Methods of Administering Hemoglobin Modulators

Abstract

Provided herein are methods for treating sickle cell disease that involve administering Compound I, a hemoglobin modulator, according to certain dosing regimens. [Formula 1] TIFF2024545496000048.tif7186

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 288,377, filed December 10, 2021, U.S. Provisional Application No. 63 / 421,524, filed November 1, 2022, and U.S. Provisional Application No. 63 / 429,376, filed December 1, 2022, each of which is incorporated by reference in its entirety herein.

[0002] The present disclosure provides a method for treating sickle cell disease comprising administering a hemoglobin modulator, Compound I, (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde, or a pharma- ceutically acceptable salt thereof, according to certain dosing regimens. [Background technology]

[0003] Sickle cell disease (SCD) is a disorder of red blood cells found especially in people of African and Mediterranean descent. The basis of SCD is found in sickle hemoglobin (HbS), which contains a point mutation to the common peptide sequence of hemoglobin A (HbA).

[0004] Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin changes conformation to bind and release oxygen. Sickle hemoglobin (HbS) contains a point mutation in which glutamic acid is replaced by valine, which predisposes HbS to polymerization under hypoxic conditions and gives HbS-containing red blood cells (RBCs) their characteristic sickle shape. Sickled RBCs are also stiffer than normal RBCs, and their loss of flexibility can lead to occlusion of blood vessels.

[0005] Compounds that modulate hemoglobin and are useful for treating disorders mediated by abnormal Hb (e.g., HbS), such as Compound I, are disclosed in U.S. Pat. No. 10,683,285, the disclosure of which is incorporated herein by reference in its entirety. Summary of the Invention [Problem to be solved by the invention]

[0006] [Means for solving the problem]

[0007] The present disclosure provides a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of a formula

[0008] [ka] or a pharma- ceutically acceptable salt thereof, followed by administering a second dose of Compound I or a pharma- ceutically acceptable salt thereof.

[0009] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, wherein administration of the first and second doses results in about 25% to about 60% hemoglobin occupancy of Compound I.

[0010] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 200 mg per day to about 1600 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 500 mg per day.

[0011] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, of about 200 mg twice daily (BID) for four days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, of 100 mg per day.

[0012] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, of about 300 mg twice daily (BID) for four days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, of 150 mg per day.

[0013] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, of about 400 mg twice daily (BID) for four days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, of 200 mg per day.

[0014] Some embodiments provide a compound for use in treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, wherein administration of the first and second doses results in about 25% to about 60% hemoglobin occupancy by Compound I.

[0015] Some embodiments provide a compound for use in the treatment of sickle cell disease in a subject in need thereof comprising administering to the subject a first dose of about 200 mg per day to about 1600 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of about 25 mg per day to about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0016] Some embodiments provide a compound for use in treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg twice daily (BID) of Compound I, or a pharma- ceutically acceptable salt thereof, followed by administration of a second dose of 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0017] Some embodiments provide a compound for use in treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 300 mg twice daily (BID) of Compound I, or a pharma- ceutically acceptable salt thereof, followed by administration of a second dose of 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0018] Some embodiments provide a compound for use in treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, of about 400 mg twice daily (BID) for four days, followed by administration of a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, of 200 mg per day. [Brief description of the drawings]

[0019] [Figure 1]FIG. 1 shows that a single dose of Compound I (top line) shows a dose-dependent increase in percent Hb occupancy in healthy volunteers. These Hb occupancies exceed those reported in healthy volunteers who received a single dose of voxerotol (bottom line) over a similar range after a single dose of Compound I, as reported in Br J Clin Pharmacol. 2019;28(6):1290-1302. [Diagram 2] FIG. 1 shows the percent hemoglobin occupancy of Compound I in healthy volunteers after receiving a first (loading) daily dose of Compound I of 300 mg for 3 days, followed by a second (maintenance) daily dose of 15 mg, 25 mg, 50 mg, or 75 mg for 14 days. [Diagram 3] FIG. 1 is a general schematic diagram showing a single dose (SD) of 100 mg and multiple ascending doses (MAD) at secondary daily dose levels of 50 mg (MAD-1), 100 mg (MAD-2), and 150 mg (MAD-3) in SCD patients, as detailed in Example 3. [Figure 4] FIG. 1 shows the change in hemoglobin after dosing with both MAD-1 and MAD-2 of Compound I in six SCD patients (i.e., at week 8 after these two rounds of treatment). [Diagram 5] FIG. 1 shows the change in reticulocytes at baseline and after dosing with both MAD-1 and MAD-2 of Compound I (i.e., after 8 weeks of treatment) in six SCD patients. [Figure 6] FIG. 1 shows the change in absolute reticulocyte counts at baseline and after dosing with both MAD-1 and MAD-2 of Compound I (i.e., after 8 weeks of treatment) in six SCD patients. [Figure 7] FIG. 1 shows the change in lactate dehydrogenase (LDH) at baseline and after dosing with both MAD-1 and MAD-2 of Compound I (i.e., after 8 weeks of treatment) in six SCD patients. [Figure 8]FIG. 1 shows the change in indirect bilirubin at baseline and after dosing with both MAD-1 and MAD-2 of Compound I (i.e., after 8 weeks of treatment) in six SCD patients. [Figure 9] FIG. 1 shows oxygen scan parameters of an SCD patient at baseline (week 8) and after dosing with both MAD-1 and MAD-2 of Compound I according to the present disclosure (i.e., at weeks 8 and 16). Elmax is the maximum deformability or extensibility (which provides information on red blood cell ("RBC") cytoskeleton mechanics), Elmin corresponds to when the RBC can least extend, and PoS refers to the point of sickling or the point on the curve where sickling begins during deoxidation. [Figure 10] Box plots showing hemoximetry of partial pressure of O2 (mmHg) at 20% saturation (p20) and 50% saturation (p50) with O2 in blood samples from SCD patients after dosing with both MAD-1 and MAD-2 of Compound I. Statistical significance was determined using Tukey's test. *P<0.05; **P<0.01; ****P<0.0001. [Figure 11] FIG. 1 shows the mean % Hb occupancy of Compound I in patients following dosing with MAD-1, MAD-2, and MAD-3. Hb occupancy data from patient 0003 at the 150 mg data point was excluded due to lack of compliance. [Figure 12] Box plots showing hemoximetry of partial pressure of O2 (mmHg) when Hb was 20% saturated (p20) and 50% saturated (p50) with O2 in blood samples from SCD patients after dosing with MAD-3 of Compound I. Statistical significance was determined using Tukey's test. [Figure 13]Figure 1 shows oxygen scan parameters for SCD patients at baseline and after 6 weeks of treatment with Compound I according to the dosing regimen of MAD-3 described in Example 3. Elmax is the maximum deformability or elongation rate (which gives information on red blood cell ("RBC") cytoskeleton mechanics) and Elmin corresponds to when the RBC is least extensible. The sickling point or the point on the curve during deoxygenation refers to the time when sickling begins. AA blood is from HbAA genotype control. [Figure 14] Figure 1 shows the percentage of sickled red blood cells in SCD patients at baseline and after 6 weeks of MAD-3 dosing of Compound I. Baseline is day 1 of MAD-3, patients were not receiving treatment. Patient 0001 (patient number 1) had a lower percentage of sickled red blood cells at baseline. [Figure 15] FIG. 1 shows observed trough hemoglobin occupancy percentages (mean and SD) compared to model predictions (shaded area) after a series of two first (loading) dose regimens administered over two days, followed by daily administration of a second (maintenance) dose of Compound I (daily dose regimens of 50 mg QD and 100 mg QD, respectively, administered over several weeks). [Figure 16] FIG. 1 shows the study scheme for Part A of the study described in Example 5. [Figure 17] FIG. 1 shows the study scheme for Part B of the study described in Example 5. [Figure 18] FIG. 1 shows the study scheme for part C of the study described in Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description 1.Definition As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0021] The term "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those of skill in the art.

[0022] Reference herein to a value or parameter with "about" includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±2.5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes a description of "X".

[0023] Throughout this disclosure, references to numerical ranges of values ​​are intended to serve as a shorthand method of referring individually to each separate value falling within the range, inclusive of the values ​​defining that range, and each separate value is incorporated herein as if it were individually recited herein.

[0024] Provided herein is a form of Compound I or a salt or solvate thereof. In some embodiments, a reference to a form of Compound I or a salt or solvate thereof means that at least 50%-99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I or its salt or solvate present in the composition is in the specified form. For example, in some embodiments, a reference to Form I of Compound I means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I present in the composition is in Form I.

[0025] The term "solid form" refers to a type of solid state material, including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs, solvates, etc. The term "polymorph" refers to a particular crystal structure having particular physical properties, such as X-ray diffraction, melting point, etc.

[0026] The term "solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present disclosure.

[0027] The term "desolvated" refers to a form of compound I, which is a solvate as described herein, from which solvent molecules have been partially or completely removed. Desolvation techniques for producing desolvated forms include, but are not limited to, exposing the form of compound I (solvate) to vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, the desolvated form of compound I may be anhydrous, i.e. completely free of solvent molecules, or may be partially solvated, where the solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0028] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and are more formally described as liquids, even though they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs that is characterized by a change of state, typically second-order ("glass transition").

[0029] Any formula or structure containing compound I provided herein is also intended to represent the unlabeled form and isotopically labeled form of the compound.It is understood that for any given atom, isotopes can be present essentially in the ratio according to their natural abundance, or one or more specific atoms can be enriched with one or more isotopes using synthetic methods known to those skilled in the art.Thus, hydrogen can have, for example, 1 H, 2 H, 3 H, and carbon, e.g. 11 C. 12 C. 13 C. 14 C, and oxygen includes e.g. 16 O. 17 O. 18 O, and nitrogen includes e.g. 13 N, 14 N, 15 N, and sulfur, e.g.32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S is included, and fluorine is, e.g. 17 F, 18 F, 19 F, and chlorine, e.g. 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl etc. are included.

[0030] "Pharmaceutically acceptable" or "physiologically acceptable" refers to those forms, compositions, dosage forms and other materials described herein that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0031] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is biologically and otherwise desirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when the forms described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable non-toxic addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. In some embodiments, pharma- ceutically acceptable salts do not include salts of primary amines.

[0032] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or delaying the worsening or progression of a disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of a disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the condition, causing partial or complete remission of a disease or condition, enhancing the effect of another pharmaceutical agent, delaying the progression of a disease, improving quality of life, and / or prolonging survival).

[0033] "Prevention" or "preventing" refers to the treatment of any disease or condition such that the clinical symptoms of the disease or condition do not develop. The compounds described herein, the solid forms described herein, or salts or solvates thereof, in some embodiments, may be administered to subjects (including humans) at risk or who have a family history of a disease or condition.

[0034] "Subject" refers to an animal, such as a mammal (including a human), that is or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0035] The term "therapeutically effective amount" or "effective amount" of a compound or solid form, or a salt or solvate thereof, described herein means an amount sufficient to effectively perform a treatment that, when administered to a subject, results in a therapeutic benefit, such as amelioration of symptoms or delay in disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of sickle cell disease. The therapeutically effective amount may vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be easily determined by one of ordinary skill in the art.

[0036] In some embodiments, a therapeutically effective amount can also be ascertained by evaluating biomarkers of the disease or disorder being treated. For SCD, biomarkers include blood Hb levels, hemolysis (e.g., by blood bilirubin levels), percent Hb occupancy by the compound, partial pressure of O2 when Hb is 20% saturated (p20) or 50% saturated (p50) with O2, and maximum RBC deformability under normoxic conditions (EI max ), minimum RBC deformability under hypoxic conditions (EI min ), and determining the specific pO2 level at which RBC sickling occurs, i.e., sickling point (PoS). Therapeutic efficacy in SCD may also include measuring oxygen delivery to tissues, including, for example, microvasculature oxygen saturation, cerebral blood flow, oxygen uptake rate, and cerebral oxygen consumption rate, which may be measured, for example, by diffuse correlation spectroscopy (DSC) and / or frequency domain near infrared spectroscopy (FDNIRS).

[0037] In some embodiments, the therapeutically effective amount is determined by measuring the hemoglobin percentage occupied by the compound, i.e., Hb occupancy percentage.Hb occupancy percentage is a measure of target engagement defined as the percentage of hemoglobin bound by the compound (e.g., Compound I), calculated as the molar concentration of the compound (e.g., Compound I) in RBC divided by the molar concentration of hemoglobin in RBC (mean corpuscular hemoglobin concentration calculated from hematology panel).The value of the concentration of the compound (e.g., Compound I) in RBC is calculated from whole blood and plasma concentration and hematocrit.

[0038] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within an individual organism, such as within an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside an individual organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the forms described herein and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the forms described herein and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages of administration of an embodiment of the present disclosure for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used to set up in vivo treatment protocols for experimental purposes or within the clinic. Other ex vivo uses for which the forms and compositions described herein may be suitable are described below or will be apparent to those skilled in the art.Selected forms described herein may be further characterized to investigate safety or tolerated dosage in human or non-human subjects.Such properties may be investigated using methods generally known to those skilled in the art.

[0039] The term "hemoglobin," as used herein, refers to any hemoglobin protein, including normal hemoglobin (HbA) and abnormal hemoglobins, such as sickle hemoglobin (HbS).

[0040] The term "sickle cell disease" refers to diseases mediated by sickle hemoglobin (HbS), which arise from a single point mutation in hemoglobin (Hb). Sickle cell disease includes sickle cell anemia (HbSS), hemoglobin SC disease (HbSC), hemoglobin S beta-plus-thalassemia (HbS / β+) and hemoglobin S beta-zero-thalassemia (HbS / β0).

[0041] "First dose" refers to an initial dose, or a series of such doses, of a compound described herein given to achieve a target therapeutic level in a subject at a desired time. In some embodiments, "first dose" refers to a "loading dose". In some embodiments, "loading dose" refers to a "first dose".

[0042] "Second dose" refers to a dose, or a series of such doses, of a compound described herein that is administered to maintain a desired therapeutic level of the compound in a subject. In some embodiments, "second dose" refers to a "maintenance dose". In some embodiments, "maintenance dose" refers to a "second dose".

[0043] The target therapeutic level can be assessed based on percent hemoglobin occupancy or a parameter related thereto, for example, the concentration of Compound I in the subject's blood relative to the subject's hematocrit.

[0044] 2. Compound I and its method of use Provided herein is a method for treating sickle cell disease (SCD). Sickle hemoglobin (HbS) contains a point mutation in which glutamic acid is replaced by valine, which predisposes HbS to polymerization under hypoxic conditions, giving HbS-containing red blood cells their characteristic sickle shape. Sickled red blood cells are also stiffer than normal red blood cells, and their loss of flexibility can lead to occlusion of blood vessels. Because polymerization occurs only under hypoxic, deoxygenated conditions, it is contemplated that therapeutic approaches will maintain HbS in an oxygenated state.

[0045] Provided herein is a method for treating sickle cell disease (SCD) comprising administering (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde (Compound I) or a pharma- ceutically acceptable salt thereof. Compound I has the formula:

[0046] [ka]

[0047] Compound I is a hemoglobin modulator and its synthesis and method of use are described in US Pat. No. 10,683,285.

[0048] In some embodiments, compound I is in a solid form.

[0049] In some embodiments, compound I is a crystalline form. In some embodiments, compound I is a crystalline form (form I of compound I) characterized by X-ray powder diffraction including the following peaks: 18.3, 23.4, and 26.1 °2θ±0.2 °2θ, as determined using Cu-Kα radiation on a diffractometer. In some embodiments, the diffractogram further includes one or more peaks at 10.8 or 17.3 °2θ±0.2 °2θ. In some embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) curve including an endotherm at about 111 °C (onset temperature).

[0050] Amorphous Compound I can be made according to methods known in the art. A solution of amorphous Compound I in acetonitrile (>540 mg / mL) was refrigerated for 4 days, then placed in a freezer for 1 day. The solid was filtered and dried under nitrogen to obtain Form I of Compound I.

[0051] Form I of Compound I was also prepared as follows: amorphous Compound I was slurried in ether for 1 day at ambient temperature by seeding with Form I of Compound I from another experiment (prepared as described herein) to obtain Form I of Compound I.

[0052] X-ray powder diffraction (XRPD): XRPD diagrams were generated using unvalidated software, SSCI Pattern Match 3.0.4. XRPD patterns were collected on a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptically graded multilayer mirror was used to focus the CuKα X-rays through the specimen onto the detector. Prior to analysis, silicon specimens (NIST SRM 640e or NIST SRM 640f) were analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge were used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.2.2b or v.5.5.

[0053] Differential Scanning Calorimetry (DSC): DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. A tau lag adjustment is performed with indium, tin, and zinc. Temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustment is then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC pan and the weight was accurately recorded. The pan was then inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The lid of the pan was pierced prior to analyzing the sample. Samples were analyzed from -30°C to 250°C at 10° / min.

[0054] Some embodiments provided herein include a method of administering compound I or a pharma- ceutically acceptable salt thereof. Some embodiments provided herein include a method of administering compound I. Some embodiments provided herein include a method of administering a pharma- ceutically acceptable salt of compound I. In some embodiments, the dose of the pharma- ceutically acceptable salt of compound I is adjusted to be equivalent to the dose of compound I.

[0055] Some embodiments provide a method for treating sickle cell disease by administration of Compound I or a pharmaceutically acceptable salt thereof, where the administration results in a hemoglobin occupancy of about 25% to about 80%.Some embodiments provide a method for treating sickle cell disease by administration of Compound I or a pharmaceutically acceptable salt thereof, where the administration results in a hemoglobin occupancy of about 20% to about 60%.

[0056] Some embodiments provide a method for treating sickle cell disease by administration of Compound I or a pharma- ceutically acceptable salt thereof, wherein the administration results in a hemoglobin occupancy of about 30% to about 50%.

[0057] It is contemplated that the methods described herein can achieve targeted hemoglobin occupancy and obtain desired hematological effects, thus improving clinical outcomes in individuals with SCD (e.g., reducing the number of vaso-occlusive crises).

[0058] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of a formula

[0059] [ka] or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of compound I or a pharmaceutically acceptable salt thereof, whereafter administration of the first and second doses results in about 25% to about 80% hemoglobin occupancy by compound I.

[0060] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of a formula

[0061] [ka] or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of compound I or a pharmaceutically acceptable salt thereof, whereafter administration of the first and second doses results in about 25% to about 60% hemoglobin occupancy by compound I.

[0062] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of a formula

[0063] [ka] or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of compound I or a pharmaceutically acceptable salt thereof, wherein administration of the first dose and the second dose results in about 30% to about 50% hemoglobin occupancy by compound I.

[0064] In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 80%. In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 75%. In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 70%. In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 65%. In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 60%. In some embodiments, the hemoglobin occupancy percentage provided by administration of Compound I is about 25% to about 55%.

[0065] In some embodiments, the hemoglobin occupancy percentage (provided by administration of Compound I) is about 25% to about 50%. In some embodiments, the hemoglobin occupancy percentage is about 25% to about 45%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 60%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 55%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 50%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 45%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 40%. In some embodiments, the hemoglobin occupancy percentage is about 30% to about 35%. In some embodiments, the hemoglobin occupancy percentage is about 35% to about 60%. In some embodiments, the hemoglobin occupancy percentage is about 35% to about 55%. In some embodiments, the hemoglobin occupancy percentage is about 35% to about 50%. In some embodiments, the hemoglobin occupancy percentage is about 35% to about 40%. In some embodiments, the hemoglobin occupancy percentage is about 40% to about 60%. In some embodiments, the hemoglobin occupancy percentage is about 40% to about 55%. In some embodiments, the hemoglobin occupancy percentage is about 40% to about 50%. In some embodiments, the hemoglobin occupancy percentage is about 40% to about 45%.

[0066] In some embodiments, the hemoglobin occupancy percentage can be calculated as described herein. In some embodiments, the hemoglobin occupancy percentage is the molar ratio of compound I concentration to Hb concentration in red blood cells.

[0067] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, for 1, 2, 3, 4, 5, 6, or 7 days to achieve a target therapeutic level in the subject, followed by administering a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, thereafter maintaining the target therapeutic level in the subject, wherein the first dose is greater than the second dose on a daily dose basis.

[0068] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, for 1, 2, 3, 4, 5, 6, or 7 days to achieve a target therapeutic level in the subject, followed by administering a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, to maintain the target therapeutic level in the subject, wherein the first dose is greater than the second dose on a daily dose basis (i.e., the first dose per day is greater than the second dose per day).

[0069] In some embodiments, the ratio of the first dose to the second dose is about 88:1 to about 2:1. In some embodiments, the ratio of the first dose to the second dose is about 60:1 to about 2:1. In some embodiments, the ratio of the first dose to the second dose is about 40:1 to about 2:1. In some embodiments, the ratio of the first dose to the second dose is about 20:1 to about 2:1. In some embodiments, the ratio of the first dose to the second dose is about 10:1 to about 2:1.

[0070] In some embodiments, the ratio of the first dose per day to the second dose per day is about 88:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 60:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 40:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 20:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 10:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 4:1 to about 2:1. In some embodiments, the ratio of the first dose per day to the second dose per day is about 9:1 to about 4:1.

[0071] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 100 mg per day to about 2200 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 500 mg per day.

[0072] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 200 mg per day to about 1600 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 500 mg per day.

[0073] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 300 mg per day to about 1500 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 500 mg per day.

[0074] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 300 mg per day to about 1500 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 250 mg per day.

[0075] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 300 mg per day to about 900 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 250 mg per day.

[0076] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof of about 200 mg per day to about 900 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by a second dose of Compound I or a pharma- ceutically acceptable salt thereof of about 25 mg per day to about 250 mg per day.

[0077] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 200 mg per day to about 900 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 200 mg per day.

[0078] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 200 mg per day to about 900 mg per day for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 150 mg per day.

[0079] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 1600 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1-5 days, followed by administration of a second dose of about 50 mg per day to about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0080] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof from about 300 mg per day to about 1500 mg per day for 1 to 5 days, followed by administration of a second dose of Compound I or a pharma- ceutically acceptable salt thereof from about 50 mg per day to about 500 mg per day.

[0081] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1-5 days, followed by administration of a second dose of about 50 mg per day to about 250 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, the first dose is administered for 1-7 days. In some embodiments, the first dose is administered for 1-6 days. In some embodiments, the first dose is administered for 1-5 days. In some embodiments, the first dose is administered for 1-4 days. In some embodiments, the first dose is administered for 1-3 days. In some embodiments, the first dose is administered for 1-2 days.

[0083] Some embodiments provide a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 300 mg per day to about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1-3 days, followed by administration of a second dose of about 50 mg per day to about 250 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments, the first dose comprises about 100 mg per day to about 2200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 2000 mg per day of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 1800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, the first dose comprises about 200 mg per day to about 1600 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 300 mg per day to about 1500 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 1500 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 1000 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 900 mg per day of compound I or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments, the first dose comprises about 1500 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 1400 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 1300 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 1200 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 1100 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 1000 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 900 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 800 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 700 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 600 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 500 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 400 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 300 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 200 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the first dose comprises about 100 mg of compound I or a pharma- ceutically acceptable salt thereof per day.

[0087] In some embodiments, the first dose is administered for 1-7 days. In some embodiments, the first dose is administered for 1-6 days. In some embodiments, the first dose is administered for 1-5 days. In some embodiments, the first dose is administered for 1-4 days. In some embodiments, the first dose is administered for 1-3 days. In some embodiments, the first dose is administered for 1-2 days.

[0088] In some embodiments, the first dose is administered for 7 days. In some embodiments, the first dose is administered for 6 days. In some embodiments, the first dose is administered for 5 days. In some embodiments, the first dose is administered for 4 days. In some embodiments, the first dose is administered for 3 days. In some embodiments, the first dose is administered for 2 days. In some embodiments, the first dose is administered for 1 day.

[0089] In some embodiments, the first dose is administered for 1, 2, 3, or 4 days. In some embodiments, the first dose is administered for 1, 2, or 3 days.

[0090] In some embodiments, the first dose comprises: about 600 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 500 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. Includes.

[0091] In some embodiments, the first dose comprises: about 700 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0092] In some embodiments, the first dose comprises: about 800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0093] In some embodiments, the first dose comprises: about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0094] In some embodiments, the first dose comprises: about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered for at least one day; about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by 1, 2, 3, or 4 days thereafter; It is.

[0095] In some embodiments, the first dose comprises: about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day for three consecutive days. It is.

[0096] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0097] In some embodiments, the first dose comprises: about 1000 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 900 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0098] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, followed by one or two days of administration. It is.

[0099] In some embodiments, the first dose comprises: about 600 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; Thereafter, about 500 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered daily thereafter. It is.

[0100] In some embodiments, the first dose comprises: about 700 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; Thereafter, about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered daily thereafter. It is.

[0101] In some embodiments, the first dose comprises: about 800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; Thereafter, about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered daily thereafter. It is.

[0102] In some embodiments, the first dose comprises: about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day thereafter. It is.

[0103] In some embodiments, the first dose comprises: about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by administration of about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day for 1, 2, or 3 days; It is.

[0104] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; Thereafter, about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered daily thereafter. It is.

[0105] In some embodiments, the first dose comprises: about 1000 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; Thereafter, about 900 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered daily thereafter. It is.

[0106] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; and about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day thereafter. It is.

[0107] In some embodiments, the first dose comprises: About 600 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, Then, for one day, administer about 500 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0108] In some embodiments, the first dose comprises: About 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, Then, for one day, administer about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0109] In some embodiments, the first dose comprises: About 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, Then, for one day, administer about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0110] In some embodiments, the first dose comprises: About 900 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, Then, for one day, administer about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0111] In some embodiments, the first dose comprises: About 500 mg of Compound I or a pharma- ceutically acceptable salt thereof per day, Then, for one day, administer about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0112] In some embodiments, the first dose comprises: about 1000 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; Then, for one day, administer about 900 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0113] In some embodiments, the first dose comprises: about 300 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; Then, for one day, administer about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day. It is.

[0114] In some embodiments of the methods described herein, the methods include administering a first dose of about 50 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the methods include administering a first dose of about 100 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0115] In some embodiments, the method includes administering a first dose of about 75 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 150 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0116] In some embodiments, the method includes administering a first dose of about 100 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0117] In some embodiments, the method includes administering a first dose of about 150 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0118] In some embodiments, the method includes administering a first dose of about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 400 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0119] In some embodiments, the method includes administering a first dose of about 250 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0120] In some embodiments, the method includes administering a first dose of about 150 mg of compound I or a pharma- ceutically acceptable salt thereof four times a day (QID) for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 150 mg of compound I or a pharma- ceutically acceptable salt thereof every 6 hours (Q6H) for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 200 mg of compound I or a pharma- ceutically acceptable salt thereof three times a day (TID) for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 300 mg of compound I or a pharma- ceutically acceptable salt thereof twice a day (BID) for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 600 mg of compound I or a pharma- ceutically acceptable salt thereof per day for 1, 2, 3, 4, 5, 6, or 7 days.

[0121] In some embodiments, the method includes administering a first dose of about 150 mg of compound I or a pharma- ceutically acceptable salt thereof four times a day (QID) for four days. In some embodiments, the method includes administering a first dose of about 150 mg of compound I or a pharma- ceutically acceptable salt thereof every six hours (Q6H) for four days. In some embodiments, the method includes administering a first dose of about 200 mg of compound I or a pharma- ceutically acceptable salt thereof three times a day (TID) for four days. In some embodiments, the method includes administering a first dose of about 300 mg of compound I or a pharma- ceutically acceptable salt thereof twice a day (BID) for four days. In some embodiments, the method includes administering a first dose of about 600 mg of compound I or a pharma- ceutically acceptable salt thereof per day for four days.

[0122] In some embodiments, the method includes administering a first dose of about 350 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 700 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0123] In some embodiments, the method includes administering a first dose of about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0124] In some embodiments, the method includes administering a first dose of about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0125] In some embodiments, the method includes administering a first dose of about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the method includes administering a first dose of about 1000 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days.

[0126] A first dose is administered for 1, 2, 3, 4, 5, 6, or 7 days to achieve a target therapeutic level of compound I or a pharma- ceutically acceptable salt thereof in the subject, and then a second dose of compound I or a pharma- ceutically acceptable salt thereof is administered to maintain the target therapeutic level in the subject thereafter. In some embodiments, the therapeutic level of compound I is determined by measuring the percent hemoglobin occupied by compound I, or Hb occupancy %.

[0127] In some embodiments, the second dose is from about 25 mg per day to about 300 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, the second dose is from about 25 mg per day to about 275 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0129] In some embodiments, the second dose is from about 25 mg per day to about 250 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the second dose is from about 25 mg per day to about 225 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0131] In some embodiments, the second dose is from about 25 mg per day to about 200 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0132] In some embodiments, the second dose is from about 25 mg per day to about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0133] In some embodiments, the second dose is from about 25 mg per day to about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0134] In some embodiments, the second dose is from about 25 mg per day to about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0135] In some embodiments, the second dose is from about 25 mg per day to about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0136] In some embodiments, the second dose is from about 25 mg per day to about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0137] In some embodiments, the second dose is from about 50 mg per day to about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0138] In some embodiments, the second dose is from about 50 mg per day to about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0139] In some embodiments, the second dose is about 25 mg per day to about 600 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is about 25 mg per day to about 550 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is about 25 mg per day to about 500 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is about 25 mg per day to about 450 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is about 25 mg per day to about 400 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is about 25 mg per day to about 350 mg per day of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the second dose is from about 25 mg per day to about 300 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0140] In some embodiments, the second dose is about 25 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 50 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 75 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 100 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 125 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 150 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 175 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 200 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 225 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 250 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 275 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 300 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 350 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 400 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 450 mg of compound I or a pharma- ceutically acceptable salt thereof per day. In some embodiments, the second dose is about 500 mg of compound I or a pharma- ceutically acceptable salt thereof per day.

[0141] In some embodiments, the second dose is administered once daily (QD).

[0142] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0143] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0145] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof; The first dose is about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and followed by administration of a second dose of about 150 mg per day of Compound I or a pharma- ceutically acceptable salt thereof. A method is provided.

[0146] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0147] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0148] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0149] In some embodiments, the first dose comprises: about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0150] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0151] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0152] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0153] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0154] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0155] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof; The first dose is about 500 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and followed by administration of a second dose of about 100 mg per day of Compound I or a pharma- ceutically acceptable salt thereof. A method is provided.

[0156] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0157] In some embodiments, the first dose comprises: about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0158] Some embodiments include a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I or a pharma- ceutically acceptable salt thereof; The first dose is about 300 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 200 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and followed by administration of a second dose of about 50 mg per day of Compound I or a pharma- ceutically acceptable salt thereof. A method is provided.

[0159] In some embodiments, the first dose comprises: about 600 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 500 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0160] In some embodiments, the first dose comprises: about 700 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the first dose comprises: about 800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0162] In some embodiments, the first dose comprises: about 800 mg per day of Compound I or a pharma- ceutically acceptable salt thereof, administered daily; followed by daily administration of about 700 mg of Compound I or a pharma- ceutically acceptable salt thereof per day; and This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the first dose is about 100 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0164] In some embodiments, the first dose is about 100 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0165] In some embodiments, the first dose is about 100 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 25 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0166] In some embodiments, the first dose is about 150 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0167] In some embodiments, the first dose is about 150 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments, the first dose is about 150 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, the first dose is about 150 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0170] In some embodiments, the first dose is about 150 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 25 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0171] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0172] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0173] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0174] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0175] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0176] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0177] In some embodiments, the first dose is about 200 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 25 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0178] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0179] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0180] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0182] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0183] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0184] In some embodiments, the first dose is about 400 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0185] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0186] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0187] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0188] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0189] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0190] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0191] In some embodiments, the first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0192] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0194] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0195] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0196] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0197] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0198] In some embodiments, the first dose is about 600 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0199] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0200] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0201] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0202] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0203] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0204] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0205] In some embodiments, the first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0206] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0207] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0208] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0209] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0210] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0211] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0212] In some embodiments, the first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0213] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0214] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0215] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0216] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0217] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0218] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0219] In some embodiments, the first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0220] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0221] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0222] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0223] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0224] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0225] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0226] In some embodiments, the first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0227] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0228] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0229] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0230] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0231] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0232] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0233] In some embodiments, the first dose is about 800 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0234] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0235] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0236] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0237] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0238] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0239] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0240] In some embodiments, the first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0241] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0242] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0243] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0244] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0245] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0246] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0247] In some embodiments, the first dose is about 900 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0248] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0249] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0250] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0251] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0252] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0253] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0254] In some embodiments, the first dose is about 450 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0255] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0256] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0257] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0258] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0259] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0260] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0261] In some embodiments, the first dose is about 1000 mg of Compound I, or a pharma- ceutically acceptable salt thereof, administered per day for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0262] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0263] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 175 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0264] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 150 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0265] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 125 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0266] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 100 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0267] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 75 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0268] In some embodiments, the first dose is about 500 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days; This is followed by administration of a second dose of about 50 mg per day of Compound I, or a pharma- ceutically acceptable salt thereof.

[0269] In some embodiments, the first dose is administered for 4 days. In some embodiments, the first dose is administered for 5 days. In some embodiments, the first dose is administered for 6 days. In some embodiments, the first dose is administered for 7 days.

[0270] In some embodiments, a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered twice daily (BID), and a second dose of Compound I is then administered once daily (QD).

[0271] In some embodiments, a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered three times daily (TID) and a second dose of Compound I is then administered once daily (QD).

[0272] In some embodiments, a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered four times daily (QID), and a second dose of Compound I is then administered once daily (QD).

[0273] In some embodiments, a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered every six hours (Q6H), and a second dose of Compound I is administered once a day thereafter (QD).

[0274] In some embodiments, the second dose of compound I or a pharma- ceutically acceptable salt thereof is administered once a day (QD). In some embodiments, the second dose of compound I or a pharma- ceutically acceptable salt thereof is administered twice a day (BID). In some embodiments, the second dose of compound I or a pharma- ceutically acceptable salt thereof is administered three times a day (TID). In some embodiments, the second dose of compound I or a pharma- ceutically acceptable salt thereof is administered four times a day (QID). In some embodiments, the second dose of compound I or a pharma- ceutically acceptable salt thereof is administered every six hours (Q6H).

[0275] In some embodiments, a first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered twice daily (BID), and a second dose of Compound I, or a pharma- ceutically acceptable salt thereof, is then administered once daily (QD).

[0276] In the embodiments disclosed herein, the second dose is administered for as long as the patient requires or would benefit from the therapeutic effect provided by such administration.

[0277] In some embodiments, the second dose is administered for 1-4 weeks. In some embodiments, the second dose is administered for 1-5 weeks. In some embodiments, the second dose is administered for 1-6 weeks. In some embodiments, the second dose is administered for 1-7 weeks. In some embodiments, the second dose is administered for 1-8 weeks. In some embodiments, the second dose is administered for 1-9 weeks. In some embodiments, the second dose is administered for 1-10 weeks. In some embodiments, the second dose is administered for 1-20 weeks. In some embodiments, the second dose is administered for 1-30 weeks. In some embodiments, the second dose is administered for 1-40 weeks. In some embodiments, the second dose is administered for 1-50 weeks. In some embodiments, the second dose is administered for 1-60 weeks. In some embodiments, the second dose is administered for 1-70 weeks. In some embodiments, the second dose is administered for 1-80 weeks. In some embodiments, the second dose is administered for 1-90 weeks. In some embodiments, the second dose is administered for 1-100 weeks.

[0278] In some embodiments, the second dose is administered for at least 1 week. In some embodiments, the second dose is administered for at least 2 weeks. In some embodiments, the second dose is administered for at least 3 weeks. In some embodiments, the second dose is administered for at least 4 weeks. In some embodiments, the second dose is administered for at least 5 weeks. In some embodiments, the second dose is administered for at least 6 weeks. In some embodiments, the second dose is administered for at least 7 weeks. In some embodiments, the second dose is administered for at least 8 weeks. In some embodiments, the second dose is administered for at least 9 weeks. In some embodiments, the second dose is administered for at least 10 weeks. In some embodiments, the second dose is administered for at least 15 weeks. In some embodiments, the second dose is administered for at least 20 weeks. In some embodiments, the second dose is administered for at least 30 weeks. In some embodiments, the second dose is administered for at least 40 weeks. In some embodiments, the second dose is administered for at least 50 weeks. In some embodiments, the second dose is administered for at least 60 weeks. In some embodiments, the second dose is administered for at least 70 weeks. In some embodiments, the second dose is administered for at least 8 weeks. In some embodiments, the second dose is administered for at least 90 weeks. In some embodiments, the second dose is administered for at least 100 weeks.

[0279] In some embodiments, the second dose is administered for at least 1 year. In some embodiments, the second dose is administered for at least 2 years. In some embodiments, the second dose is administered for at least 3 years. In some embodiments, the second dose is administered for at least 4 years. In some embodiments, the second dose is administered for at least 5 years. In some embodiments, the second dose is administered for at least 6 years. In some embodiments, the second dose is administered for at least 7 years. In some embodiments, the second dose is administered for at least 8 years. In some embodiments, the second dose is administered for at least 9 years. In some embodiments, the second dose is administered for at least 10 years.

[0280] In some embodiments, the second dose is administered for the life of the subject, hi some embodiments, the second dose is administered until the death of the subject.

[0281] In some embodiments, the first dose and the second dose are administered consecutively. For example, in some embodiments, the first dose is administered consecutively for four days, and the second dose is first administered on the fifth day.

[0282] In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 20 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 16 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% 8 hours to about 12 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof.

[0283] In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 55% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 50% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 45% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 40% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 35% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof.

[0284] In some embodiments, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% after a loading dose regimen as described herein. For example, in some embodiments, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% after a loading dose regimen comprising administration of 300 mg of Compound I or a pharma- ceutically acceptable salt thereof twice daily (BID) for 4 days.

[0285] In some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% prior to administration of a second dose (or maintenance dose) of Compound I or a pharma- ceutically acceptable salt thereof. For example, in some embodiments, the hemoglobin occupancy percentage in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% after a loading dose regimen comprising administration of 300 mg of Compound I or a pharma- ceutically acceptable salt thereof twice daily (BID) for 4 days and prior to administration of a second dose (or maintenance dose) of Compound I or a pharma- ceutically acceptable salt thereof.

[0286] In some embodiments, administration of Compound I, or a pharma- ceutically acceptable salt thereof, results in a hematocrit value of about 20% to about 50% in the subject.

[0287] In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of at least about 20% in the subject. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of at least about 30% in the subject. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of about 40% in the subject. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of about 45% in the subject.

[0288] In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 50 μg / mL to about 800 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 95 μg / mL to about 775 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 95 μg / mL to about 750 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 140 μg / mL to about 700 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 190 μg / mL to about 650 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 250 μg / mL to about 475 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 300 μg / mL to about 450 μg / mL. In some embodiments, administration of compound I or a pharma- ceutically acceptable salt thereof results in a blood concentration of compound I of about 300 μg / mL to about 475 μg / mL.

[0289] In some embodiments, the administration of Compound I or a pharma- ceutically acceptable salt thereof is about 1,200 μg * hour / mL ~ approx. 19,200μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 2,280 μg * hour / mL ~ approx. 18,600μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 2,280 μg * hour / mL ~ approx. 18,000μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 3,360 μg * hour / mL ~ approx. 16,800μg* AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 4,560 μg * hour / mL ~ approx. 15,600μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 6,000 μg * hour / mL ~ approx. 11,400μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 7,200 μg * hour / mL~approx. 10,800μg * AUC of Compound I in hours / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 7,200 μg * hour / mL ~ approx. 11,400μg * AUC of Compound I in hours / mL 0~24 results.

[0290] In some embodiments, the administration of Compound I or a pharma- ceutically acceptable salt thereof is about 1,200 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 2,280 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 3,360 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 4,560 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 6,000 μg * AUC of Compound I > hr / mL 0~24In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 7,200 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 10,800 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 11,400 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 15,600 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 16,800 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 18,000 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 18,600 μg * AUC of Compound I > hr / mL 0~24 In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 19,000 μg * AUC of Compound I > hr / mL 0~24 results.

[0291] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition. In some embodiments, Compound I is administered as a pharmaceutical composition.

[0292] In some embodiments, Compound I, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0293] Some embodiments provided herein further comprise administering an additional therapeutic agent.

[0294] In some embodiments, the additional therapeutic agent is a hemoglobin modulator. In some embodiments, the additional therapeutic agent is useful for treating sickle cell disease. In some embodiments, the additional therapeutic agent is useful for treating complications of sickle cell disease. Non-limiting examples of complications of sickle cell disease include iron overload, pain, infection, acute chest syndrome, stroke, and pulmonary hypertension. In some embodiments, the additional therapeutic agent is hydroxyurea, L-glutamine, crizanlizumab, or deferiprone. In some embodiments, the additional therapeutic agent is hydroxyurea.

[0295] It should be understood that the method of treatment embodiments of the present disclosure may be presented in a use-type format.

[0296] Thus, the disclosure provides a compound for use in a method of treating sickle cell disease in a subject in need thereof, wherein the compound is Compound I or a pharma- ceutically acceptable salt thereof, and the method is as described herein.

[0297] Some embodiments of the disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, the compound having the formula

[0298] [ka] or a pharma- ceutically acceptable salt thereof, and the method comprises administering to the subject a first dose of compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days followed by administration of a second dose of compound I or a pharma- ceutically acceptable salt thereof, wherein administration of the first and second doses results in about 25% to about 60% hemoglobin occupancy by compound I.

[0299] In some embodiments of the compound for use, administration of the first and second doses of Compound I, or a pharma- ceutically acceptable salt thereof, results in about 30% to about 50% hemoglobin occupancy by Compound I, or a pharma- ceutically acceptable salt thereof.

[0300] Some embodiments of the disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, the compound having the formula

[0301] [ka] or a pharma- ceutically acceptable salt thereof, and the method comprises administering to the subject a first dose of compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of compound I or a pharma- ceutically acceptable salt thereof from about 25 mg per day to about 500 mg per day.

[0302] Some embodiments of the disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, the compound having the formula

[0303] [ka] or a pharma- ceutically acceptable salt thereof, and the method comprises administering to the subject a first dose of about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for four days, followed by administration of a second dose of 100 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0304] Some embodiments of the disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, the compound having the formula

[0305] [ka] or a pharma- ceutically acceptable salt thereof, and the method comprises administering to the subject a first dose of about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof for four days, followed by administration of a second dose of 150 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0306] Some embodiments of the disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, the compound having the formula

[0307] [ka]

[0308] or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject a first dose of about 400 mg twice daily (BID) of Compound I or a pharmaceutically acceptable salt thereof for 4 days, followed by a second dose of 200 mg per day of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments of the compound for use in a method for treating sickle cell disease, the method comprises administering to the subject a first dose of about 300 mg per day to about 1500 mg per day of Compound I or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day to about 250 mg per day of Compound I or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments of the compounds for use in a method for treating sickle cell disease, the method comprises administering to the subject a first dose of about 200 mg per day to about 900 mg per day of Compound I or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, or 7 days, followed by administration of a second dose of about 25 mg per day to about 250 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0310] In some embodiments of the compound for use in the method of treating sickle cell disease, the second dose is about 25 mg per day, 50 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 200 mg per day, or 250 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0311] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 400 mg of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0312] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 600 mg of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0313] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 800 mg of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0314] In some embodiments of the method described herein or in some embodiments of the compound for use in the method for treating sickle cell disease, the first dose of compound I or a pharma- ceutically acceptable salt thereof is administered once a day (QD), twice a day (BID), three times a day (TID), four times a day (QID), or every six hours (Q4H). In some embodiments of the method described herein or in some embodiments of the compound for use, the first dose of compound I or a pharma- ceutically acceptable salt thereof is administered once a day (QD). In some embodiments of the method described herein or in some embodiments of the compound for use, the first dose of compound I or a pharma- ceutically acceptable salt thereof is administered twice a day (BID). In some embodiments of the method described herein or in some embodiments of the compound for use, the first dose of compound I or a pharma- ceutically acceptable salt thereof is administered three times a day (TID). In some embodiments of the method or the compound for use described herein, the first dose of compound I or its pharmaceutically acceptable salt is administered four times a day (QID).In some embodiments of the method or the compound for use described herein, the first dose of compound I or its pharmaceutically acceptable salt is administered every six hours (Q4H).

[0315] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 200 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0316] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 300 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0317] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 200 mg three times a day (TID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0318] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 150 mg four times a day (QID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0319] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 150 mg every 6 hours (Q6H) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0320] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose is about 400 mg twice daily (BID) of Compound I or a pharma- ceutically acceptable salt thereof administered for 4, 5, 6, or 7 days, followed by a second dose of about 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, or 200 mg per day of Compound I or a pharma- ceutically acceptable salt thereof.

[0321] In some embodiments of the compounds for use in the methods of treating sickle cell disease, the first dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered for four days.

[0322] In some embodiments of the compound for use in the method for treating sickle cell disease, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 1 week, at least 10 weeks, or at least 50 weeks.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 1 week.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 10 weeks.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 50 weeks.

[0323] In some embodiments of the compound for use in the method for treating sickle cell disease, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 1 year, at least 5 years, or at least 10 years.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 1 year.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 5 years.In some embodiments of the compound for use, the second dose of compound I or a pharmaceutically acceptable salt thereof is administered for at least 10 years.

[0324] In some embodiments of the compound for use in the method of treating sickle cell disease, the second dose of Compound I or a pharma- ceutically acceptable salt thereof is administered for the life of the subject.In some embodiments of the compound for use, the second dose of Compound I or a pharma- ceutically acceptable salt thereof is administered until the death of the subject.

[0325] In some embodiments of the compound for use, the second dose of Compound I, or a pharma- ceutically acceptable salt thereof, is administered once daily (QD).

[0326] In some embodiments of the compound for use in the method of treating sickle cell disease, the hemoglobin occupancy percentage in the subject provided by administration of compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 24 hours after completion of administration of the first dose (or loading dose) of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments of the compound for use, the hemoglobin occupancy percentage in the subject provided by administration of compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 20 hours after completion of administration of the first dose (or loading dose) of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments of the compound for use, the hemoglobin occupancy percentage in the subject provided by administration of compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 16 hours after completion of administration of the first dose (or loading dose) of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments of the compound for use, the percent hemoglobin occupancy in the subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% 8 hours to about 12 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharma- ceutically acceptable salt thereof. In some embodiments of the compound for use, administration of the first and second doses of Compound I results in about 30% to about 50% hemoglobin occupancy by Compound I.

[0327] In some embodiments of the compounds for use in the method of treating sickle cell disease, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% after a loading dose regimen as described herein. For example, in some embodiments of the compounds for use, the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% after a loading dose regimen comprising administration of 300 mg of Compound I or a pharma- ceutically acceptable salt thereof twice daily (BID) for four days.

[0328] In some embodiments of the compound for use in a method for treating sickle cell disease, the percent hemoglobin occupancy in the subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% prior to administration of a second dose (or maintenance dose) of Compound I or a pharma- ceutically acceptable salt thereof. For example, in some embodiments of the compound for use, the percent hemoglobin occupancy in the subject provided by administration of Compound I or a pharma- ceutically acceptable salt thereof reaches about 25% to about 60% following a loading dose regimen comprising administration of 300 mg of Compound I or a pharma- ceutically acceptable salt thereof twice daily (BID) for 4 days and prior to administration of a second dose (or maintenance dose) of Compound I or a pharma- ceutically acceptable salt thereof.

[0329] In some embodiments of the compound for use in the method for treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit value of about 20% to about 50% in the subject.

[0330] In some embodiments of the compound for use in the method for treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of at least about 20% in the subject. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of at least about 30% in the subject. In some embodiments of the compound for use, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of about 40% in the subject. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a hematocrit of about 45% in the subject.

[0331] In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 50 μg / mL to about 800 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 95 μg / mL to about 775 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 95 μg / mL to about 750 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 140 μg / mL to about 700 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 190 μg / mL to about 650 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 250 μg / mL to about 475 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 300 μg / mL to about 450 μg / mL. In some embodiments of the compounds for use in the method of treating sickle cell disease, administration of compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of compound I of about 300 μg / mL to about 475 μg / mL.

[0332] In some embodiments of the compound for use in the method of treating sickle cell disease, the administration of Compound I or a pharma- ceutically acceptable salt thereof is at least about 1,200 μg * hour / mL~approx. 19,200μg * AUC of Compound I in hours / mL 0~24In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 2,280 μg * hour / mL ~ approx. 18,600μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 2,280 μg * hour / mL ~ approx. 18,000μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 3,360 μg * hour / mL ~ approx. 16,800μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 4,560 μg * hour / mL ~ approx. 15,600μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 6,000 μg * hour / mL ~ approx. 11,400μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 7,200 μg * hour / mL~approx. 10,800μg * AUC of Compound I in hours / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 7,200 μg * hour / mL ~ approx. 11,400μg * AUC of Compound I in hours / mL 0~24 results.

[0333] In some embodiments of the compound for use in the method of treating sickle cell disease, the administration of Compound I or a pharma- ceutically acceptable salt thereof is at least about 1,200 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 2,280 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 3,360 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a total of about 4,560 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in about 6,000 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 7,200 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 10,800 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 11,400 μg * AUC of Compound I > hr / mL 0~24In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 15,600 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 16,800 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 18,000 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 18,600 μg * AUC of Compound I > hr / mL 0~24 In some embodiments of the compound for use in the method of treating sickle cell disease, administration of Compound I or a pharma- ceutically acceptable salt thereof results in a dose of about 19,000 μg * AUC of Compound I > hr / mL 0~24 results.

[0334] In some embodiments of the compounds for use in the methods of treating sickle cell disease, a first dose of Compound I or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition. In some embodiments of the compounds for use in the methods of treating sickle cell disease, a second dose of Compound I or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition.

[0335] In some embodiments of the compounds for use in the methods of treating sickle cell disease, Compound I, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0336] In some embodiments of the compound for use in the method of treating sickle cell disease, Compound I is a crystalline form (Form I of Compound I) characterized by X-ray powder diffraction containing the following peaks: 18.3°, 23.4°, and 26.1°2θ±0.2°2θ, as determined using Cu-Kα radiation on a diffractometer.

[0337] In some embodiments of the compound for use in the method of treating sickle cell disease, the diffractogram further comprises one or more peaks at 10.8° or 17.3° 2θ±0.2° 2θ.

[0338] In some embodiments of the compound for use in the method of treating sickle cell disease, the crystalline form is characterized by a differential scanning calorimetry (DSC) curve that includes an endotherm at about 111° C. (onset temperature).

[0339] In some embodiments of the compound for use in the method of treating sickle cell disease, the use in treating sickle cell disease further comprises administering an additional therapeutic agent.

[0340] In some embodiments of the compound for use in the method of treating sickle cell disease, the additional therapeutic agent is a hemoglobin modulator. In some embodiments, the additional therapeutic agent is useful for treating sickle cell disease. In some embodiments, the additional therapeutic agent is useful for treating complications of sickle cell disease. Non-limiting examples of complications of sickle cell disease include iron overload, pain, infection, acute chest syndrome, stroke, and pulmonary hypertension. In some embodiments, the additional therapeutic agent is hydroxyurea, L-glutamine, crizanlizumab, or deferiprone. In some embodiments, the additional therapeutic agent is hydroxyurea.

[0341] In some embodiments of the compounds for use in the methods of treating sickle cell disease, the additional therapeutic agent is hydroxyurea.

[0342] 3. Pharmaceutical Compositions and Methods of Administration Compound I described herein, or its pharmaceutically acceptable salt, or its crystalline form can be administered in pharmaceutical composition.Therefore, provided herein is a pharmaceutical composition comprising one or more of the compound I described herein, or its salt or solvate forms, and one or more pharmaceutically acceptable vehicles, such as carriers, adjuvants and excipients.Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.Such compositions are prepared in a manner well known in the pharmaceutical field.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17 th Ed.(1985), and Modern Pharmaceutics, Marcel Dekker, Inc.3 rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0343] The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents.

[0344] The pharmaceutical composition can be administered in a single or multiple first and / or second doses.The pharmaceutical composition can be administered by various methods, including, for example, rectal, oral buccal, intranasal and transdermal routes.In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0345] One method of administration is parenterally, for example, by injection.The form in which the pharmaceutical composition described herein can be incorporated for administration by injection includes, for example, aqueous or oily suspension or emulsion, using sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixir, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical vehicles.

[0346] Oral administration can be another route for administering the compounds described herein, the solid forms described herein, or salts or solvates thereof. Administration can be performed, for example, by capsules or enteric coated tablets. When making pharmaceutical compositions containing at least one of the compounds described herein, the solid forms described herein, or salts or solvates thereof, the active ingredient is usually diluted by an excipient and / or enclosed in such a carrier that can be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active ingredient, soft and hard gelatin capsules, injectable sterile solutions, and packaged sterile powders.

[0347] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup, and methylcellulose.In addition, the formulation may include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate, sweeteners, and flavoring agents.

[0348] Compositions comprising at least one compound or solid form, or salt or solvate thereof, described herein, can be formulated to provide rapid, sustained or delayed release of active ingredient after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are shown in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compound or solid form, or salt or solvate thereof, described herein, in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0349] To prepare solid compositions, such as tablets, the main active ingredient can be mixed with pharmaceutical excipients to form a preformulation solid composition containing the homogeneous mixture of the compound or solid form described herein, or its salt or solvate.When these preformulation compositions are called homogeneous, the active ingredient can be uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0350] The tablets or pills of the compound or solid form described herein, or its salt or solvate, may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the outer dosage component being in the form of an envelope that covers the inner dosage component.The two components may be separated by an enteric layer that helps to resist disintegration in the stomach and allows the inner component to pass unchanged into the duodenum or to be delayed in release.Various materials may be used for such enteric layer or coating, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, acetyl alcohol and cellulose acetate.

[0351] Compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharma-ceutically acceptable solvents may be nebulized by using inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a tent-type face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally. EXAMPLES

[0352] Example 1: Healthy Volunteer and Single Ascending Dose (SAD) Study To evaluate the safety and tolerability of single ascending doses of Compound I, 48 healthy volunteers aged 18-55 years (42 fasted and 6 fed) were administered single ascending doses (50 mg-2200 mg) of Compound I, whereas 16 healthy volunteers aged 18-55 years (14 fasted and 2 fed) were administered placebo in a double-blind, randomized, sequential fashion.

[0353] The primary endpoints were safety and tolerability, and key secondary endpoints included PK and food (high-fat meal) effect.

[0354] Demographics and baseline characteristics of healthy volunteers in the blinded studies are summarized in Table 1 and were similar across groups. Details of the open-label, but identical, studies are included in Table 2. All groups in the blinded studies consisted of six healthy volunteers who received Compound I and two healthy volunteers who received placebo.

[0355] [Table 1]

[0356] [Table 2]

[0357] Adverse events occurring after treatment in the blinded study were mostly grade 1 or 2 using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, as shown in Table 3. Adverse events in the same but open-label study are shown in Table 4. The few adverse events considered drug-related resolved with little or no intervention. No adverse events indicated tissue hypoxia.

[0358] [Table 3]

[0359] [Table 4-1]

[0360] [Table 4-2]

[0361] Whole blood pharmacokinetic (PK) parameters using actual sample collection times and hemoglobin occupancy after single ascending doses are shown in Table 5 (containing data from both healthy volunteers and SCD subjects) and Table 6 (containing data from healthy volunteer subjects only).

[0362] [Table 5]

[0363] [Table 6]

[0364] C max and AUC inf The mean blood to plasma ratios for C ranged from 20 to 42 and 177 to 219 for the dose range of 50 to 2200 mg, respectively. max and AUC inf The mean RBC to plasma ratios for the 50 to 2200 mg dose ranged from 49 to 99 and 420 to 530, respectively.

[0365] Percent hemoglobin occupancy was calculated as follows, where MCHC refers to mean corpuscular hemoglobin concentration and Hct refers to hematocrit: Hb occupancy %=[Compound I] RBC / MCHC [Compound I] RBC =([Compound I] 全血 -(1-Hct)[Compound I] 血漿 ) / Hct

[0366] A single dose of Compound I demonstrated a dose-dependent increase in percent Hb occupancy in healthy volunteers (Figure 1). There was no observable difference in Hb occupancy between fasted and fed states (200 mg). These Hb occupancies exceed those reported in healthy volunteers who received a single dose of voxerotol over a similar range.

[0367] Example 2: Healthy Volunteers and Multiple Ascending Dose (MAD) To evaluate the safety and tolerability of multiple ascending doses (MAD) of Compound I, seven healthy volunteers aged 18-55 years were administered a loading dose of 300 mg of Compound I for 3 days, followed by maintenance doses of 15 mg, 25 mg, 50 mg, or 75 mg of Compound I for 14 days. Three healthy volunteers aged 18-55 years were administered placebo for 14 days. Primary endpoints were safety and tolerability, and key secondary endpoints included effects on PK and electrocardiogram (ECG) parameters.

[0368] As shown in Figure 2, Compound I demonstrated linear, dose-proportional PK in cohorts using multiple ascending doses in healthy volunteers.

[0369] To evaluate the safety and tolerability of multiple ascending doses of Compound I, a separate study was initiated in healthy volunteers aged 18-55 years. Four cohorts of 10 subjects each (n=7 for Compound I, n=3 for placebo) were evaluated in a sequential, double-blind fashion. To reach steady-state levels, each subject received a loading dose regimen for 3 or 4 days, followed by drug once daily for up to 14 days. Primary endpoints were safety and tolerability, and key secondary endpoints included effects on PK and electrocardiogram (ECG) parameters. Table 7 below provides an overview of the doses of Compound I or placebo used in each cohort.

[0370] [Table 7]

[0371] Endpoints were safety (clinical study laboratory results, adverse events, electrocardiogram (DCG) parameters, physical examination findings) and tolerability, and PK.

[0372] The demographics and baseline characteristics of healthy volunteers for all cohorts are summarized in Table 8.

[0373] [Table 8]

[0374] Treatment-emergent adverse events are summarized in Table 9.

[0375] [Table 9]

[0376] The study drug was well tolerated. Safety data were not analyzed by cohort at this time because the study was ongoing and blinded. A grade 4 CPK elevation was reported but was attributed to strenuous exercise at the end of the study and therefore was not related to study drug.

[0377] Preliminary whole blood PK parameters (geometric mean and CV%) and hemoglobin occupancy in healthy volunteers for the 15 mg, 25 mg, 50 mg, and 75 mg MAD cohorts are summarized in Table 10. Plasma PK parameters are presented in Table 11.

[0378] [Table 10]

[0379] [Table 11]

[0380] Example 3: Sickle Cell Disease (SCD Cohort) The study design for single dose (SD) and multiple ascending dose (MAD-1, MAD-2, and MAD-3) cohorts of subjects with sickle cell disease is shown in Figure 3.

[0381] Patients aged 18-60 years with HbSS (homozygous for SCD) who demonstrated a baseline Hb ≥ 5.5 g / dL and ≤ 10.5 g / dL and no vaso-occlusive crises (VOCs) or transfusions during the 30-day screening period were administered a single dose of 100 mg of Compound I (single dose period, SD cohort; see Table 5 in Example 1, SCD 100 mg).

[0382] MAD-1 and MAD-2 cohorts After a washout period of at least 56 days (so that the excretion PK of compound I can be evaluated), patients receive a loading dose of 300 mg per day of compound I for 1 day, followed by a daily dose of 200 mg per day of compound I, and then a maintenance dose of 50 mg per day of compound I for 5 weeks ("MAD-1 cohort").The same patients then receive another loading dose of 500 mg per day of compound I for 1 day, followed by a daily dose of 400 mg per day of compound I, and then a maintenance dose of 100 mg per day of compound I for 3 weeks ("MAD-2 cohort").The total treatment period of MAD-1 cohort and MAD-2 cohort was 8 weeks.

[0383] The primary endpoints were safety and tolerability. Key secondary endpoints included PK and the relationship between time-matched Compound I concentrations and changes from baseline in clinical measures of anemia and hemolysis.

[0384] Pharmacodynamic (PD) markers, such as p20 (partial pressure of O2 at which Hb is 20% saturated with O2) and p50 (partial pressure of O2 at which Hb is 50% saturated with O2), were determined by measuring oxygen equilibrium curves (OEC) after two dose escalations. OECs were generated by hemoximetry, which measures the binding affinity of O2 to Hb in relation to the degree of Hb-O2 saturation relative to the partial pressure of O2 (pO2).

[0385] Demographics and baseline characteristics of the SCD cohort are summarized in Table 12. Treatment-emergent adverse events for the SCD cohort are summarized in Tables 13A and 13B. The majority of treatment-emergent adverse events were grade 1 or 2 and unrelated to study drug. Compound I was safe and well tolerated in both the single ascending dose portion and the multiple ascending dose phase.

[0386] [Table 12]

[0387] [Table 13]

[0388] [Table 14]

[0389] The PK profile of a single 100 mg dose in whole blood and plasma was evaluated using standard non-compartmental analysis. Findings from SCD subjects were compared to those in healthy subjects, as shown in Table 14. Preliminary PK parameter estimates of Compound I in whole blood from SCD subjects were elimination t 1 / 2 ,A.U.C.,T. max , and blood to plasma ratios differed from healthy subjects. 1 / 2 and T maxoccurred almost three times more rapidly or earlier, respectively, in SCD than in healthy subjects, and the blood to plasma ratio was about 30% of the value in healthy subjects (most likely due to fewer RBCs compared to healthy subjects). For the plasma compartment, the difference between the two populations was the excretion t 1 / 2 This was most notable for , which was also approximately 2.5 times more rapid in favor of SCD.

[0390] [Table 15]

[0391] Figure 4 shows the change in hemoglobin at week 8 after two rounds of Compound I treatment (days 56-112) in six SCD patients. At the end of the study, Hb increased up to 1.3 g / dL (mean increase of 2.3 g / dL) and all six subjects experienced improvement in hemolytic markers including reticulocytes (Figure 5), absolute reticulocyte count (Figure 6), lactate dehydrogenase (LDH) (Figure 7), and indirect bilirubin (Figure 8). Mean (SD) percent Hb occupancy in plasma and whole blood, or trough (C) of study drug after 5 weeks of 50 mg QD and 3 weeks of 100 mg QD, was 0.01 mg / dL. min ) and apparent peak level (C max The values ​​at which the C value for the 100 mg cohort was reached are shown in Table 15. max The individual Hb occupancy values ​​ranged from 19.7% to 41.8%. C min and C. max There was little difference between the values, which is consistent with findings in healthy subjects. At the 100mg dose level, two of six patients achieved Hb occupancy of more than 40%. The mean values ​​are consistent with those observed during the weeks preceding those obtained at the end of the treatment period with 50mg and 100mg once daily, or at weeks 5 and 7 of repeated dose treatment (maintenance dose).

[0392] [Table 16]

[0393] The mean increase in hematocrit from baseline to the end of the 8th week of treatment was 6.5%. After the last dose of Compound I, study drug concentrations were assessed for approximately 15 weeks, and excretion rates were 1 / 2 The mean time to baseline was approximately 10 days. This was accompanied by a decrease in mean hemoglobin of 2.2 g / dL. After this 15-week washout period, the mean hematocrit of the five subjects returned to baseline levels (23.46% vs. 23.02%).

[0394] These red blood cells were analyzed for deformability using an ektacytometer laser optical rotational red blood cell analyzer (Lorrca, RR Mechatronics, NL) at defined shear stress values ​​with increasing osmotic gradients (osmolarity scan), and using a newer technique that exposes red blood cells to stepwise deoxygenation (oxygen scan). All patients showed improvement in red blood cell health as demonstrated by oxygen scan studies (Figure 9).

[0395] Hemoximetry box plots (Figure 10) show p20 and p50 values ​​of blood collected from patients with SCD (n=6) during dosing with Compound I. p20 and p50 values ​​for baseline (week 8) to week 10, and week 13 to week 16 represent the dosing periods of 50 mg and 100 mg Compound I, respectively. Both p20 and p50 values ​​decreased from baseline, indicating that Compound I corrects blood Hb and increases Hb-O2 affinity in a dose-dependent manner. These changes in p20 and p50 values ​​during treatment with Compound I correspond to a left shift in OEC relative to baseline (no treatment). The change in p20 per dose is greater than the change in p50, representing a more sensitive measure of Hb correction and indicative of increased Hb-O2 affinity. These results indicate that measurements of OEC allow sensitive monitoring of the degree of increase in Hb-O2 affinity and are indicative of Hb correction by Compound I during treatment.

[0396] MAD-3 cohort As previously mentioned, four of the six patients who participated in the MAD-1 and MAD-2 studies proceeded to the MAD-3 study (n=4). Data are provided for patient 003, who was not compliant with the MAD-3 dosing regimen.

[0397] After completion of the MAD-2 study and a washout period of approximately 8 months, selected patients (n=4) received a loading dose of 300 mg BID for 4 days, followed by a maintenance dose of 150 mg QD (MAD-3 cohort).

[0398] The primary endpoints were safety and tolerability. Key secondary endpoints included PK and the relationship between time-matched Compound I concentrations and changes from baseline in clinical measures of anemia and hemolysis.

[0399] Pharmacodynamic (PD) markers, such as p20 and p50, were determined by measuring OECs generated by hemoximetry.

[0400] Demographic and baseline characteristics of the MAD-3 SCD cohort are summarized in Table 16. Treatment-emergent adverse events for the MAD-3 SCD cohort are summarized in Table 17.

[0401] [Table 17]

[0402] [Table 18]

[0403] Hematocrit and Hb levels at week 6 for patients enrolled in the MAD-3 cohort are shown in Table 18.

[0404] [Table 19]

[0405] Compound I concentrations in whole blood and plasma at week 6 for patients enrolled in the MAD-3 cohort are shown in Table 19.

[0406] [Table 20]

[0407] The % Hb occupancy of Compound I at week 6 for patients enrolled in the MAD-3 cohort is shown in Table 20.

[0408] [Table 21]

[0409] The mean Hb occupancy % of patients enrolled in all three cohorts, MAD-1, MAD-2, and MAD-3, respectively, is shown in FIG.

[0410] Hemoximetry box plots showing p20 and p50 values ​​for blood collected from patients participating in the MAD-3 cohort are shown in Figure 12. Improvements in red blood cell health were also observed in the same MAD-3 cohort of SCD patients, as shown in Figure 13. A summary of the changes in the percentage of sickled red blood cells for SCD patients across all MAD-3 cohorts is shown in Figure 14.

[0411] conclusion In adults with SCD, treatment with Compound I using the dosing regimen described herein, with maintenance doses of 100 mg and 150 mg QD, resulted in mean Hb occupancy greater than 30%, elevated hematocrit, and elevated Hb levels. Compound I at a daily maintenance dose of 150 mg was well tolerated in adults with SCD. Results from hemoximetry, ektacytometry, and peripheral blood smears suggest that Compound I at maintenance doses of 100 mg and 150 mg improves red blood cell health.

[0412] Example 4: Model-Informed Dose Selection for Repeat Dosing of Compound I A "learn and validate" approach was used to select the first dose for studies in healthy volunteers and patients with sickle cell disease (SCD) and included two steps: (1) developing a non-mechanistic population pharmacokinetic (popPK) model using available data and continually refining it to characterize plasma and whole blood concentrations, and (2) using Monte Carlo simulations to select a first (loading) dose suitable to achieve the targeted Hb occupancy for the second (maintenance) dose during the first week of treatment in subsequent cohorts.

[0413] The first dose selected by the model achieved steady state concentrations within one week and was maintained by a second dose of 50 mg, as demonstrated by the consistent trough concentrations observed compared to model predictions over the duration of treatment, as shown in Figure 15. The sequence was repeated with the first dose selected by the new model achieving steady state concentrations within one week and was maintained by a second dose of 100 mg.

[0414] Using a popPK model, a first (loading) dose of 300 mg twice daily (BID) for 4 days, followed by a second (maintenance) dose of 150 mg per day thereafter, was selected to achieve a target Hb occupancy of 38%-59%.

[0415] Example 5: A Phase 2 / 3 Randomized Multicenter Study of Compound I Administered Orally to Participants with Sickle Cell Disease and an Open-Label Pharmacokinetic Study in Pediatric Participants with Sickle Cell Disease This example describes a three-part Phase 2 / 3 study of Compound I administered orally to participants with SCD.

[0416] Part A Part A of the study is a phase 2, randomized, open-label, dose-ranging study in approximately 60 adult participants with SCD. The primary objective of Part A of the study is to evaluate the effect of Compound I in adult participants with SCD, as measured by changes in hemoglobin. The study scheme for Part A of the study is shown in FIG. 16.

[0417] Participants will be screened for eligibility for the study from Day -28 to Day -1. Eligible participants will be randomized based on a 1:1 (100 mg:150 mg) allocation on Day 1 to receive their initial dose (loading dose) of Compound I. After completion of Day 1 assessments and subsequent loading doses, participants will continue to receive their maintenance dose daily through Week 12.

[0418] After at least 6 weeks of dosing in the six adult participants in the 150 mg treatment group has been completed, safety, tolerability, and available PK, Hb occupancy, and PD data will be reviewed to evaluate whether the maintenance dose can be escalated up to 200 mg.

[0419] After the decision to include a higher dose treatment arm is made, subsequently enrolled participants will be randomized 1:1:1 (100 mg:150 mg:up to 200 mg Compound I, respectively) or in an adaptive manner to ensure balance, to receive a loading dose regimen over 4 days, followed by daily maintenance doses through week 12. The loading dose to be used in this study will not exceed 2200 mg in any 24-hour period.

[0420] The proposed loading and maintenance doses to achieve the desired exposure and targeted Hb occupancy % for each dose group are shown in Table 21 below.

[0421] [Table 22]

[0422] The primary endpoint of Part A of the study is to assess the change in hemoglobin from baseline to week 12.

[0423] Secondary endpoints of Part A of the study are to evaluate the effect of Compound I on clinical measures of total hemoglobin and hemolysis, as well as to evaluate the safety and tolerability and PK and PD characteristics of administration of multiple doses of Compound I. Additional secondary endpoints of Part B of the study also include: Proportion of participants with Hb increase from baseline >1 g / dL by week 12, Percent change from baseline in hemolytic measures including indirect bilirubin, absolute reticulocyte count and %, and LDH through week 12; - incidence of adverse events, changes in laboratory assessments, ECGs, and vital signs; The effect of Hb on OECs as measured by p50 up to 12 weeks, and These PK parameters after the first dose (T max AUC of 0~24 , C max , T max , blood to plasma (B:P) ratio.

[0424] Exploratory endpoints for Part A of the study are to evaluate the effect of Compound I on neurocognitive function, erythropoietin (EPO) levels, quality of life (QOL) assessments, RBC deformability, RBC mitochondrial content, VOCs, and other biomarkers. Additional exploratory endpoints for Part A of the study include: Change from baseline to week 12 in executive function composite score as assessed by the NIH Toolbox Cognition Module (Dimensional Change Card Sorting Test) Sort Test, Flanker Inhibitory Control and Attention Test, and Pattern Comparison Processing Speed ​​Test. Change from baseline in EPO levels to week 12, Changes from baseline in quality of life assessments including PGI-C, CGI-C, EQ-5D-5L, and PROMIS-29 through week 12; Changes from baseline in RBC deformability and RBC mitochondrial content through week 12 · Annualized rate of VOCs up to 12 weeks, Time from randomization to first VOC, Changes from baseline in other biomarkers at week 12 (including genomic analysis, membrane fragility, flow adhesion, and protein markers by multiplex assay that may include ICAM, VCAM, P-selectin, E-selectin, ACR, KIM, and hemolytic markers such as haptoglobin, hemopexin, soluble C3, and cell-free hemoglobin levels).

[0425] Part B Part B is a phase 3, randomized, double-blind, placebo-controlled study in adult and pediatric participants. Part B will begin after selecting the optimal dose from Part A of the study. Part B of the study will evaluate the safety and efficacy of Compound I in increasing Hb response in approximately 380 adult and pediatric participants with SCD, with approximately 190 participants receiving placebo and approximately 190 participants receiving the optimal dose of Compound I selected from Part A of the study. The study scheme for Part B of the study is shown in FIG. 17.

[0426] The primary objective of Part B of the study is to evaluate the effect of the optimal dose of Compound I compared with placebo, as measured by hemoglobin response, in adult and pediatric participants with SCD.

[0427] In Part B of the study, participants will be screened for eligibility for the study from day -28 to day -1. Eligible adult participants will be randomized based on a 1:1 (Compound I:placebo) allocation on day 1 to receive the participant's initial dose (loading dose) at the clinical site. After completion of the day 1 assessment and subsequent loading doses, participants will continue to receive the participant's maintenance dose daily from week 1 through week 48. Participants will return to the clinical site for safety, efficacy, and PK / PD evaluations. Incidence of VOC events will be collected every 4 weeks. After completion of treatment at week 48 (day 337), participants will return 8 weeks later (week 56, day 393), approximately 5 half-lives after the last dose, for a final follow-up visit. Participants may choose to enroll in the OLE study under a separate protocol after completing the week 48 visit. Participants who do not enter the OLE study will be followed for approximately 8 weeks after completion of dosing to further evaluate safety.

[0428] The primary endpoint of Part B of the study is to assess the proportion of participants who achieve a rise in Hb from baseline of >1 g / dL at 48 weeks.

[0429] Secondary endpoints of Part B of the study are to evaluate the effects of Compound I compared with placebo on total hemoglobin, clinical measures of hemolysis, and related clinical outcomes, as well as to evaluate the safety and tolerability of daily administration of Compound I for 48 weeks. Additional secondary endpoints include: · Annualized rate of VOC through the end of the 48th week, Proportion of participants with Hb increase of >1 g / dL from baseline at week 24; Change from baseline in Hb to weeks 24 and 48 Percent change from baseline in hemolytic measures including indirect bilirubin, absolute reticulocyte count and %, and LDH through week 48; Changes from baseline to week 48 in quality of life assessments including PGI-C, CGI-C, and PROMIS-29 physical function, anxiety, depression, fatigue, social functioning, pain interference, and pain intensity; - incidence of adverse events, changes in laboratory assessments, ECGs, and vital signs; Trough plasma and blood concentrations, B:P ratio, Percent Hb occupancy by week 48, Time from randomization to first VOC, Time to first increase in Hb from baseline >1 g / dL during the study.

[0430] Exploratory endpoints for Part B of the study are to evaluate the effect of Compound I compared to placebo on neurocognitive function, EPO levels, quality of life assessments, RBC deformability, RBC mitochondrial content, VOCs, and renal biomarkers. Additional exploratory endpoints include: Changes from baseline in other biomarkers through week 48 (including genomic analysis [optional] membrane fragility, flow adhesion, and protein markers by multiplex assays that may include ICAM, VCAM, P-selectin, E-selectin, ACR, KIM, and hemolytic markers such as haptoglobin, hemopexin, soluble C3, and cell-free hemoglobin levels) Change from baseline in executive ability composite score through week 48 as assessed by the NIH Toolbox Cognitive Module (using the Dimensional Change Card Sorting Test, the Flanker Inhibitory Control and Attention Test, and the Pattern Comparison Processing Speed ​​Test); Change from baseline in EPO levels through week 48 Change from baseline in quality of life assessments, including EQ-5D-5L, through week 48; Change from baseline in RBC deformability and mitochondrial content through Week 48.

[0431] Part C Part C of the study is a single-arm, open-label, multiple-dose PK study in four age group cohorts of pediatric participants with SCD, and the multiple-dose portion of Part C of the study will begin after doses are selected for Part B of the study. The study scheme for Part B of the study is shown in FIG. 18.

[0432] Pediatric participants will be assessed for study eligibility during a 35-day screening period (screening was allowed to be extended further due to limited blood draws in pediatric participants). On study day 1, eligible pediatric participants will receive a single dose of Compound I (100 mg dose for cohort C1, dose levels for cohorts C2, C3, and C4 will be determined based on emerging data). Safety, tolerability, and available PK data for Compound I will be evaluated approximately 7 weeks after at least four participants in each cohort have completed single dose (SD) dosing, and those data will recommend progression to multiple dose (MD) dosing. Pediatric participants will receive a loading dose regimen over 4 days (starting on day 1 of MD), followed by once-daily dosing for a total treatment duration of 14 days. The dose given in the MD portion will be informed by emerging clinical trial data and will not exceed dose levels established as safe in adult clinical trials or previous pediatric cohorts. Participants may choose to enroll in an open-label extension (OLE) study under a separate protocol after completing the MD week 2 visit. Participants who do not enter the OLE study will be followed for approximately 8 weeks after completion of dosing to further evaluate safety.

[0433] Part C consists of four cohorts. · Cohort C1 will include approximately 10 participants aged 12-18 years and at least 30% of participants must be aged 12-15 years or younger. · Cohort C2 will include approximately 10 participants aged 6-12 years and at least 30% of participants must be aged 6-9 years or younger. Cohort C3 will include approximately 10 participants aged 2-6 years. Cohort C4 will include approximately 7 participants aged 6 months to less than 2 years.

[0434] Cohorts C2-C4 will begin after completion of 14 days of MD dosing and Data Monitoring Committee (DMC) review of safety, tolerability, and PK data have been evaluated in at least four participants from the preceding cohorts. Up to 10 additional participants may be enrolled in each cohort as needed to evaluate additional dose levels and / or to further characterize PK or safety if deemed necessary. Participants from Part C will not be eligible for enrollment in Part B of the study.

[0435] Inclusion criteria Important inclusion criteria for Parts A, B, and C include: Males or females with SCD. Documentation of SCD genotype homozygous for the sickle cell allele (HbSS) or double heterozygous for sickle hemoglobin (HbS) and β-0 thalassemia (HbSB) can be based on laboratory test history or must be confirmed by laboratory testing during screening, Hb ≥ 5.5 and ≤ 10.5 g / dL during screening and deemed stable by the investigator; For participants taking hydroxyurea (HU) and / or L-glutamine, the doses must have been stable for at least 90 days prior to signing or consenting to the ICF and no need for dose adjustments is anticipated during the study in the opinion of the investigator; · Female participants of childbearing potential must agree to use highly effective contraception or remain abstinent from the start of the study until 120 days after the final dose of study drug. Non-sterile men with partners of childbearing potential must agree to use highly effective contraception during the study and for 120 days after the final dose of study drug. In addition, non-sterile men with partners of childbearing potential must agree to use condoms or remain sexually abstinent during the study and for 120 days after the final dose of study drug. Female participants of childbearing potential must have a negative pregnancy test prior to administration of study drug; Participant provided written informed consent (for adult participants in Parts A and B) or written parent / guardian informed consent and participant assent has been obtained in accordance with Institutional Review Board (IRB) / Ethics Committee (EC) policies and requirements consistent with International Conference on Harmonisation (ICH) guidelines (for pediatric participants in Part B and Part C).

[0436] Important additional inclusion criteria for Part A include: Age 18-65 at screening Men must agree not to donate sperm from the start of the study until 120 days after their final dose.

[0437] Important additional inclusion criteria for Part B include: Ages 12 to 65 years or younger at screening. Participants aged 12 to 18 years or younger will be enrolled in Part B only after the safety evaluation of Cohort C1 of Part C. Men must agree not to donate sperm from the start of the study until 120 days after their final dose. ≥ 2 and ≤ 10 VOCs during the 12-month screening period.

[0438] Exclusion criteria Important exclusion criteria for Parts A, B, and C include: >10 VOCs during 12-month screening, -Breastfeeding or pregnant female participants, Regularly receiving scheduled RBC transfusion therapy (also called chronic, prophylactic, or preventative transfusions) or receiving an RBC or exchange transfusion for any reason within 90 days prior to Day 1; Hospitalization for sickle cell crisis or other vaso-occlusive event within 14 days prior to signing the ICF, Alanine aminotransferase (ALT) laboratory screening test value >4 times the upper limit of normal (ULN) for age, Acute illness or clinically significant bacterial, fungal, parasitic, or viral infection requiring treatment, including acute bacterial infection requiring antibiotics within 14 days prior to study drug administration; Participants with known active hepatitis A, B, or C, or human immunodeficiency virus (HIV), Participants with active symptomatic coronavirus disease 2019 (COVID-19) infection, Estimated glomerular filtration rate (eGFR) of 60 mL / min / 1.73 m at the time of the screening visit as calculated by the central laboratory 2 less than 18 years of age or on chronic dialysis History of malignancy requiring chemotherapy and / or radiation within the past 2 years prior to treatment on Day 1 (topical treatment for non-melanoma skin malignancies is excluded), History of unstable or worsening cardiac or pulmonary disease within 6 months prior to consent; Have received a COVID-19 vaccine authorized by a local regulatory authority (first dose, second dose, or booster dose) within 7 days prior to Day 1; -had received EPO or other hematopoietic growth factor treatment within 28 days prior to signing the ICF or was expected to require such agents during the study; Current or recent voxerotol use. Recent use is defined as within the 10 days prior to Day 1. Current or recent use of crizanlizumab. Recent use is defined as within 90 days prior to Day 1. Ongoing or recent use of a strong or moderate inducer of cytochrome P450 (CYP) or CYP3A4 / CYP3A5, where recent is defined as 5 elimination half-lives prior to Day 1 or within 14 days, whichever is longer; Ongoing or recent use of a strong or moderate inhibitor of CYP3A4 / CYP3A5, where recent is defined as within 5 elimination half-lives prior to Day 1; Ongoing or recent use of the P-glycoprotein substrates digoxin or dabigatran, where recent is defined as within 5 elimination half-lives prior to Day 1; Use of prohibited prescription or non-prescription drugs and dietary supplements (including herbal and alternative medicines). Marijuana use is permitted, except for the 24 hours prior to the neurocognitive evaluation, as outlined in the assessment schedule. Known allergy to Compound I or other Hb polymerization inhibitors, History of severe allergic reactions to any substance (including anaphylaxis) or a history of status asthmaticus, · Less likely to comply with study procedures.

[0439] For Part C, important additional exclusion criteria include: · History of stroke or meets criteria for primary prevention of stroke (history of two transcranial Doppler [TCD] measurements ≥ 200 cm / sec by non-imaging TCD or ≥ 185 cm / sec by TCDi) is the only one included.

[0440] dose Dose selection is based on safety and PK results from previous studies described in Examples 1, 2, and 3.

[0441] A loading dose is administered, followed by daily maintenance doses in a multiple dose regimen.

[0442] Treatment duration In Part A, all adult participants will receive maintenance medication until approximately week 12.

[0443] In Part B, all adult and pediatric participants will receive maintenance medication for 48 weeks.

[0444] In Part C, pediatric participants in Cohort C1 will receive a single dose of 100 mg, followed by daily dosing starting at approximately week 8 and continuing for 14 days. Multiday dosing regimens for all Part C cohorts and single dose levels for Cohorts C2-C4 will be informed by emerging data. Doses utilized will not exceed those determined to be tolerated in the adult or older pediatric cohorts. Cohorts C3 and C4 in Part C will receive Compound I either as a powder for oral solution or as a dispersible tablet.

[0445] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains, and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference was individually incorporated by reference in its entirety.

[0446] Those skilled in the art should easily understand that the present disclosure is fully adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variants and compositions currently described herein as representative of preferred embodiments are illustrative and are not intended to limit the scope of the present disclosure. Modifications and other uses thereof will occur to those skilled in the art and are encompassed within the spirit of the present disclosure and defined by the scope of the claims.

Claims

1. 1. A pharmaceutical composition for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of a compound of formula 【Chemical 1】 or a pharmaceutically acceptable salt thereof for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days; subsequently administering a second dose of Compound I or a pharmaceutically acceptable salt thereof; A pharmaceutical composition, wherein administration of the first dose and the second dose results in about 25% to about 60% hemoglobin occupancy by Compound I.

2. 1. A pharmaceutical composition for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of from about 200 mg per day to about 1600 mg per day of a formula 【Chemistry 2】 or a pharmaceutically acceptable salt thereof for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days; followed by administering a second dose of Compound I or a pharmaceutically acceptable salt thereof of from about 25 mg per day to about 500 mg per day.

3. The subject is administered a first dose of about 200 mg per day to about 900 mg per day of the formula 【Chemistry 4】 or a pharmaceutically acceptable salt thereof for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days; 3. The pharmaceutical composition of claim 2, wherein the second dose is about 25 mg per day to about 250 mg per day of Compound I or a pharmaceutically acceptable salt thereof.

4. 3. The pharmaceutical composition of claim 2, wherein the second dose is about 150 mg of Compound I or a pharmaceutically acceptable salt thereof per day.

5. 3. The pharmaceutical composition of claim 2, wherein the first dose is about 400 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day for 4, 5, 6, or 7 days, followed by a second dose of about 150 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day.

6. 3. The pharmaceutical composition of claim 2, wherein the first dose is about 600 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day for 4, 5, 6, or 7 days, followed by a second dose of about 150 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day.

7. 3. The pharmaceutical composition of claim 2, wherein the first dose is about 800 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day for 4, 5, 6, or 7 days, followed by a second dose of about 150 mg of Compound I or a pharmaceutically acceptable salt thereof administered per day.

8. 3. The pharmaceutical composition of claim 2, wherein the first dose of Compound I or a pharmaceutically acceptable salt thereof is administered once daily (QD).

9. 3. The pharmaceutical composition of claim 2, wherein the first dose of Compound I or a pharmaceutically acceptable salt thereof is administered twice daily (BID).

10. 3. The pharmaceutical composition of claim 2, wherein the second dose of Compound I or a pharmaceutically acceptable salt thereof is administered once daily (QD).

11. 3. The method of claim 2, wherein Compound I or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

12. 3. The pharmaceutical composition of claim 2, wherein Compound I or a pharmaceutically acceptable salt thereof is administered orally.

13. The pharmaceutical composition of claim 2, further comprising administering an additional therapeutic agent.

14. 14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agent is hydroxyurea.

15. 2. The pharmaceutical composition of claim 1, wherein the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharmaceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 24 hours after completion of administration of a first dose (or loading dose) of Compound I or a pharmaceutically acceptable salt thereof.

16. 16. The pharmaceutical composition of claim 15, wherein the percent hemoglobin occupancy in a subject provided by administration of Compound I or a pharmaceutically acceptable salt thereof reaches about 25% to about 60% about 8 hours to about 12 hours after completion of administration of the first dose (or loading dose) of Compound I or a pharmaceutically acceptable salt thereof.

17. 10. The pharmaceutical composition of claim 1, wherein the percent hemoglobin occupancy in the subject provided by administration of Compound I or a pharmaceutically acceptable salt thereof reaches about 25% to about 60% prior to administration of a second dose (or maintenance dose) of Compound I or a pharmaceutically acceptable salt thereof.

18. 3. The pharmaceutical composition of claim 2, wherein administration of Compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of Compound I of about 50 μg / mL to about 800 μg / mL.

19. 19. The pharmaceutical composition of claim 18, wherein administration of Compound I or a pharmaceutically acceptable salt thereof results in a blood concentration of Compound I of about 300 μg / mL to about 475 μg / mL.

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