acceptable salt of Compound 1. In some aspects, the pharmaceutical formulations of the disclosure are comprised of amorphous Compound 1, or an amorphous pharmaceutically acceptable salt of Compound 1, or an amorphous solvate of Compound 1, or an amorphous solvate of a pharmaceutically acceptable salt of Compound 1. It should be understood that, as described herein, a pharmaceutical composition of the disclosure comprises at least one of the following: Compound 1, a pharmaceutically acceptable salt of Compound 1, a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in a variety of solid state forms. In some aspects, a pharmaceutical composition comprises at least one of the following: a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, a crystalline form of a solvate of Compound 1, or a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1. In some aspects, a pharmaceutical composition comprises at least one of the following: an amorphous form of Compound 1, an amorphous form of a pharmaceutically acceptable salt of Compound 1, an amorphous form of a solvate of Compound 1, or an amorphous form of a solvate of a pharmaceutically acceptable salt of Compound 1. In other aspects, a pharmaceutical composition comprises a mixture of one or more of the following: a crystalline or amorphous form of Compound 1, a crystalline or amorphous form of a pharmaceutically acceptable salt of Compound 1, a crystalline or amorphous form of a solvate of Compound 1, or a crystalline or amorphous form of a solvate of a pharmaceutically acceptable salt of Compound 1.

[0120] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 into association with at least one excipient and / or one or more other accessory ingredients, and then, if necessary and / or desirable, filling and / or shaping (by any number of methods) themixture into a dosage form and / or packaging the product into a desired single- or multi-dose unit.

[0121] Pharmaceutical compositions comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 into association with an excipient, such as, for example, a carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing one or more of the crystalline or amorphous forms of the disclosure with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients (excipients). Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more excipients such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0122] Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 can be combined in an intimate admixture with one or more pharmaceutical excipients according to conventional pharmaceutical compounding techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for oral administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as excipients, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, antioxidants, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders,antioxidants, and disintegrating agents can be used in the case of oral solid preparations. In some aspects, compositions can be made without employing the use of lactose. For example, suitable oral dosage forms include, but are not limited to, powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0123] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, silicified microcrystalline cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0124] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cationexchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone) (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.

[0125] Exemplary surface active agents and / or emulsifiers include, but are not limited to, 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., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (c.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 (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60),sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), polyvinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0126] Exemplary binding agents include, but are not limited to, 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, silicified 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.

[0127] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), silicified microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0128] Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little of a disintegrant may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used in the dosage forms comprising Compound 1 as described herein or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1 or a pharmaceutically acceptable salt of a solvate of Compound 1. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. In some aspects, about 0.5 to about 15weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in a pharmaceutical composition of the disclosure. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0129] Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certainaspects, the preservative is an antioxidant. In other aspects, the preservative is a chelating agent.

[0130] Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0131] Exemplary chelating agents include, but are not limited to, 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. Exemplary antimicrobial preservatives include, but are not limited to, 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.

[0132] Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0133] Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0134] Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0135] Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.

[0136] Exemplary buffering agents include, but are not limited to, 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 saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0137] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 2 weight percent of the pharmaceutical composition.

[0138] Exemplary natural oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, 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, macadamia 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 buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. 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.

[0139] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various scenting / perfuming, sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0140] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. In some aspects, coatings, such as for example, film coatings, may be used for cosmetic purposes (i.e., to preserve and / or protect the surface of the tablet) and / or to prevent sticking during manufacturing. In other aspects, film coatings may be used to aid in swallowing. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Film coatings may be used, such as, for example, Opadry® II Blue film coat [polyvinyl alcohol, titatnium dioxide, macrogol / polyethylene glycol, talc, FD&C blue #2 / indigo carmine aluminum lake / E132] and the like.

[0141] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0142] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0143] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0144] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0145] Within the aforementioned group, ionic surfactants include, but are not limited to, lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. Ionic surfactants may also include, but are not limited to, the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / di glycerides, citric acid esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate,linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0146] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0147] Other hydrophilic-non-ionic surfactants may include, but are not limited to, PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 com oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, polyglyceryl -10-oleate, Tween 40,Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and pol oxamers.

[0148] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof.

[0149] In one aspect, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the disclosure and to minimize precipitation of the compound of the disclosure. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0150] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol (PEG), polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; polyethylene glycol 660 12-hydroxy stearate, amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, s-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, s-caprolactone and isomers thereof, 5-valerolactone and isomers thereof, P -butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0151] Mixtures of solubilizers may also be used. Examples include, but are not limited to, mixtures of one or more of the following: triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.

[0152] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of less than about 10%, less than about 25%, less than about 50%, about 100%, or up to less than about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as less than about 5%, less than about 2%, less than about 1% or even less. Typically, the solubilizer may be present in an amount of less than about 1% to about 100%, more typically less than about 5% to less than about 25% by weight.

[0153] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, filmcoatings, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0154] In one aspect, the excipient is selected from one or more of mannitol, sorbitol, inositol, silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), pregelatinized starch (starch 1500), microcrystalline starch, Sodium Stearyl Fumarate, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, polyvinyl alcohol, titatnium dioxide, macrogol / polyethylene glycol, sorbitan fatty acid esters, talc, FD&C blue #2 / indigo carmine aluminum lake / E132.

[0155] In one aspect, the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, Sodium Stearyl Fumarate,polyvinyl alcohol, titatnium dioxide, macrogol / polyethylene glycol, talc, FD&C blue #2 / indigo carmine aluminum lake / E132.

[0156] In one aspect, the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), croscarmellose Sodium, Sodium Stearyl Fumarate, and Opadry® II Blue film coat.

[0157] In one aspect, the excipient is selected from one or more of mannitol, pregelatinized starch (starch 1500), hydrogenated vegetable oil, and Opadry® II Blue film coat.

[0158] In one aspect, the excipient is selected from one or more of sorbitol, cross- sodium carboxymethyl starch (sodium starch glycolate), zinc stearate, and Opadry® II Blue film coat.

[0159] In one aspect, the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, Sodium Stearyl Fumarate, polyvinyl alcohol, titatnium dioxide, macrogol / polyethylene glycol, talc, FD&C blue #2 / indigo carmine aluminum lake / E132, olyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tri stearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol.

[0160] In some aspects, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), is administered in or administered as an oral dosage form.

[0161] In some aspects, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), is administered as a tablet.

[0162] In some aspects, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or apharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), is administered as a capsule.

[0163] As used herein, the terms “as”, “in” and “as part of’ when referring to the administration of the active pharmaceutical ingredient (i.e., Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) are used interchangeably and mean that the active pharmaceutical ingredient is contained in an oral dosage form, including, for example, a tablet, capsule, granules / minitablets, lozenge, syrup and the like.

[0164] In some aspects, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered as part of a spray-dried dispersion. In some aspects, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered as part of a pharmaceutical composition comprising a spray-dried dispersion comprising at least one polymer selected from copovidone, hypromellose acetate succinate based amorphous solid, medium grade (HPMCAS-MG), and polyvinylpyrrolidone / vinyl acetate copolymer (PVPVA).

[0165] In one aspect, the tablet composition comprises about 2% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 98% w / w (±2%) comprising one or more excipients.

[0166] In one aspect, the tablet composition comprises about 5% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 95% w / w (±2%) of one or more excipients.

[0167] In one aspect, the tablet composition comprises about 7% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 93% w / w (±2%) of one or more excipients.

[0168] In one aspect, the tablet composition comprises about 10% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 90% w / w (±2%) of one or more excipients.

[0169] In one aspect, the tablet composition comprises about 12% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 88% w / w (±2%) of one or more excipients.

[0170] In one aspect, the tablet composition comprises about 15% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 85% w / w (±2%) of one or more excipients.

[0171] In one aspect, the tablet composition comprises about 18% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 82% w / w (±2%) of one or more excipients.

[0172] In one aspect, the tablet composition comprises about 20% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 80% w / w (±2%) of one or more excipients.

[0173] In one aspect, the tablet composition comprises about 25% w / w (±1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 75% w / w (±2%) of one or more excipients.

[0174] In certain embodiments, provided is a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable excipient that has been processed to generate particles of a consistent size (“milled powder”). In certain embodiments, processing the milled powder comprises milling a composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable excipient for an amount of time suitable to bring about a desired particle size. In some aspects, the particle size of the milled powder is less than about 200 pm. In some aspects, the particle size of the milled powder is less than about 100 pm. In some aspects, the particle size of the milled powder is less than about 75 pm. In some aspects, the particle size of the milled powder is less than about 50 pm. In some aspects, the particle size of the milled powder is less than about 45 pm.In some aspects, the particle size of the milled powder is less than about 40 pm. In some aspects, the particle size of the milled powder is less than about 35 pm. In some aspects, the particle size of the milled powder is less than about 30 pm. In some aspects, the particle size of the milled powder is less than about 25 pm. In some aspects, the particle size of the milled powder is less than about 20 pm. In some aspects, the particle size of the milled powder is less than about 15 pm. In some aspects, the particle size of the milled powder is less than about 10 pm. In some aspects, the particle size of the milled powder is less than about 5 pm. In some aspects, the particle size of the milled powder is less than about 1 pm. In some aspects, the particle size of the milled powder is less than about 500 nm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 200 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 100 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 75 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 50 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 45 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 40 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 35 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 45 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 40 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 35 pm. In some aspects, the particle size of the milled powder is about 45 pm. In some aspects, the particle size of the milled powder is about 40 pm. In some aspects, the particle size of the milled powder is about 35 pm. In some aspects, the particle size of the milled powder is about 30 pm. In some aspects, the particle size of the milled powder is about 25 pm. In some aspects, the particle size of the milled powder is about 5 pm. In some aspects, the particle size of the milled powder is about 4 pm. In some aspects, the particle size of the milled powder is about 3 pm. In some aspects, the particle size of the milled powder is about 2 pm. In some aspects, the particle size of the milled powder is about 1 pm. The term “about,” as used herein with respect to particle size, means + / - 5 pm.

[0175] In some aspects, at least 90% of a representative sample of the milled powder has a particle size of less than about 100 pm, about 90 pm, about 80 pm, about 70 pm, about 60 pm, about 50 pm, about 40 pm, about 30 pm, about 20 pm, or about 10 pm. In some aspects,at least about 90% of a representative sample of the milled powder has a particle size of less than about 60 pm.

[0176] In some aspects, the pharmaceutical composition comprises amorphous Compound 1. In some aspects, the pharmaceutical composition comprises amorphous Compound 1 and at least one excipient. In some aspects, the pharmaceutical composition comprises a solid dispersion. In still other aspects, the pharmaceutical composition comprises amorphous Compound 1, or an amorphous pharmaceutically acceptable salt of Compound 1, or an amorphous solvate of Compound 1, or an amorphous solvate of a pharmaceutically acceptable salt of Compound 1 in a solid dispersion.

[0177] In some aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and one or more polymer(s). In other aspects, the solid dispersion is a spray dried dispersion. In some aspects, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, one or more polymer(s), and one or more surfactant(s). In some aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and at least one polymer. In some aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, at least one polymer, and at least one surfactant.

[0178] In certain aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises the non-salt (free form) of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a pharmaceutically acceptable salt of Compound 1. In certain aspects the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a non-stoichiometric pharmaceutically acceptable salt of Compound 1. In certain other aspects the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a stoichiometric pharmaceutically acceptable salt of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises the monohydrate freeform of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises non-hydrated (anhydrous) free form of Compound 1.

[0179] In some aspects, the solid dispersion comprises at least one polymer that is a water-soluble polymer. In other aspects, the solid dispersion comprises at least one polymer that is a cellulosic polymer. In further aspects, the solid dispersion comprises at least one polymer that is a cellulose ether, cellulose ester, cellulose co-carboxyester, cellulose phthalate, cellulose succinate, or mixtures thereof. In yet other aspects, the solid dispersion comprises at least on...

Claims

CLAIMSListing of Claims:

1. A method of treating sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to a subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

2. A method for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1 , or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

3. The method of claim 2, wherein the subject’s hemoglobin concentration increases about 1.0 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

4. The method of claim 2 or 3, wherein the subject’s hemoglobin concentration increases about 1.5 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

5. The method of any one of claims 2-4, wherein the subject’s hemoglobin concentration increases about 2.0 g / dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

6. The method of any one of claims 2-5, wherein the subject’s hemoglobin concentration increases about 1.0 g / dL to about 3.5 g / dL as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

7. The method of any one of Claims 2-6, wherein the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 45 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

8. The method of any one of Claims 2-7, wherein the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 30 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

9. The method of any one of Claims 2-8, wherein the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

10. The method of Claim 2, wherein the subject’s hemoglobin concentration increases about 1.0 g / dL or more as compared to baseline after about 8 days of administration ofCompound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

11. The method of Claim 2, wherein the subject’s hemoglobin concentration increases about 1.5 g / dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

12. A method for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

13. The method of Claim 12, wherein the one or more markers of hemolysis are selected from lactate dehydrogenase (LDH), indirect bilirubin, and percent reticulocyte (% reticulocyte).

14. The method of claim 12 or 13, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

15. The method of any one of claims 12-14, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

16. The method of any one of claims 12-15, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 40% or more following as compared to baseline administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

17. The method of claim 12 or 13, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 30% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

18. The method of claim 12 or 13, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s LDH of about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

19. The method of any one of claims 12-18, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

20. The method of any one of claims 12-19, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 30% or more as compared to baseline following administration of Compound 1, or apharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

21. The method of any one of claims 12-18, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 20% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

22. The method of any one of claims 12-18, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s indirect bilirubin of about 40% to about 55% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

23. The method of any one of claims 12-22, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

24. The method of any one of claims 12-23, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocytes of about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

25. The method of any one of claims 12-22, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

26. The method of any one of claims 12-22, wherein reducing one or more markers of hemolysis is characterized by a reduction in the subject’s % reticulocyte of about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

27. The method of claim 12, wherein one or more markers of hemolysis is reduced by about 30% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

28. The method of claim 12 or 27, wherein one or more markers of hemolysis is reduced by about 30% to about 40% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

29. The method of any one of claims 12, 27, and 28, wherein one or more markers of hemolysis is reduced by about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

30. The method of any one of claims 13-29, wherein the one or more markers of hemolysis are measured in the blood of the subject.

31. A method for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, whereinCompound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

32. The method of Claim 31, wherein the subject’s lactate dehydrogenase is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

33. The method of claim 31 or 32, wherein the subject’s lactate dehydrogenase is reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

34. The method of any one of claims 31-33, wherein the subject’s lactate dehydrogenase is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

35. The method of claim 33, wherein the subject’s lactate dehydrogenase is reduced by about 30% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

36. The method of any one of claims 32-35, wherein the subject’s lactate dehydrogenase is reduced by about 40% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

37. A method for reducing cell-free heme concentration as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

38. The method of claim 37, wherein the subject’s cell-free heme concentration is reduced by about 10% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

39. The method of claim 37 or 38, wherein the subject’s cell-free heme concentration is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

40. The method of any one of claims 37-39, wherein the subject’s cell-free heme concentration is reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

41. The method of claim 37, wherein the subject’s cell-free heme concentration is reduced by about 10% to about 80% compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

42. The method of claim 37 or 41, wherein the subject’s cell-free heme concentration is reduced by about 30% to about 40% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

43. The method of claim 37, wherein the subject’s cell-free heme concentration is reduced to less than or equal to about 5 mg / dL following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

44. A method for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

45. The method of claim 44, wherein the number or frequency of VOC events are reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

46. The method of claim 44 or 45, wherein the number or frequency of VOC events are reduced by about 40% or more as compared to baseline following administration ofCompound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

47. The method of any one of claims 44-46, wherein the number or frequency of VOC events are reduced by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

48. The method of claim 44, wherein the number or frequency of VOC events are reduced by about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

49. The method of claim 44 or 48, wherein the number or frequency of VOC events are reduced by about 50% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

50. The method of any one of claims 44-49, wherein the number or frequency of VOC events are measured over the course of one year (12 months).

51. A method for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvateof a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

52. The method of claim 51, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

53. The method of claim 51 or 52, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

54. The method of any one of claims 51-53, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

55. The method of claim 51, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

56. The method of claim 51 or 55, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 50% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

57. The method of any one of claims 51 and 55-56, wherein the number or frequency of sickle cell pain crisis (SCPC) events are reduced by about 30% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt ofCompound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

58. The method of any one of claims 51-57, wherein sickle cell pain crisis (SCPC) events comprise pain in one or more of the hands, feet, chest, arms, backjoints, or legs of the subject.

59. The method of any one of claims 51-58, wherein the reduction in the number or frequency of sickle cell pain crisis (SCPC) events is measured over the course of a year (12 months).

60. A method for reducing the number or frequency of hospitalization visits for treatment of VOC (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

61. A method for treating anemia in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

62. The method of claim 61, wherein the anemia is dyserythropoietic anemia.

63. The method of claim 61, wherein the anemia is hemolytic anemia.

64. A method for improving the quality of life (QoL) as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

65. The method of claim 64, wherein improving the quality of life comprises improving the overall feeling and function of the subject as determined by one or more tests selected from Patient-Reported Outcomes Measurements Information System (PROMIS) PainIntensity, Adult Sickle Cell Quality of Life Measurements Information System (ASCQ-Me-) Pain Impact, Patient-Reported Outcomes Measurements Information System (PROMIS) Physical Function, Patient Global Impressions of Severity and Change (PGIS and PGIC), European Quality of Life (EuroQoL) Group 5-level EQ-5D, Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F), Adult Sickle Cell Quality of Life Measurement (ASCQ-Me-), Patient-Reported Outcome Measurement Information System® (PROMIS) and the Six Minute Walking Test (6MWT).

66. The method of claim 65, wherein improving the overall feeling and function of the subject comprises a reduction of symptoms.

67. The method of claim 66, wherein the symptoms include one or more of shortness of breath, fatigue, tiredness, dizziness, pain, rapid heartbeat, eyesight problems, fussiness, and weakness.

68. The method of claim 65, wherein improving the overall feeling and function of the subject comprises an improvement in the six minute walking test (6MWT) as compared to baseline.

69. A method for reducing fatigue as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

70. The method of claim 69, wherein fatigue is measured using one or more of the following assessment systems: Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F), Patient-Reported Outcome Measurements Information System (PROMIS) Fatigue, and / or Adult Sickle Cell Quality of Life Measurement (ASCQ-Me).

71. The method of claim 69 or 70, wherein a reduction in fatigue is characterized by at least at 5 -point change in the subject’s fatigue score as compared to baseline.

72. The method of any one of claims 69-71, wherein a reduction in fatigue is characterized by at least at 8-point change in the subject’s fatigue score as compared to baseline.

73. The method of any one of claims 69-72, wherein a reduction in fatigue is characterized by at least at 10-point change in the subject’s fatigue score as compared to baseline.

74. The method of claim 69, wherein a reduction in fatigue is characterized by a change of between 5- and 10-points in the subject’s fatigue score as compared to baseline.

75. A method for reducing at least one marker of erythropoiesis as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

76. The method of claim 75, wherein at least one marker of erythropoiesis is selected from absolute reticulocyte count, % reticulocyte and erythropoietin.

77. The method of any claim 76, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s % reticulocyte of about 10% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

78. The method of any one of claims 75-77, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s % reticulocyte of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

79. The method of any one of claims 75-78, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s % reticulocyte of about 10% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

80. The method of any one of claims 75-79, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s percent (%) reticulocyte of about 50% to about 60% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

81. The method of claim 75, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s erythropoietin of about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

82. The method of claims 75 or 81, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s erythropoietin of about 20% to about 65% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

83. The method of any one of claims 75, 81, and 82, wherein reducing at least one marker of erythropoiesis is characterized by a reduction in the subject’s erythropoietin of about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

84. The method of any one of claims 75-83, wherein the at least one marker of erythropoiesis is measured in the blood of the subject.

85. A method for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

86. The method of claim 85, wherein the subject’s erythropoietin is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

87. The method of claim 85 or 86, wherein the subject’s erythropoietin is reduced by about 20% to about 65% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

88. The method of any one of claims 85-87, wherein the subject’s erythropoietin is reduced by about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

89. A method for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, wherein Compound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

90. The method of claim 89, wherein the subject’s ATP concentration is increased by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

91. The method of claim 89 or 90, wherein the subject’s ATP concentration is increased by about 60% or more as compared to baseline following administration of Compound 1, or apharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

92. The method of any one of claims 89-91, wherein the subject’s ATP concentration is increased by about 70% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

93. The method of claim 89, wherein the subject’s ATP concentration is increased by about 50% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

94. The method of claim 89 or 93, wherein the subject’s ATP concentration is increased by about 60% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

95. The method of any one of claims 89, 93, and 94, wherein the subject’s ATP concentration is increased by about 70% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

96. A method for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering Compound 1 :Compound 1 or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, to the subject, whereinCompound 1 is administered at a dose of about 1 mg to about 30 mg; or wherein the pharmaceutically acceptable salt of Compound 1, the solvate of Compound 1, or the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.

97. The method of claim 96, wherein the subject’s 2,3 DPG concentration is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

98. The method of claim 96 or 97 wherein the subject’s 2,3 DPG concentration is reduced by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

99. The method of any one of claims 96-98, wherein the subject’s 2,3 DPG concentration is reduced by about 60% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

100. The method of claim 96, wherein the subject’s 2,3 DPG concentration is reduced by about 40% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

101. The method of claim 96 or 100, wherein the subject’s 2,3 DPG concentration is reduced by about 50% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

102. The method of any one of claims 96, 100, and 101, wherein the subject’s 2,3 DPG concentration is reduced by about 60% to about 70% as compared to baseline followingadministration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

103. The method of any one of claims 1-102, wherein Compound 1 is administered at a dose of about 1 mg to about 15 mg; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 1 mg to about 15 mg of Compound 1.

104. The method of any one of claims 1-103, wherein Compound 1 is administered at a dose of about 1 mg to about 10 mg; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 1 mg to about 10 mg of Compound 1.

105. The method of any one of claims 1-104, wherein Compound 1 is administered at a dose of about 1 mg to about 5 mg; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 1 mg to about 5 mg of Compound 1.

106. The method of any one of claims 1-103, wherein Compound 1 is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg, once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of Compound 1, once daily.

107. The method of any one of claims 1-103 and 106, wherein Compound 1 is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg,once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg, of Compound 1, once daily.

108. The method of any one of claims 1-103, 106, and 107, wherein Compound 1 is administered at a dose of about 2 mg, once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 2 mg of Compound 1, once daily.

109. The method of any one of claims 1-103, 106, and 107, wherein Compound 1 is administered at a dose of about 5 mg, once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 5 mg of Compound 1, once daily.

110. The method of any one of claims 1-104, wherein Compound 1 is administered at a dose of about 2.5 mg, about 5 mg or about 7.5 mg, once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 2.5 mg, about 5 mg, or about 7.5 mg of Compound 1, once daily.

111. The method of claim 110, wherein Compound 1 is administered at a dose of about 7.5 mg once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 7.5 mg of Compound 1, once daily.

112. The method of claim 110, wherein Compound 1 is administered at a dose of about 2.5 mg, once daily; or wherein the pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered at a dose that is equivalent to about 2.5 mg of Compound 1, once daily.

113. The method according to any one of claims 1-112, wherein the subject has had 0 or 1 sickle cell pain crises (SCPCs) in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

114. The method according to any one of claims 1-112, wherein the subject has had at least 2 sickle cell pain crises (SCPCs) in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

115. The method according to any one of claims 1-112, wherein the subject has had no more than 10 sickle cell pain crises (SCPCs) in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

116. The method according to any one of claims 1-115, wherein the subject has a hemoglobin level of about 5.5 g / dL to about 10.5 g / dL prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

117. The method of any one of claims 1-116, wherein Compound 1 is a pharmaceutically acceptable salt.

118. The method of any one of claims 1-116, wherein Compound 1 is a solvate.

119. The method of any one of claims 1-116, wherein Compound 1 is a solvate of a pharmaceutically acceptable salt.

120. The method of any one of claims 1-119, wherein Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered as a tablet.

121. The method of any one of claims 1-120, wherein the subject is administered at least one of hydroxyurea (HU), L-glutamine and crizanlizumab in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 for the treatment of sickle cell disease.

122. The method of any one of claims 1-121, wherein the subject is administered folic acid in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

123. The method of claim 122, wherein the subject is administered the equivalent of at least about 0.8 mg / day of folic acid.

124. The method of any one of claims 1-123, wherein Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered in a pharmaceutical composition.

125. The method of any one of claims 1-124, wherein the subject is aged 16 years or older.

126. The method according to any one of claims 1-124, wherein the subject is aged 18 years or older.

127. The method according to any one of claims 1-124, wherein the subject is aged 12 years or older.

128. The method according to any one of claims 1-127, wherein the subject has been previously treated with another PK activator and has discontinued treatment with said PK activator prior to administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.

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