DL- and l-β-hydroxybutyrate and methods of use thereof

Abstract

Methods of increasing plasma exposure of Compound (II) in a subject, modulating or enhancing cardiovascular function in said patient or methods of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof, comprising administering to a subject an effective amount or formulation of a compound selected from Compound (I) or Compound (II), a pharmaceutically acceptable salt thereof, and an ester thereof. Additionally, this disclosure provides processes for synthesizing enantiomerically enriched salts of Compound (II).

Description

TITLE: DL- AND L-P-HYDROXYBUTYRATE AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of and priority to U.S. Applications No.63 / 722,262, filed November 19, 2024, and 63 / 549,104, filed February 2, 2024; each of which are incorporated herein by reference.INTRODUCTION

[0002] Ketone bodies such as P-hydroxybutyrate (3-OHB) and acetoacetate (AcAc) have been shown to be effective in treating cardiovascular, metabolic, renal, skeletal muscle, liver or neurological diseases.

[0003] Recent studies have shown that increasing ketone bodies in the blood following administration of ketone salts or ketone esters can improve cardiac function in patients.

[0004] While a healthy heart derives most of its energy from a -oxidation pathway using fatty acids and glucose as a fuel source, a failing heart experiences a metabolic shift away from using fatty acids and glucose to using ketone bodies as a fuel source. This is partly because the P-oxidation pathway becomes dysregulated and can be bypassed by ketone oxidation. Here, ketone bodies like 3-OHB can thus serve as a method for treating heart failure.

[0005] Additionally, heart failure can be considered a condition associated with acute or chronic cardiac and systemic inflammation. Ketone bodies also possess anti-inflammatory properties and have been shown to suppress cardiac inflammation.

[0006] D-3-OHB is rapidly oxidized as a fuel source and, endogenous levels of D-3-OHB are the predominant enantiomer in circulation. In contrast, L-3-OHB has a slower oxidation rate than D-3-OHB and is present in the circulation at significantly lower levels than D-3- OHB (-3.6% of total circulating 3-OHB). After oral administration of a 50:50 racemic salt mixture, L-3-OHB is metabolized differently than D-3-OHB, resulting in higher exposure levels of L-3-OHB in blood than those with D-3-OHB.

[0007] In vitro, it has been shown that a formulation containing D-3-OHB versus a formulation containing racemic 3-OHB had opposing effects on induced pluripotent stem cell cardiac myocytes electrophysiology (iPS-CMs). In cardiac myocytes isolated from failinghuman hearts, inclusion of D-3-0HB as a fuel source improves cardiac contractility to levels comparable to cardiac myocytes isolated from non-failing human hearts.

[0008] In vivo, most studies investigating the physiologic effects of exogenous ketones have administered either a racemic salt version of 3-OHB or the D-3-OHB enantiomeric form, if the stereochemistry of 3-OHB is at all mentioned.

[0009] Little is known about the in vitro and in vivo activities of L-3-OHB. The DMPK (drug metabolism and pharmacokinetics) and ADME (absorption, distribution, metabolism, and excretion) properties of exogenously administered D- and L-3-OHB are not described. Furthermore, the physiological roles of the L-3-OHB are also unknown.SUMMARY

[0010] The disclosure relates to a compound selected from the group consisting of:(Compound I) (Compound II) a pharmaceutically acceptable salt thereof, an ester thereof, and methods of using the same. In some embodiments, the compound is Compound I, a mixture of D-3-OHB and L-3-OHB. In some embodiments, the compound is Compound I, (DL-3-OHB) a racemic mixture of D- 3-OHB and L-3-OHB. In some embodiments, the compound is Compound II (L-3-OHB).

[0011] In some embodiments, the pharmaceutically acceptable salt is selected from a nonlimiting list of salts including sodium salt, magnesium salt, calcium salt, lithium salt, and potassium salt.

[0012] In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the compound is Compound III. In some embodiments, the compound is Compound IV.(Compound III) (Compound IV)

[0013] In some embodiments, the pharmaceutically acceptable salt is a magnesium salt.In some embodiments, the compound is Compound V. In some embodiments, the compound is Compound VI.(Compound V) (Compound VI)

[0014] In some embodiments, the pharmaceutically acceptable salt is a calcium salt. In some embodiments, the compound is Compound VII. In some embodiments, the compound is Compound VIII.(Compound VII) (Compound VIII)

[0015] In some embodiments, the pharmaceutically acceptable salt is a lithium salt. In some embodiments, the compound is Compound IX. In some embodiments, the compound isCompound X.(Compound IX) (Compound X)

[0016] In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the compound is Compound XI. In some embodiments, the compound is Compound XII.(Compound XI) (Compound XII)

[0017] In some embodiments, the compound is an ester of Compound I or an ester ofCompound II. In some embodiments, the compound is selected from the group of:

[0018] In some embodiments, the disclosure provides a method of increasing plasma exposure of Compound II in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0019] In some embodiments, the disclosure provides a method of modulating or enhancing cardiovascular function in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0020] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in increasing plasma exposure of Compound II in a subject in need thereof.

[0021] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in modulating or enhancing cardiovascular function in a subject in need thereof.

[0022] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for modulating or enhancing cardiovascular function in a subject in need thereof.

[0023] In some embodiments, the disclosure also provides a method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0024] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

[0025] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

[0026] In some embodiments, the acute, sub-acute, sub-chronic, or chronic disease is a cardiovascular, metabolic, renal, skeletal muscle, liver, or neurological diseases.

[0027] The disclosure also provides methods for preparing a pharmaceutically acceptable salt of Compound I or Compound II.BRIEF DESCRIPTION OF THE FIGURES

[0028] The figures are for illustration purposes only and do not provide any limitation on the disclosure.

[0029] Figure 1 (left) illustrates the effect a single oral dose administration of 3000 mg / kg of Compound III on stroke volume (SV) in chronic rat MI. Figure 1 (right) illustrates the effect a single oral dose administration of 1500 mg / kg of Compound IV on SV in chronic rat MI. Unlike Compound III, Compound IV increased SV in chronic rat MI. SV is calculated using the accepted and standardized equation: SV = (i x radius of Aorta2) x VTI, where radius = diameter / 2 and VTI = velocity time integral in aorta.

[0030] Figure 2 (left) illustrates the effect of a single oral dose administration of 3000 mg / kg of Compound III on cardiac output in chronic rat MI. Figure 2 (right) illustrates the effects of a single oral dose administration of 1500 mg / kg of Compound IV cardiac output in chronic rat MI. Both Compounds III and IV trend to increase cardiac output in chronic rat MI. Cardiac output (CO) is calculated as the product of SV and heart rate.

[0031] Figure 3 (left) illustrates the effects of a single oral dose administration of 3000 mg / kg of Compound III on ejection fraction (EF) in chronic rat MI. Figure 3 (right) illustrates the effects of a single oral dose administration of 1500 mg / kg of Compound IV on ejection fraction in chronic rat MI. Both Compounds III and IV increase ejection fraction in chronic rat MI.

[0032] Figure 4 (left) illustrates the effects of a single oral dose administration of 3000 mg / kg of Compound III on left ventricular end systolic volume (LVESV) in chronic rat MI. Figure 4 (right) illustrates the effects of a single oral dose administration of 1500 mg / kg of Compound IV on left ventricular end systolic volume (LVESV) in chronic rat ML Compound III, but not Compound IV, significantly decreases LVESV in chronic rat ML

[0033] Figure 5 (left) illustrates the effects of a single oral dose administration of 3000 mg / kg of Compound III on left ventricular end diastolic volume (LVEDV) in chronic rat ML Figure 4 (right) illustrates the effects of a single oral dose administration of 1500 mg / kg Compound IV on left ventricular end diastolic volume (LVEDV) in chronic rat MI. Compound III, but not Compound IV, significantly decreased LVEDV in chronic rat ML

[0034] Figure 6 (left) illustrates the mean relative change on cardiac function parameters in chronic rat MI following a single oral dose administration of 3000 mg / kg of Compound III. Figure 6 (right) illustrates the mean relative change on cardiac function parameters in chronic rat MI following a single oral dose administration of 1500 mg / kg of Compound IV. Parameters include left ventricular end-diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), EF, SV, CO, and heart rate (HR). Following oral administration of Compound III, LVESV and LVEDV were reduced, and EF was increased relative to measurements at baseline. Following oral administration of Compound IV, EF and SV were increased relative to baseline.

[0035] Figures 7 illustrates the acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses as following oral administration of vehicle and two single doses each Compound III in spontaneously hypertensive rats (SHR), respectively.

[0036] Figures 8 illustrates the acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses as following oral administration of vehicle and two single doses each sodium D-3-OHB in spontaneously hypertensive rats (SHR), respectively.

[0037] Figures 9 illustrates the acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses as following oral administration of vehicle and two single doses each Compound IV in spontaneously hypertensive rats (SHR), respectively.

[0038] Figure 10 illustrates the acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses of orally administered Compound III at 1000 and 3000 mg / kg compared to vehicle treated in SHR.

[0039] Figure 1 1 illustrates acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses for orally administered sodium D-3-OHB at 500 and 1500 mg / kg compared to vehicle treated in SHR.

[0040] Figure 12 illustrates acute (short-term) systolic, diastolic, and mean arterial pressures, and heart rate responses for orally administered Compound IV at 750 and 1500 mg / kg compared to vehicle treated in SHR.

[0041] Figure 13 illustrates plasma exposures of D-3-0HB and Compound II following oral administration of vehicle and Compound III at 3000 mg / kg in SHR.

[0042] Figure 14 illustrates plasma exposures of D-3-OHB and Compound II following oral administration of vehicle and Compound IV at 1500 mg / kg in SHR.

[0043] Figure 15 illustrates the plasma exposures and PK data of Compound II and D-3- OHB in fed Sprague-Dawley rats when Compound III is administered by oral gavage at 3000 mg / kg and by IV at 1000 mg / kg.

[0044] Figure 16 illustrates the plasma exposure and PK data of D-3-OHB in fed Sprague- Dawley rats when sodium D-3-OHB is administered by oral gavage at 1500 mg / kg and by IV at 500 mg / kg.

[0045] Figure 17 illustrates the plasma exposure and PK data of Compound II in fed Sprague-Dawley rats when Compound IV is administered by oral gavage at 1500 mg / kg and by IV at 500 mg / kg. Key pharmacokinetic parameters measured include half-life (P / i), volume of distribution (Vdss), clearance (Cl), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), and bioavailability (%F).

[0046] Figure 18 illustrates plasma exposures, Cmax, Tmax, AUC, and %F for D-3-OHB and Compound II when Compound III is administered by oral gavage at 1500, 750, and 375 mg / kg.

[0047] Figure 19 illustrates the plasma exposures and PK data of Compound II and D-3- OHB in fed beagle dogs when Compound III is administered by oral gavage at 1500 mg / kg and by IV at 500 mg / kg.

[0048] Figure 20 illustrates the plasma exposure and PK data of sodium D-3-OHB in fed beagle dogs when D-3-OHB is administered by oral gavage at 1500 mg / kg and by IV at 500 mg / kg.

[0049] Figure 21 illustrates the plasma exposures of Compound II and D-3-OHB and PK data in fed beagle dogs when Compound IV is administered at 500 mg / kg administered by oral gavage and by IV at 150 mg / kg.

[0050] Figure 22 illustrates the plasma exposures of Compound II and D-3-OHB in fed Sprague-Dawley rats following administration of Compound XIII.

[0051] Figure 23 illustrates the plasma exposures of Compound II and D-3-OHB in fed Sprague-Dawley rats following administration of Compound XV.

[0052] Figure 24 illustrates the plasma exposures of Compound II and D-3-OHB in fed Sprague-Dawley rats following administration of Compound XVII.

[0053] Figure 25 illustrates the plasma exposures of Compound II and D-3-OHB in fed Sprague-Dawley rats following administration of Compound XVIII.

[0054] Figure 26 illustrates the plasma exposures of Compound II and D-3-OHB in fed Sprague-Dawley rats following administration of Compound XIX.

[0055] Figure 27 depicts the results of a study of Caco2 permeability of D-3-OHB and Compound II.

[0056] Figure 28 depicts the results of a study of metabolic stability of Compound II in primary human, rat, and dog hepatocytes.DETAILED DESCRIPTION

[0057] This application discloses the administration of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof and evaluates the plasma exposure of L-3-OHB (Compound II) in a subject. The disclosure also evaluates the pharmacological, pharmacokinetic, and synthetic data for Compound II.

[0058] A person of skill in the art would know how to use the nonlimiting examples of methods and measurements provided in this application to treat an acute, sub-acute, subchronic, or chronic disease.Compounds

[0059] The disclosure relates to a compound selected:(Compound I) (Compound II) a pharmaceutically acceptable salt thereof, and an ester thereof. In some embodiments, the compound is Compound I, a pharmaceutically acceptable salt thereof, or an ester thereof. In some embodiments, the compound is Compound II, a pharmaceutically acceptable salt thereof, or an ester thereof. In some embodiments, the compound is Compound I. In some embodiments, the compound is Compound II. In some embodiments, the compound is a pharmaceutically acceptable salt of Compound I. In some embodiments, the compound is apharmaceutically acceptable salt of Compound II. Tn some embodiments, the compound is an ester of Compound I. In some embodiments, the compound is an ester of Compound II.

[0060] In some embodiments, the compound is Compound I, a mixture of D-3-OHB and Compound II. In some embodiments, the compound is Compound I a racemic mixture (i.e. 0% ee) of D-3-OHB and Compound II.

[0061] In some embodiments, the compound is Compound II. In some embodiments, Compound II may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0062] In some embodiments, the pharmaceutically acceptable salt is selected from a nonlimiting list of salts including sodium salt, magnesium salt, calcium salt, lithium salt, and potassium salt.

[0063] In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the compound is Compound III. In some embodiments, the compound is Compound IV.(Compound III) (Compound IV)

[0064] In some embodiments, Compound III is a racemic mixture of D and L enantiomers (i.e. 0% ee). In some embodiments, Compound IV may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0065] In some embodiments, the pharmaceutically acceptable salt is a magnesium salt.In some embodiments, the compound is Compound V. In some embodiments, the compound is Compound V.

[0066] In some embodiments, Compound V is a racemic mixture of D and L enantiomers (i.e. 0% ee). In some embodiments, Compound VI may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0067] In some embodiments, the pharmaceutically acceptable salt is a calcium salt. In some embodiments, the compound is Compound VII. In some embodiments, the compound is Compound VIII.(Compound VII) (Compound VIII)

[0068] In some embodiments, Compound VII is a racemic mixture of D and L enantiomers (i.e. 0% ee). In some embodiments, Compound VIII may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0069] In some embodiments, the pharmaceutically acceptable salt is a lithium salt. In some embodiments, the compound is Compound IX. In some embodiments, the compound is Compound X.(Compound IX) (Compound X)

[0070] In some embodiments, Compound IX is a racemic mixture of D and L enantiomers (i.e. 0% ee). In some embodiments, Compound X may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0071] Tn some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the compound is Compound XI. In some embodiments, the compound is Compound XII.(Compound XI) (Compound XII)

[0072] In some embodiments, Compound XI is a racemic mixture of D and L enantiomers (i.e. 0% ee). In some embodiments, Compound XII may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0073] In some embodiments, the compound is an ester of Compound I or an ester of Compound II. In some embodiments, the compound is selected from the group of:0074] In some embodiments, the compound is Compound XIII

[0075] In some embodiments, Compound XIII is a racemic mixture of D and L enantiomers (i.e. 0% ee).

[0076] In some embodiments, the compound is Compound XIV

[0077] In some embodiments, Compound XIV may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0078] In some embodiments, the compound is Compound XV

[0079] In some embodiments, Compound XV is a racemic mixture of D and L enantiomers (i.e. 0% ee).

[0080] In some embodiments, the compound is Compound XVI

[0081] In some embodiments, Compound XVI may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure.

[0082] In some embodiments, the compound is Compound XVII

[0083] In some embodiments, Compound XVII may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% diasteriomerically pure.

[0084] In some embodiments, the compound is Compound XVIII

[0085] In some embodiments, Compound XVIII may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% diasteriomerically pure.

[0086] In some embodiments, the compound is Compound XIX

[0087] In some embodiments, Compound XIX may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% diasteriomerically pure.

[0088] Esters of Compound I and Compound II are also disclosed in U.S. Patent No. 11,773,051 and the synthesis of acceptable esters is disclosed in U.S. Patent No. 12,037,317; the entire contents of which are hereby incorporated by reference.Methods

[0089] In some embodiments, the disclosure provides a method of modulating or enhancing cardiovascular function in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0090] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in increasing plasma exposure of Compound II subject in need thereof.

[0091] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in modulating or enhancing cardiovascular function in a subject in need thereof.

[0092] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for modulating or enhancing cardiovascular function in a subject in need thereof.

[0093] In some embodiments, the disclosure also provides a method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0094] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

[0095] In some embodiments, the disclosure provides a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

[0096] In some embodiments, the disease is a cardiovascular, metabolic, renal, skeletal muscle, liver, or neurological diseases.

[0097] Nonlimiting examples of methods to monitor cardiovascular function include catheterization (e.g., Swan-Ganz), imaging (e.g., echo, MRI, PET, etc.), continuous monitoring (e.g., Holter, telemetry, etc.), serum biomarkers (e.g, Troponin T, NTproBNP, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and catecholamine), or exercise stress test.

[0098] Nonlimiting examples of heart failure indications include Heart Failure with preserved Ejection Fraction (HFpEF), Heart Failure with Reduced Ejection Fraction (HFrEF), Heart Failure with Mid-Range Ejection Fraction (HFmEF), Acute Decompensated Heart Failure (ADHF), and Acute Heart Failure (AHF).

[0099] Nonlimiting examples of measurements to determine the efficacy of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for enhancing or modulating cardiovascular function related to HFpEF, HFrEF, and HFmEF include improvement in exercise tolerance (e.g., six-minute walk test, 6MWT) or multiple cardiopulmonary exercise testing (CPET, where the specific readout is maximal oxygen consumption, also known as VCHnax) measures, quality of life (QoL, including Kansas City Cardiomyopathy Questionnaire (KCCQ)), measuring N-terminal prohormone brain natriuretic protein (NTproBNP, circulating biomarker of efficacy), grip strength, energetics profile, and skeletal muscle and respiratory readouts.

[0100] Nonlimiting examples of measurements to determine the efficacy of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for enhancing or modulating cardiovascular function related to HFpEF, HFrEF, and HFmEF include reduction in ESV (Left Ventricular End Systolic Volume (LVESV), improvement in exercise tolerance (e.g., 6MWT) or multiple CPET measures and QoL (e.g, KCCQ), measuring NTproBNP levels, prevention of hospitalization for cardiovascular events, and energetics profile, and skeletal muscle and respiratory readouts.

[0101] Nonlimiting examples of measurements to determine the efficacy of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for enhancing or modulating cardiovascular function related to AHF include measuring number of days in hospital for cardiovascular events (or discharge readiness), measuring number of days between hospital admissions measuring NTproBNP levels, renal function, TnT (Troponin T, a circulating biomarker of cardiac damage), and diuretic response, energetics profile, and measuring less or no change in arrhythmia.

[0102] In some embodiments, cardiovascular function is enhanced or modulated.

[0103] In some embodiments, an “enhancement” in cardiovascular function is relative to baseline levels in a subject prior to administration of a compound of the disclosure.

[0104] In some embodiments, a “modulation” of cardiovascular function is relative to baseline levels in a subject prior to administration of a compound of the disclosure.

[0105] In some embodiments, an “enhancement” or “modulation” of cardiovascular function is relative to known, standard levels, in a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or veterinary animal.

[0106] In some embodiments, the veterinary animal is any domesticated or wild animal. Exemplary veterinary animals include canines (dogs), felines (cats), leporines (rabbits),assinines (donkeys), bovines (cows), ovines (sheep), porcines (pigs), equines (horses), and caprines (goats).

[0107] In some embodiments, the veterinary animal is an equine, a canine, or a feline.

[0108] In some embodiments, the veterinary animal is an equine.

[0109] In some embodiments, the veterinary animal is a companion animal. In some embodiments, a companion animal is a pet. Exemplary companion animals include canines and felines. Other companion animals are known in the art.

[0110] In some embodiments, the veterinary animal is a canine or feline.

[0111] In some embodiments, the veterinary animal is a canine.

[0112] In some embodiments, the veterinary animal is a feline.

[0113] In some embodiments, the administration of the compound is oral, intranasal, intramuscular, intratracheal, transdermal, subcutaneous, intradermal, topical application, intravenous, vaginal, nasal, or by other parenteral routes of administration.

[0114] In some embodiments, the administration of the compound is oral.

[0115] In some embodiments, the administration of the compound is intravenous.

[0116] In some embodiments, the subject is administered 1 mg / kg to 4000 mg / kg of a compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof.

[0117] In some embodiments, the subject is administered 1 mg / kg to 3000 mg / kg of the compound. For example, the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.

[0118] In some embodiments, the compound is administered at least once per day.

[0119] In some embodiments, the compound is administered once per day.

[0120] In some embodiments, the compound is administered twice per day.

[0121] In some embodiments, the compound is administered three times per day.

[0122] In some embodiments, the subject is administered a composition comprising a therapeutically effective amount of the compound.

[0123] In some embodiments, the composition is a pharmaceutical composition.

[0124] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0125] The pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate, magnesium stearate, compritol 888 ATO, precirol ATO 5, Polyox WSR N750, and Polyox WSR 205), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0126] In some embodiments, the pharmaceutical composition further comprises a filler (such as microcrystalline cellulose), a binder (such as Kollidon 30), and a modified release agent (such as Methocel K100).

[0127] In some embodiments, the composition is a dietary supplement.

[0128] In some embodiments, a dietary supplement comprises one or more nutrients to increase the amount of said nutrient consumed by a subject.

[0129] In some embodiments, a dietary supplement comprises one or more nutrients to increase the amount of said nutrient already within the body.

[0130] In some embodiments, a dietary supplement is provided in addition to food consumed by the subject.

[0131] In some embodiments, a dietary supplement is provided as a pill, a capsule, a tablet, a powder, or a liquid.

[0132] In some embodiments, the nutrient is a compound of the disclosure.

[0133] In some embodiments, the subject is exposed to 1 M to 4000 pM of the Compound II or D-3-OHB. In some embodiments, the subject is exposed to 1 pM to 4000 pM of the Compound II. In some embodiments, the subject is exposed to 10 pM to 3000 pM of Compound II. For example, the subject is exposed to 100 pM to 2900 pM, or 200 pM to 2800 M, or 300 pM to 2700 pM, or 400 pM to 2600 M, or 300 M to 2500 pM, or 400 pM to 2400 M, or 500 pM to 2300 pM, or 600 pM to 2200 M, or 700 M to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM.

[0134] In some embodiments, the subject has an acute, sub-acute, sub-chronic, or chronic disease.

[0135] In some embodiments, the subject has an acute, sub-acute, sub-chronic, or chronic disease selected from a cardiovascular, metabolic, renal, skeletal muscle, liver, and neurological diseases.

[0136] In some embodiments, the acute, sub-acute, sub-chronic, or chronic disease is cardiovascular disease. Non-limiting examples of cardiovascular disease include, but are not limited to, congestive heart failure, HFpEF, diastolic dysfunction, diastolic heart failure, hypertrophic cardiomyopathy, HFrEF, systolic heart dysfunction, systolic heart failure, dilated cardiomyopathy, HFmEF, AHF, ADHF, right heart failure, right heart hypertrophy, restrictive cardiomyopathy, disorders related decreased coronary blood flow, vascular disorder resulting from cardiac and renal complications, stroke, ischemia / reperfusion damage,ischemia / reperfusion associated with organ transplant, lung transplant, pulmonary transplant or cardiac transplant, reperfusion injury, endothelial dysfunction, myocardial infarction, myocardial ischemia, diabetic cardiomyopathy, migraine, vascular cognitive impairment, cerebral vasospasm, peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, Raynaud's syndrome or phenomenon, critical limb ischemia, intermittent claudication, microcirculation abnormalities, and cardiogenic shock.

[0137] In some embodiments, the disease treated is an acute, sub-acute, sub-chronic, or chronic disease.

[0138] In some embodiments, an “acute disease” is defined as a disease of rapid onset and is resolved within 1-7 days upon treatment.

[0139] In some embodiments, a “sub-acute disease” is defined as a disease of less rapid onset and short duration (e.g., is resolved within 7-30 days, 1-4 weeks, or 1 month upon treatment).

[0140] In some embodiments, a “sub-chronic disease” is defined as a disease of long duration (e.g., is resolved within 4-24 weeks, or 1-6 months upon treatment).

[0141] In some embodiments, a “chronic disease” is defined as a disease that develops slowly, lasts 6 months or more, and requires ongoing medical attention or changes to activity of daily living or both.

[0142] In some embodiments, the acute, sub-acute, sub-chronic, or chronic disease is a cardiovascular, metabolic, renal, skeletal muscle, liver, or neurological diseases.

[0143] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or veterinary animal. In some embodiments, the subject is a human.

[0144] In some embodiments, the veterinary animal is any domesticated or wild animal. Exemplary veterinary animals include canines (dogs), felines (cats), leporines (rabbits), assinines (donkeys), bovines (cows), ovines (sheep), porcines (pigs), equines (horses), and caprines (goats).Synthesis

[0145] The disclosure also provides processes for preparing a pharmaceutically acceptable salt of Compound I.

[0146] In some embodiments, the disclosure provides a process for preparing a pharmaceutically acceptable salt of Compound II:(Compound II), wherein a pharmaceutically acceptable salt of Compound I is 97% to less than 100% enantiomerically enriched or is enantiomerically pure, wherein the process comprises:(a) reacting the acceptable salt of Compound II that is less than 97% enantiomerically enriched with a first reagent to produce Intermediate A:(Intermediate A);(b) reacting Intermediate A with a second reagent to produce Compound II:OH O O^OH(Compound II); and(c) reacting Compound II with a third reagent to produce the acceptable salt of Compound I that is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

[0147] It will be appreciated that certain compounds of this invention may exist as separate stereoisomers or enantiomers and / or mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a “wedge” (^) or “hash” (••'''' ) bond to a stereogenic atom indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a “wavy” bond (^ ) to a stereogenic atom indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a ''' (“straight”) bond to a stereogenic atom indicates where there is a mixture (e.g., a racemate or enrichment). As A used in the chemical structures disclosed herein, a ' (a “wavy” line perpendicular to a “straight” bond to group “A”) indicates that group “A” is a substituent whose point of attachment is at the end of the bond that terminates at the “wavy” line. As used herein, a stereogenic atom that is notated with an (Z>) or (L) or (7?) or (.S’) indicates the stereochemical designation of the stereogenic atom. (Z>) is equivalent to an (7?) designation under the Cahn- Ingold-Prelog convention and (L) is equivalent to an (5) designation under the Cahn-Ingold- Prelog convention.

[0148] For example, the D-enantiomers of the compounds may he depicted as:

[0149] In some embodiments, a pharmaceutically acceptable salt of Compound I is 97- 99% enantiomerically enriched. In some embodiments, a pharmaceutically acceptable salt of Compound I is enantiomerically pure.

[0150] In some embodiments, step (a) is performed in the presence of an optionally substituted benzyl halide and one or more solvents.

[0151] Non-limiting examples of suitable solvents that may be used in this disclosure include, for example, water (H2O), methanol (MeOH), methylene chloride or dichloromethane (DCM; CH2CI2), acetonitrile (MeCN; CH3CN), N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N- methylpyrrolidone (NMP).

[0152] In some embodiments, the benzyl halide is substituted.

[0153] In some embodiments, the substituted benzyl halide is selected from:

[0154] In some embodiments, the halide of the substituted benzyl halide is selected from iodide, bromide, and chloride.

[0155] In some embodiments, the benzyl halide is unsubstituted.

[0156] In some embodiments, the benzyl halide is selected from benzyl chloride (BnCl), benzyl bromide (BnBr), and benzyl iodide (Bnl).

[0157] In some embodiments, the benzyl halide is BnBr.

[0158] In some embodiments, one or more solvents are selected from DMF, acetone, acetonitrile, DMSO, DMF, DCM, and THF.

[0159] In some embodiments, the solvent is DMF.

[0160] In some embodiments, Intermediate A is purified by chromatography.

[0161] In some embodiments, the chromatography comprises a solvent system.

[0162] In some embodiments, the chromatography is silica gel chromatography.

[0163] In some embodiments, the solvent system comprises petroleum ether.

[0164] In some embodiments, the solvent system comprises ethyl acetate.

[0165] In some embodiments, the solvent system comprises two or more solvents.

[0166] In some embodiments, the solvent system comprises petroleum ether and ethyl acetate.

[0167] In some embodiments, the solvent system comprises 1:99 to 99: 1 of petroleum ether to ethyl acetate.

[0168] In some embodiments, the solvent system is 50:1 petroleum ether to ethyl acetate.

[0169] In some embodiments, the solvent system is 5:1 petroleum ether to ethyl acetate.

[0170] In some embodiments, the solvent system is a gradient.

[0171] In some embodiments, the gradient of the solvent system has a start point of 50: 1 petroleum ether to ethyl acetate and the end point of 5:1 petroleum ether to ethyl acetate.

[0172] In some embodiments, the solvent system is isocratic.

[0173] In some embodiments, Intermediate A is 93% to greater than 99% pure or is enantiomerically pure.

[0174] In some embodiments, Intermediate A is 96% to less than 100% enantiomerically enriched or is enantiomerically pure.

[0175] In some embodiments, Intermediate A is enantiomerically pure.

[0176] In some embodiments, Intermediate A is further purified by chromatography.

[0177] In some embodiments, the chromatography comprises a mobile phase.

[0178] In some embodiments, the chromatography is supercritical fluid chromatography (SFC).

[0179] In some embodiments, the mobile phase comprises ethanol (EtOH).

[0180] In some embodiments, the mobile phase comprises aqueous ammonia

[0181] In some embodiments, the mobile phase comprises more than one solvent.

[0182] In some embodiments, the mobile phase comprises EtOH and NH3(a<y).

[0183] In some embodiments, the mobile phase is 99.9% EtOH and 0.1% NHdc / ^).

[0184] In some embodiments, the mobile phase is a gradient.

[0185] In some embodiments, the mobile phase is isocratic.

[0186] In some embodiments, Intermediate A is 97% to less than 100% enantiomerically enriched. In some embodiments, Intermediate A is enantiomerically pure.

[0187] In some embodiments, step (b) is performed in the presence of hydrogen gas (H2), a palladium catalyst, and one or more solvents.

[0188] In some embodiments, the palladium catalyst is palladium on carbon (Pd / C) or palladium on alumina (Pd / Al).

[0189] In some embodiments, the palladium catalyst is Pd / C.

[0190] In some embodiments, the solvent is THF.

[0191] In some embodiments, step (c) is performed in the presence of one or more bases and one or more solvents.

[0192] In some embodiments, the base is an alkali metal carbonate.

[0193] Non-limiting examples of alkali metal carbonate bases that may be used in this disclosure include, for example, sodium carbonate (Na2CC>3), potassium carbonate (K2CO3), cesium carbonate (CS2CO3), lithium carbonate (U2CO3), sodium bicarbonate (NaHCOs), magnesium carbonate (MgCO , calcium carbonate (CaCO j and potassium bicarbonate (KHCO3).

[0194] In some embodiments, when the acceptable salt of Compound I or II is sodium, the alkali metal carbonate is Na2CO3 or NaHCCh.

[0195] In some embodiments, when the acceptable salt of Compound I or II is potassium, the alkali metal carbonate is KHCO3 or K2CO3.

[0196] In some embodiments, when the acceptable salt of Compound I or II is lithium, the alkali metal carbonate is Li2CO3.

[0197] In some embodiments, when the acceptable salt of Compound I or II is calcium, the alkali metal carbonate is CaCOs.

[0198] In some embodiments, when the acceptable salt of Compound I or II is magnesium, the alkali metal carbonate is MgCCh.

[0199] In some embodiments, the solvent is water.

[0200] In some embodiments, step (c) comprises addition of ethyl acetate to the Compound XIV, the one or more bases, and the one or more solvents to form an aqueous phase and an organic phase.

[0201] In some embodiments, the method further comprises separating the aqueous phase from the organic phase.

[0202] In some embodiments, the aqueous phase is lyophilized.

[0203] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is precipitated from a solution comprising the solid from the lyophilized aqueous phase and THF, EtOH, or a mixture thereof.

[0204] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a sodium salt.

[0205] In some embodiments, this disclosure provides Compound III and IV.

[0206] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a magnesium salt.

[0207] In some embodiments, this disclosure provides Compound V and VI.

[0208] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a calcium salt.

[0209] In some embodiments, this disclosure provides Compound VII and VIII.

[0210] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a lithium salt.

[0211] In some embodiments, this disclosure provides Compound IX and X.

[0212] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a potassium salt.

[0213] In some embodiments, this disclosure provides Compound XI and XII.

[0214] In some embodiments, the precipitated acceptable salt of Compound I or II is washed by:(a) adding the precipitated acceptable salt of Compound I or II to THF and EtOH to form a mixture;(b) stirring the mixture for about 5 h;(c) filtering the stirred mixture to obtain acceptable salt of Compound I or II as a filter cake;(d) washing the acceptable salt of Compound I or II filter cake with THF; and(e) drying the acceptable salt of Compound I or II filter cake in vacuo.

[0215] This disclosure further provides a process to enantiomerically enrich a pharmaceutically acceptable salt of Compound II:(Compound I) that is less than 97% enantiomerically enriched, wherein the process comprises:(a) reacting a pharmaceutically acceptable salt of Compound I that is less than 97% enantiomerically enriched with a first reagent to produce Intermediate A:(Intermediate A);(b) reacting Intermediate A with a second reagent to produce Compound II:OH 0 O^OH(Compound II); and(c) reacting Compound II with a third reagent to produce a pharmaceutically acceptable salt of Compound II that is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

[0216] In some embodiments, step (a) is performed in the presence of an optionally substituted benzyl halide and one or more solvents.

[0217] In some embodiments, the benzyl halide is substituted.

[0218] In some embodiments, the substituted benzyl halide is selected from:

[0219] In some embodiments, the benzyl halide is unsubstituted.

[0220] In some embodiments, the benzyl halide is selected from benzyl chloride (BnCl), benzyl bromide (BnBr), and benzyl iodide (Bnl).

[0221] In some embodiments, the benzyl halide is BnBr.

[0222] In some embodiments, one or more solvents is selected from DMF, acetonitrile, and THF.

[0223] In some embodiments, a solvent is DMF.

[0224] In some embodiments, Intermediate A is purified by chromatography.

[0225] In some embodiments, the chromatography comprises a solvent system.

[0226] In some embodiments, the chromatography is silica gel chromatography.

[0227] In some embodiments, the solvent system used in the chromatography comprises petroleum ether.

[0228] In some embodiments, the solvent system comprises ethyl acetate.

[0229] In some embodiments, the solvent system comprises two or more solvents.

[0230] In some embodiments, the solvent system comprises petroleum ether and ethyl acetate.

[0231] In some embodiments, the solvent system is 50:1 petroleum ether to ethyl acetate.

[0232] In some embodiments, the solvent system is 5:1 petroleum ether to ethyl acetate.

[0233] In some embodiments, the solvent system is a gradient.

[0234] In some embodiments, the solvent system is isocratic.

[0235] In some embodiments, Intermediate A is 93% to greater than 99% pure.

[0236] In some embodiments, Intermediate A is 96% to less than 100% enantiomerically enriched or is enantiomerically pure.

[0237] In some embodiments, Intermediate A is purified.

[0238] In some embodiments, Intermediate A is further purified by chromatography.

[0239] In some embodiments, the chromatography comprises a mobile phase.

[0240] In some embodiments, the chromatography is supercritical fluid chromatography (SFC).

[0241] In some embodiments, the mobile phase comprises ethanol (EtOH).

[0242] In some embodiments, the mobile phase comprises aqueous ammonia (NH3(a )).

[0243] In some embodiments, the mobile phase comprises more than one solvent.

[0244] In some embodiments, the mobile phase comprises EtOH and NHdur / j.

[0245] In some embodiments, the mobile phase comprises 99.9% EtOH and 0.1%NH (a^).

[0246] In some embodiments, the mobile phase is a gradient.

[0247] In some embodiments, the mobile phase is isocratic.

[0248] In some embodiments, Intermediate A is less than 100% enantiomerically enriched.

[0249] In some embodiments, Intermediate A is enantiomerically pure.

[0250] In some embodiments, step (b) is performed in the presence of hydrogen gas (H2), a palladium catalyst, and one or more solvents.

[0251] In some embodiments, the palladium catalyst is palladium on carbon (Pd / C) or palladium on alumina (Pd / Al).

[0252] In some embodiments, the palladium catalyst is Pd / C.

[0253] In some embodiments, the solvent is THF.

[0254] In some embodiments, step (c) is performed in the presence of one or more bases and a one or more solvents.

[0255] In some embodiments, the base is an alkali metal carbonate.

[0256] In some embodiments, when the acceptable salt of Compound II is sodium, the alkali metal carbonate is ISfeCCh or NaHCCh.

[0257] In some embodiments, when the acceptable salt of Compound II is potassium, the alkali metal carbonate is KHCO3 or K2CO3.

[0258] In some embodiments, when the acceptable salt of Compound II is lithium, the alkali metal carbonate is L12CO3.

[0259] In some embodiments, when the acceptable salt of Compound II is calcium, the alkali metal carbonate is CaCOs.

[0260] In some embodiments, when the acceptable salt of Compound II is magnesium, the alkali metal carbonate is MgCO-.

[0261] In some embodiments, the solvent is water.

[0262] In some embodiments, step (c) comprises the addition of ethyl acetate to the Compound II, the one or more bases, and the one or more solvents to form an aqueous phase and an organic phase.

[0263] In some embodiments, step (c) further comprises separating the aqueous phase from the organic phase.

[0264] In some embodiments, step (c) further comprises lyophilizing the aqueous phase.

[0265] In some embodiments, step (c) further comprises precipitating a pharmaceutically acceptable salt of Compound I from a solution comprising a solid and THF, EtOH, or a mixture thereof.

[0266] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a sodium salt.

[0267] In some embodiments, this disclosure provides Compound III and IV.

[0268] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a magnesium salt.

[0269] In some embodiments, this disclosure provides Compound V and VI.

[0270] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a calcium salt.

[0271] In some embodiments, this disclosure provides Compound VII and VIII.

[0272] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a lithium salt.

[0273] In some embodiments, this disclosure provides Compound IX and X.

[0274] In some embodiments, a pharmaceutically acceptable salt of Compound I or II is a potassium salt.

[0275] In some embodiments, this disclosure provides Compound XI and XII.

[0276] In some embodiments, the precipitated pharmaceutically acceptable salt ofCompound I is further washed by:(a) adding the precipitated acceptable salt of Compound II to THF and EtOH to form a mixture;(b) stirring the mixture for about 5 h;(c) filtering the stirred mixture to obtain Compound I as a filter cake;(d) washing the acceptable salt of Compound II filter cake with THF; and(e) drying the acceptable salt of Compound II filter cake in vacuo.Exemplary embodiments

[0277] A listing of exemplary embodiments includes:Embodiment 1. A method of modulating or enhancing cardiovascular function in a subject in need thereof, comprising administering to the subject an effective amount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).Embodiment 2. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of modulating or enhancing cardiovascular function in a subject in need thereof.Embodiment 3. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for modulating or enhancing cardiovascular function in a subject in need thereof.Embodiment 4. The method or compound for use of any one of embodiments 1-3, wherein the pharmaceutically acceptable salt is selected a sodium salt, a magnesium salt, a calcium salt, a lithium salt, and a potassium salt.Embodiment 5. The method or compound for use of any one of embodiments 1-4, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound VII), (Compound (Compound IX), (Compound X),(Compound XVI), (Compound XVII),(Compound XVIII), and (Compound XIX).Embodiment 6. The method or compound for use of any of embodiments 1-3, wherein the compound is selected from Compound I.Embodiment 7. The method or compound for use of any of embodiments 1-3, wherein the compound is Compound II.Embodiment 8. The method or compound for use of embodiment 5, wherein the compound is selected from Compound III.Embodiment 9. The method or compound for use of embodiment 5, wherein the compound is selected from Compound IV.Embodiment 10. The method or compound for use of embodiment 5, wherein the compound is selected from Compound V.Embodiment 11. The method or compound for use of embodiment 5, wherein the compound is selected from Compound VI.Embodiment 12. The method or compound for use of embodiment 5, wherein the compound is selected from Compound VII.Embodiment 13. The method or compound for use of embodiment 5, wherein the compound is selected from Compound VIII.Embodiment 14. The method or compound for use of embodiment 5, wherein the compound is selected from Compound IX.Embodiment 15. The method or compound for use of embodiment 5, wherein the compound is selected from Compound X.Embodiment 16. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XI.Embodiment 17. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XII.Embodiment 18. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XIII.Embodiment 19. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XIV.Embodiment 20. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XV.Embodiment 21. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XVI.Embodiment 22. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XVII.Embodiment 23. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XVIII.Embodiment 24. The method or compound for use of embodiment 5, wherein the compound is selected from Compound XIX.Embodiment 25. The method or compound for use of embodiment 1, wherein the compound selected from Compounds II, IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 26. The method or compound for use of embodiment 25, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 27. The method or compound for use of embodiment 25, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 28. The method or compound for use of embodiment 25, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 29. The method or compound for use of embodiment 25, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 30. The method or compound for use of embodiment 25, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 31. The method or compound for use of embodiment 25, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 32. The method or compound for use of embodiment 25, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 33. The method or compound for use of embodiment 25, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 34. The method or compound for use of embodiment 25, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 35. The method or compound for use of embodiment 25, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 36. The method or compound for use of embodiment 25, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 37. The method or compound for use of any one of embodiments 1-36, wherein the subject is a human or a veterinary animal.Embodiment 38. The method or compound for use of any one of embodiments 1-36, wherein the subject is human.Embodiment 39. The method or compound for use of any one of embodiments 1-36, wherein the subject is the veterinary animal.Embodiment 40. The method or compound for use of any one of embodiments 1-39, wherein administration of the compound is oral.Embodiment 41. The method or compound for use of any one of embodiments 1-39, wherein administration of the compound is intravenous.Embodiment 42. The method or compound for use of any one of embodiments 1-41, wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.Embodiment 43. The method or compound for use of any one of embodiments 1-42, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.Embodiment 44. The method or compound for use of any one of embodiments 1-43, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.Embodiment 45. The method or compound for use of any one of embodiments 1-44, wherein the subject is exposed to 1 pM to 4000 pM of Compound II.Embodiment 46. The method or compound for use of any one of embodiments 1-45, wherein the subject is exposed to 10 M to 3000 pM of Compound II.Embodiment 47. The method or compound for use of any one of embodiments 1-46, wherein the subject is exposed to 100 M to 2900 pM, or 200 pM to 2800 pM, or 300 pM to 2700 M, or 400 M to 2600 pM, or 300 pM to 2500 M, or 400 pM to 2400 pM, or 500 pM to 2300 pM, or 600 M to 2200 pM, or 700 pM to 2100 pM, or 800 M to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.Embodiment 48. The method or compound for use of any one of embodiments 1-47, wherein the compound is administered once per day.Embodiment 49. The method or compound for use of any one of embodiments 1-47, wherein the compound is administered twice per day.Embodiment 50. The method of compound for use of any one of embodiments 1-47, wherein the compound is administered three times a day.Embodiment 51. The method or compound for use of any one of embodiments 1-50, wherein the subject is administered a composition comprising a therapeutically effective amount of the compound.Embodiment 52. The method or compound for use of embodiment 51 , wherein the composition is a pharmaceutical composition.Embodiment 53. The method or compound for use of embodiment 52, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.Embodiment 54. The method or compound for use of embodiment 52, wherein the composition is a dietary supplement.Embodiment 55. The method or compound for use of embodiment 54, wherein the dietary supplement comprises one or more nutrients to increase the amount of said nutrient consumed by a subject.Embodiment 56. The method or compound for use of embodiment 54 or 55, wherein the dietary supplement comprises one or more nutrients to increase the amount of said nutrient already within the body.Embodiment 57. The method or compound for use of any one of embodiments 54-56, wherein the dietary supplement is provided in addition to food consumed by the subject.Embodiment 58. The method or compound for use of any one of embodiments 54-57, wherein the dietary supplement is provided as a pill, a capsule, a tablet, a powder, or a liquid.Embodiment 60. The method or compound for use of any one of embodiments 1-58, wherein the subject has an acute, sub-acute, sub-chronic, or chronic disease.Embodiment 61. The method or compound for use of embodiment 60, wherein the acute, sub-acute, sub-chronic, or chronic disease is selected from cardiovascular, metabolic, renal, skeletal muscle, liver, or neurological diseases..Embodiment 62. The method or compound for use of embodiment 60 or 61, the acute, sub-acute, sub-chronic, or chronic disease includes congestive heart failure, HFpEF, diastolic dysfunction, diastolic heart failure, hypertrophic cardiomyopathy, HFrEF, systolic heart dysfunction, systolic heart failure, dilated cardiomyopathy, HFmEF, AHF, ADHF, right heart failure, right heart hypertrophy, restrictive cardiomyopathy, disorders related decreased coronary blood flow, vascular disorder resulting from cardiac and renal complications, stroke, ischemia / reperfusion damage, ischemia / reperfusion associated with organ transplant, lung transplant, pulmonary transplant or cardiac transplant, reperfusion injury, endothelial dysfunction, myocardial infarction, myocardial ischemia, diabetic cardiomyopathy, migraine, vascular cognitive impairment, cerebral vasospasm, peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, Raynaud’s syndrome or phenomenon, critical limb ischemia, intermittent claudication, microcirculation abnormalities, and cardiogenic shock.Embodiment 63. A method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof, comprising administering to the subject an effectiveamount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).Embodiment 64. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.Embodiment 65. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.Embodiment 66. The method or compound for use of any one of embodiments 63-65, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound VII), (Compound (Compound IX), (Compound X),(Compound XVI), (Compound XVII),(Compound XVIII), and (Compound XIX).Embodiment 67. The method or compound for use of any one of embodiments 63-65, wherein the compound is selected from Compound I.Embodiment 68. The method or compound for use of any one of embodiments 63-65, wherein the compound is Compound II.Embodiment 69. The method or compound for use of embodiment 65, wherein the compound is selected from Compound III.Embodiment 70. The method or compound for use of embodiment 65, wherein the compound is selected from Compound IV.Embodiment 71. The method or compound for use of embodiment 65, wherein the compound is selected from Compound V.Embodiment 72. The method or compound for use of embodiment 65, wherein the compound is selected from Compound VI.Embodiment 73. The method or compound for use of embodiment 65, wherein the compound is selected from Compound VII.Embodiment 74. The method or compound for use of embodiment 65, wherein the compound is selected from Compound VIII.Embodiment 75. The method or compound for use of embodiment 65, wherein the compound is selected from Compound IX.Embodiment 76. The method or compound for use of embodiment 65, wherein the compound is selected from Compound X.Embodiment 77. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XI.Embodiment 78. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XII.Embodiment 79. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XIII.Embodiment 80. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XIV.Embodiment 81. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XV.Embodiment 82. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XVI.Embodiment 83. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XVII.Embodiment 84. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XVIII.Embodiment 85. The method or compound for use of embodiment 65, wherein the compound is selected from Compound XIX.Embodiment 86. The method or compound for use of embodiment 65, wherein the compound selected from Compounds IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 87. The method or compound for use of any one of embodiments 63-65, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 88. The method or compound for use of embodiment 86, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 89. The method or compound for use of embodiment 86, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 90. The method or compound for use of embodiment 86, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 91. The method or compound for use of embodiment 86, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 92. The method or compound for use of embodiment 86, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 93. The method or compound for use of embodiment 86, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 94. The method or compound for use of embodiment 86, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 95. The method or compound for use of embodiment 86, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 96. The method or compound for use of embodiment 86, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 97. The method or compound for use of embodiment 86, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 98. The method or compound for use of any one of embodiments 63-97, wherein the subject is a human or a veterinary animal.Embodiment 99. The method or compound for use of any one of embodiments 63-97, wherein the subject is human.Embodiment 100. The method or compound for use of any one of embodiments 63-97, wherein the subject is the veterinary animal.Embodiment 101. The method or compound for use of any one of embodiments 63-100, wherein administration of the compound is oral.Embodiment 102. The method or compound for use of any one of embodiments 63-100, wherein administration of the compound is intravenous.Embodiment 103. The method or compound for use of any one of embodiments 63-101, wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.Embodiment 104. The method or compound for use of any one of embodiments 63-102, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.Embodiment 105. The method or compound for use of any one of embodiments 63-104, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.Embodiment 106. The method or compound for use of any one of embodiments 63-105, wherein the subject is exposed to 1 uM to 4000 M of Compound II.Embodiment 107. The method or compound for use of any one of embodiments 63-106, wherein the subject is exposed to 10 M to 3000 pM of Compound II.Embodiment 108. The method or compound for use of any one of embodiments 63-107, wherein the subject is exposed to 100 pM to 2900 pM, or 200 pM to 2800 pM, or 300 pM to2700 uM, or 400 M to 2600 M, or 300 pM to 2500 M, or 400 pM to 2400 pM, or 500 pM to 2300 pM, or 600 pM to 2200 pM, or 700 pM to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.Embodiment 109. The method or compound for use of any one of embodiments 63-108, wherein the compound is administered once per day.Embodiment 110. The method or compound for use of any one of embodiments 63-108, wherein the compound is administered twice per day.Embodiment 111. The method of compound for use of any one of embodiments 63-108, wherein the compound is administered three times a day.Embodiment 112. A method of increasing plasma exposure of Compound II in a subject in need thereof, comprising administering to the subject an effective amount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).Embodiment 113. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of increasing plasma exposure of Compound II in a subject in need thereof.Embodiment 114. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for increasing plasma exposure of Compound II in a subject in need thereof.Embodiment 115. The method or compound for use of any one of embodiments 112-114, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound VII), (Compound (Compound IX), (Compound X),VIII),(Compound XVIII), and (Compound XIX).Embodiment 116. The method or compound for use of any one of embodiments 112-115, wherein the compound is selected from Compound I.Embodiment 117. The method or compound for use of any one of embodiments 112-115, wherein the compound is Compound II.Embodiment 118. The method or compound for use of embodiment 115, wherein the compound is selected from Compound III.Embodiment 119. The method or compound for use of embodiment 115, wherein the compound is selected from Compound IV.Embodiment 120. The method or compound for use of embodiment 115, wherein the compound is selected from Compound V.Embodiment 121. The method or compound for use of embodiment 115, wherein the compound is selected from Compound VI.Embodiment 122. The method or compound for use of embodiment 115, wherein the compound is selected from Compound VII.Embodiment 123. The method or compound for use of embodiment 115, wherein the compound is selected from Compound VIII.Embodiment 124. The method or compound for use of embodiment 115, wherein the compound is selected from Compound IX.Embodiment 125. The method or compound for use of embodiment 115, wherein the compound is selected from Compound X.Embodiment 126. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XI.Embodiment 127. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XII.Embodiment 128. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XIII.Embodiment 129. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XIV.Embodiment 130. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XV.Embodiment 131. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XVI.Embodiment 132. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XVII.Embodiment 133. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XVIII.Embodiment 134. The method or compound for use of embodiment 115, wherein the compound is selected from Compound XIX.Embodiment 135. The method or compound for use of embodiment 115, wherein the compound selected from Compounds IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 136. The method or compound for use of any one of embodiments 112-115, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 137. The method or compound for use of embodiment 135, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 138. The method or compound for use of embodiment 135, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 139. The method or compound for use of embodiment 135, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 140. The method or compound for use of embodiment 135, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 141. The method or compound for use of embodiment 135, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 142. The method or compound for use of embodiment 135, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 143. The method or compound for use of embodiment 135, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 144. The method or compound for use of embodiment 135, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 145. The method or compound for use of embodiment 135, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 146. The method or compound for use of embodiment 135, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 147. The method or compound for use of any one of embodiments 112-146, wherein the subject is a human or a veterinary animal.Embodiment 148. The method or compound for use of any one of embodiments 112-147, wherein the subject is human.Embodiment 149. The method or compound for use of any one of embodiments 112-147, wherein the subject is the veterinary animal.Embodiment 150. The method or compound for use of any one of embodiments 112-149, wherein administration of the compound is oral.Embodiment 151. The method or compound for use of any one of embodiments 112-149, wherein administration of the compound is intravenous.Embodiment 152. The method or compound for use of any one of embodiments 112-151, wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.Embodiment 153. The method or compound for use of any one of embodiments 112-152, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.Embodiment 154. The method or compound for use of any one of embodiments 112-153, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.Embodiment 155. The method or compound for use of any one of embodiments 112-154, wherein the subject is exposed to 1 pM to 4000 M of Compound II.Embodiment 156. The method or compound for use of any one of embodiments 112-155, wherein the subject is exposed to 10 pM to 3000 pM of Compound II.Embodiment 157. The method or compound for use of any one of embodiments 112-156, wherein the subject is exposed to 100 M to 2900 M, or 200 M to 2800 pM, or 300 M to 2700 pM, or 400 pM to 2600 pM, or 300 pM to 2500 pM, or 400 pM to 2400 pM, or 500 pM to 2300 pM, or 600 pM to 2200 pM, or 700 pM to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.Embodiment 158. The method or compound for use of any one of embodiments 112-157, wherein the compound is administered once per day.Embodiment 159. The method or compound for use of any one of embodiments 112-157, wherein the compound is administered twice per day.Embodiment 160. The method of compound for use of any one of embodiments 112-157, wherein the compound is administered three times a day.Embodiment 161. A process of preparing a pharmaceutically acceptable salt of Compound II:Compound II, wherein a pharmaceutically acceptable salt of Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure, wherein the process comprises:(a) reacting a pharmaceutically acceptable salt of Compound II that is less than 97% enantiomerically enriched with a first reagent to produce Intermediate A:(Intermediate A);(b) reacting Intermediate A with a second reagent to produce Compound II:(Compound II); and(c) reacting Compound II with a third reagent to produce a pharmaceutically acceptable salt of Compound II that is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.Embodiment 162. The process according to embodiment 161 , wherein the pharmaceutically acceptable salt is selected a sodium salt, a magnesium salt, a calcium salt, a lithium salt, and a potassium salt.Embodiment 163. The process according to embodiment of 162, wherein when the pharmaceutically acceptable salt of Compound I is a sodium salt.Embodiment 164. The process according to embodiment of 162, wherein when the pharmaceutically acceptable salt of Compound I is a magnesium salt.Embodiment 165. The process according to embodiment of 162, wherein when the pharmaceutically acceptable salt of Compound I is a calcium salt.Embodiment 166. The process according to embodiment of 162, wherein when the pharmaceutically acceptable salt of Compound I is a lithium salt.Embodiment 167. The process according to embodiment of 162, wherein when the pharmaceutically acceptable salt of Compound I is a potassium salt.DEFINITIONS

[0278] The nomenclature of certain compounds or substituents are used in their conventional sense, such as described in chemistry literature including but not limited to Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0279] At various places in the present disclosure, substituents, or properties of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure comprise each and every individual or sub-combination of the members of such groups and ranges.

[0280] Unless stated otherwise, the following terms and phrases have the meanings described below. The definitions are not meant to be limiting in nature and serve to provide a clearer understanding of certain aspects of the present disclosure.

[0281] Administering: As used herein, the term “administering” refers to providing a compound or composition of the disclosure to a subject.

[0282] Alkyl'. The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 alkyl indicates that the group may have from 1 to 10 (inclusive) carbon a toms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0283] Amelioration: As used herein, the term “amelioration” or “ameliorating” refers to a lessening of severity of at least one indicator of a condition or disease.

[0284] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In certain embodiments, “animal” refers to humans at any stage of development. In certain embodiments, “animal” refers to veterinary animals at any stage of development. In certain embodiments, the veterinary animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In certain embodiments, animals comprise, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In certain embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone.

[0285] About: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. The term may refer to + / - 10% of the recited value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0286] Biologically active: As used herein, the term “biologically active” refers to a characteristic of any substance or material that has activity in a biological system and / or organism. For instance, a material that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active.

[0287] Compound: Compounds of the present disclosure comprise all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen comprise tritium and deuterium. The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.

[0288] Effective Amount: As used herein, the term “effective amount” of an agent is an amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an effective amount depends upon the context in which it is being applied. For example, in the context of administering an agent that treats a cardiac disease or disorder, an effective amount of an agent is, for example, an amount sufficient to achieve treatment of the cardiac disease or disorder, as compared to the response obtained without administration of the agent.

[0289] In some embodiments, an “effective amount” or “efficacious amount” of a compound of the disclosure is 1 mg / kg to 3000 mg / kg. For example, the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.

[0290] Enantiomerically enriched: As used herein, the term “enantiomerically enriched” refers to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50, but less than 100:0. Enantiomerically enrichment is calculated by:100 where D and L represents the amount of each enantiomer observed in a mixture or isolated from a mixture.

[0291] Enantiomerically pure: As used herein, the term “enantiomerically pure” refers to a sample of a chiral substance whose enantiomeric ratio, within limits of detection, is 100:0. “Enantiomerically pure” can be used interchangeably with enantiopure.

[0292] Exposure: As used herein, “exposure” refers to the drug levels observed in the body after administration of said drug. Exposure can be measured by obtaining samples of bodily fluids (e.g. , plasma, urine, or sweat) and measuring the presence of the drug or metabolites.

[0293] Feature: As used herein, a “feature” refers to a characteristic, a property, or a distinctive element.

[0294] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).

[0295] / / ? vivo'. As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).

[0296] Veterinary animal: As used herein, a “veterinary animal” includes all animals (e.g., vertebrates) except Homo sapiens, including wild and domesticated species. Examples of vertebrate veterinary animals include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep water buffalo, and yak. Veterinary animals include nonhuman primates.

[0297] Optionally Substituted: Compounds described herein may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted,” whether preceded by the term “optionally” or not, indicates that at least one hydrogen or carbon of the “substituted” group is replaced with a substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0298] Pharmaceutically acceptable: The terms “pharmaceutically acceptable” or “therapeutically acceptable” are employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0299] Pharmaceutically acceptable excipients: The terms “pharmaceutically acceptable excipient” or “therapeutically acceptable excipient,” as used herein, refer to an ingredient other than the polymeric compositions described herein (e.g., a vehicle capable of suspending or dissolving the polymeric compound) and having the properties of being substantially nontoxic and non-inflammatory in a subject.

[0300] Pharmaceutically acceptable salts: The present disclosure also comprises pharmaceutically acceptable salts of the compounds described herein. As used herein,“pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts comprise, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts comprise acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, 4-(2-hydroxyethyl)-l -piperazineethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.Representative alkali or alkaline earth metal salts comprise sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, comprising, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine , ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure comprise the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.

[0301] Stereoisomer: As used herein, the term “stereoisomer” refers to both enantiomers and diastereomers.

[0302] Subject: As used herein, the term “subject” refers to any organism to which a compound or composition in accordance with the present disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjectscomprise animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and / or plants. The subject or patient may seek or need treatment, require treatment, is receiving treatment, will receive treatment, or is under care by a trained professional for a particular disease or condition.

[0303] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to expressly capture the potential lack of completeness inherent in many biological and chemical phenomena. Likewise, the exclusion of the term “substantially” does not preclude the same potential lack of completeness inherent in many biological and chemical phenomena.

[0304] Therapeutic Agent: The term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect. Examples of therapeutic agents include, but are not limited to oligonucleotides (e.g., sense and / or antisense DNA and / or RNA), proteins and polypeptides (e.g., hormones, growth factors), small molecules and pharmaceuticals, and cells (e.g., stem cells, epithelium cells).

[0305] Therapeutic Effective Dose and Therapeutic Effective Amount: The term “therapeutic effective dose” and “therapeutic effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered. The “therapeutically effective amount” will vary depending on the compound and / or the age, weight, gender, etc., of the subject to be treated. The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0306] Treating: As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, enhancing, improving, relieving, preventing, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / orcondition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0307] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the present disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description.

[0308] Where ranges are given, endpoints are comprised. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context of the disclosure and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0309] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the present disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[0310] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the present disclosure in its broader aspects.

[0311] While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the present disclosure.

[0312] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the presentspecification, comprising definitions, will control. Tn addition, section headings, the materials, methods, and examples are illustrative only and not intended to be limiting.EXAMPLES

[0313] The disclosure is further illustrated by the following non-limiting examples. The Examples serve only for illustration and are not intended to limit the scope of the disclosure, which is as set out in the claims.

[0314] This disclosure establishes pharmacology following administration of Compound IV, sodium D-3-OHB, and Compound III in disease-relevant models and demonstrates druglike characteristics from ADME and DMPK data for individual 3 -OHB enantiomers across multiple species.

[0315] This disclosure shows pharmacological effects for Compound II on cardiac function following single dose oral administration of Compound IV in a chronic rat model of heart failure with reduced ejection fraction (rat myocardial infarction, MI). Compound IV increases stroke volume and ejection fraction.

[0316] This disclosure demonstrates novel and unique pharmacological effects following administration of Compound III and Compound IV, in contrast to that of sodium D-3-OHB, on cardiac function (heart rate) following single dose oral administration to conscious telemetered Spontaneously Hypertensive Rats (SHR). Compound IV increases heart rate; sodium D-3-OHB has no effect on heart rate; and Compound III increases heart rate similar to the heart rate effects of Compound IV. Compound III and Compound IV track with the duration of plasma exposures of Compound II.

[0317] This disclosure demonstrates novel and unique pharmacological effects for Compound IV on hemodynamics. Unlike Compound III which increases systolic, diastolic, and mean blood pressure immediately following dose administration (0 to 8 hours), Compound IV increases blood pressure from 8 to 9 hours for systolic and mean arterial pressures, and from 4 to 10 hours for diastolic pressure. (Figure 12). The lack of blood pressure effects from 0-8-hrs for Compound IV may be explained by indirect or compensatory (e.g., vasodilatory) activities that are not observed for Compound III or sodium D-3-OHB.

[0318] This disclosure demonstrates that following oral administration of 3 -OHB salts and ketone esters, plasma exposures of Compound II and D-3-OHB depend on the compound structure administered and its enantiomeric form.

[0319] This disclosure demonstrates that Compound II has slower clearance and higher bioavailability in rats and dogs as compared to D-3-OHB.

[0320] This disclosure demonstrates that plasma Compound II exposures are dose linear, unlike D-3-OHB following oral administration of Compound III.

[0321] This disclosure demonstrates that Compound II is metabolically stable in primary human, dog and rat hepatocytes.

[0322] This disclosure demonstrates that Compound II is highly permeable in Caco-2 cells at low concentrations.

[0323] Together, the metabolic stability of Compound II in hepatocytes, the high permeability of Compound II, the higher bioavailability, the slower clearance, and the dose linearity of plasma Compound II following oral administration of Compound III and Compound IV makes L-3-OHB ketone salts or ketone esters more desirable drug candidates and Compound II the more desirable active metabolite as compared to D-3-OHB.

[0324] Based on the pharmacological and pharmacokinetic effects following administration of Compound III, sodium D-3-OHB, and Compound IV, and plasma exposure profiles of D-3-OHB and Compound II following oral administration of ketone ester structures described in this disclosure, it is anticipated that oral administration of structurally distinct ketone salts and ketone esters will confer unique dose-dependent and enantiomerspecific pharmacological responses.Example 1: Pharmacology of single oral dose of Compound III and Compound IV in chronic rat model of reduced ejection fraction (Rat MI)

[0325] Example 1 characterizes the acute response of orally administered Compound III and Compound IV in a rat model of chronic heart failure with reduced ejection fraction (rat MI model of HFrEF).

[0326] The aim of Example 1 is to test if single oral administration of Compound III and Compound IV will enhance cardiac function in a rat model of chronic myocardial infarction. Echocardiographic evaluation was performed one month following permanent coronary artery ligation and used to assess cardiac function before and 3 hours post-dose.

[0327] In Example 1 , two similar but independent protocols were performed in a rat model of chronic myocardial infarction (MI), which was induced by permanent ligation of the left anterior descending coronary artery.

[0328] On day 0, permanent ligation surgeries were performed on 15 animals. On month 1 , day 1 , echocardiography was performed in surviving rats to determine baseline values for cardiac function. On month 1, day 3, in rats with an ejection fraction <45%, Compound III at 3000 mg / kg or Compound IV at 1500 mg / kg was administered by oral gavage, and echocardiography was performed 3 hours post-dose to determine treatment effects on cardiac function.

[0329] Following baseline measurements of cardiac function one-month post-MI, single doses each of Compound III (3000 mg / kg) and Compound IV(1500 mg / kg) were administered by oral gavage to the MI rats, and key measurements of cardiac function were measured 3 hours post-dose.

[0330] Key measurements that were obtained include Stroke Volume (SV), Ejection Fraction (EF), Cardiac Output (CO), Heart Rate (HR), Left Ventricular End Systolic Volume (LVESV), and Left Ventricular End Diastolic Volume (LVEDV).

[0331] SV and CO were calculated according to the following methods:SV- (it xradius of Aorta2) x VTI radius = diameter * VVTI=velocity time integral in AortaCO=((i xradius of Aorta2)xVTI) x HR

[0332] The results are presented in Figures 1 -6. Figure 1 (right) shows an increase in stroke volume in chronic rat MI following oral administration of a single 1500 mg / kg dose of Compound IV. Figure 1 (left) shows that oral administration of a single 3000 mg / kg dose of Compound III had no significant effect on stroke volume in chronic rat MI. Figure 2 shows a trend to increase cardiac output in chronic rat MI following oral administration of a single dose of Compound III and Compound IV. Figure 3 shows an increase in ejection fraction in chronic rat MI following oral administration of a single dose of Compound III and Compound IV. Figures 4 and 5 (left) show that an oral dose of 3000 mg / kg Compound III decreases left ventricular end systolic and end diastolic volumes in chronic rat ML Figures 4 and 5 (right) show that an oral dose of 1500 mg / kg Compound IV had no significant effect on left ventricular end systolic and end diastolic volumes in chronic rat ML Figure 6 shows themean average relative change on cardiac function parameters in chronic rate MI following a single oral dose administration of Compound III and Compound IV. These figures are a bar chart depiction of data calculated from Figures 1, 2, 3, 4 and 5.

[0333] In Example 1 , unique pharmacological profiles on cardiac function can be observed following oral administration of Compound IV in chronic rat MI. Compound IV increased ejection fraction and stroke volume.Example 2: Acute cardiac function and hemodynamic responses to single oral doses of Compound III and Compound IV and sodium D-3-OHB in telemetered spontaneous hypertensive rats

[0334] Example 2 characterizes the acute response of orally administered Compound III, Compound IV, and sodium D-3-OHB in a rat model of hypertension (Spontaneous Hypertensive Rat, SHR)

[0335] The aim of Example 2 is to test if single oral dose administration of Compound III, Compound IV and sodium D-3-OHB will affect cardiac function (heart rate) and hemodynamics (systolic, diastolic and mean blood pressure) in conscious telemetered SHR.

[0336] In Example 2, the compounds were administered to fed rats by oral gavage (po), and heart rate and blood pressure (systolic, diastolic, and mean arterial pressure) were continuously collected in conscious telemetered rats from 24 hours pre-dose to 24 hours postdose.

[0337] For each 3-OHB enantiomeric form and dose, a 2x2 vehicle controlled, cross-over study was performed.

[0338] The doses utilized in this study were as follows: Compound III was administered at 3000 and 1000 mg / kg, sodium D-3-OHB at 1500 and 500 mg / kg, and Compound IV at 1500 and 750 mg / kg; and the vehicle was water. For the highest doses tested, equimolar amounts of each enantiomeric salt form were administered (3000 mg / kg Compound III, 1500 mg / kg sodium D-3-OHB, and 1500 mg / kg Compound IV).

[0339] Results as absolute values (beats per minute, bpm for heart rate, and mmHg for systolic, diastolic and mean pressures) are presented in Figures 7, 8, and 9 with data reported as 1-hour mean values from 24 hours prior to dosing and 24 hours after dosing. For each dose group, values from individual animals were pooled to determine an average for each variable at individual doses.

[0340] Results as change from time-matched baseline for heart rate and systolic, diastolic and mean blood pressures are presented in Figures 10, 11, and 12 where the differencesbetween the 24-hour pre-dose monitoring period (-24 to 0 hours) and the 24-hour post-dose monitoring period (0 to 24 hours) were determined.

[0341] The effects on heart rate and blood pressure from single dose oral administration of Compound III, sodium D-3-OHB, and Compound IV are presented as absolute values in Figures 7, 8, and 9 and as change from time-matched baseline in Figures 10, 11, 12.

[0342] Acute heart rate responses for Compound III, sodium D-3-OHB, and Compound IV were monitored in telemetered SHR and difference effects were observed for each of the enantiomeric forms.

[0343] Following administration of 3000 mg / kg Compound III, plasma exposures of D-3- OHB and Compound II were increased, with the highest levels observed 4- and 8-hours postdose (Figure 13). Following administration of Compound IV at 1500 mg / kg, plasma exposures of Compound II were increased, with highest levels observed 2-hours post-dose and remaining detectable up to 8 hours (Figure 14).

[0344] As can be seen in Figures 10, 11 and 12, oral administration of Compound III and Compound IV demonstrated a robust effect on heart rate, while oral administration of sodium D-3-OHB had no heart rate effects. The increase in heart rate conferred by Compound III and Compound IV was dose dependent. Because no heart rate response was observed for sodium D-3-OHB, the Compound III heart rate response appears to be solely driven by Compound II and is consistent with plasma exposures (Figures 13 and 15).

[0345] The effects on heart rate over 24 hours for Compound III and Compound IV in telemetered spontaneously hypertensive rats can be compared to plasma exposure of D-3- OHB and Compound II over 24 hours (Figures 13 and 14). The duration of heart rate increase following oral administration of Compound III and Compound IV track with the duration of plasma exposures of Compound II (Figures 10, 12, 13, and 14).

[0346] The data on heart rate support the increase in heart rate following oral administration of Compound III appears to be solely driven by L-3-OHB since sodium D-3- OHB has no effect on heart rate.

[0347] Acute systolic, diastolic, and mean arterial blood pressure responses for Compound III, sodium D-3-OHB, and Compound IV were monitored in conscious telemetered spontaneously hypertensive rats and found to be different for each of the enantiomeric forms.

[0348] Compound III demonstrated robust, significant, and dose dependent increases in systolic, diastolic, and mean arterial pressure for 8-hours following dosing (Figure 10),possibly explained to be driven by the increase in heart rate / cardiac function. For the highest dose of Compound III, all blood pressure responses appear to track with plasma exposures of D-3-0HB and Compound II, with plasma exposures and responses waning after 8 hours.

[0349] As compared to Compound III which increases systolic, diastolic, and mean blood pressure immediately following dose administration (0 to 8 hours), Compound IV increased blood pressure from 8 to 9 hours for systolic and mean arterial pressures, and from 4 to 10 hours for diastolic pressure. (Figure 12). In this case, the blood pressure did not appear to track with plasma exposures of Compound II, unlike the blood pressure responses for Compound III.The hemodynamic responses of Compound IV also differ from the hemodynamic responses of sodium D-3-OHB which increases systolic, diastolic, and mean arterial pressures from 6 to 9 hours.

[0350] In summary of Example 2, unique pharmacological profiles on cardiac function (heart rate) can be observed following single oral dose administration of Compound III and Compound IV but not sodium D-3-OHB in the Spontaneous Hypertensive Rat. These data show that the increase in heart rate with Compound III appears to be solely driven by Compound II since sodium D-3-OHB has no effect on heart rate.

[0351] In addition, and unlike the racemic mixture, Compound IV increased blood pressure at later timepoints only which indicates that as an individual enantiomer, Compound II may confer indirect or compensatory (e.g., vasodilatory) activities that are not observed following administration of Compound III or sodium D-3-OHB.Example 3: Pharmacokinetics of 3-OHB enantiomeric salt forms in rats and dogs

[0352] Example 3 demonstrates rat and dog plasma exposures of L- and D-3-OHB following a single dose via oral gavage (PO) and IV administration of Compound III, sodium D-3-OHB, and Compound IV.

[0353] Example 3 also provides a method to understand exposure differences between L- and D-3-OHB through key pharmacokinetic parameters (e.g., half-life (T' / 2), volume of distribution (Vdss), clearance (Cl), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), and bioavailability (%F)).

[0354] Separate groups of 3 Sprague-Dawley rats or 3 Beagle dogs each were orally and intravenously administered Compound III, sodium D-3-OHB, and Compound IV, with at least one week washout between oral and intravenous administration.

[0355] In rats, Compound III was administered at 3000 mg / kg by oral gavage and at 1000 mg / kg by IV. Compound IV was administered at 1500 mg / kg by oral gavage and at 500 mg / kg by IV. Sodium D-3-OHB was administered at 1500 mg / kg by oral gavage and at 500 mg / kg by IV.

[0356] In dogs, Compound III was administered at 1500 mg / kg by oral gavage and at 500 mg / kg IV. Compound IV was administered at 500 mg / kg by oral gavage and 150 mg / kg by IV. Sodium D-3-OHB was administered at 1500 mg / kg by oral gavage and 500 mg / kg by IV.

[0357] In a separate study, groups of 3 Sprague-Dawley rats were each administered Compound III at either 1500, 750 or 375 mg / kg by oral gavage.

[0358] When administered by IV, blood samples were collected at 0, 0.083, 0.25, 0.5, 1.0, 2.0, and 4.0 hours from start of administration. Results from rats are presented in Figures 15, 16, and 17. Results from dogs are presented in Figures 19, 20, and 21.

[0359] When administered by oral gavage, blood samples were collected at 0, 0.5, 1.0, 2.0, 4.0, and 8.0 hours from start of administration. Results from rats are presented in Figures 15, 16, 17, and 18. Results from dogs are presented in Figures 19, 20, and 21.

[0360] Following oral administration of Compound III in rats and dogs, the Cmax for Compound II was greater than the Cmax for D-3-OHB, and plasma levels of Compound II were higher at all timepoints compared to D-3-OHB (Figures 15, 18 and 19).

[0361] Following oral administration of Compound III in rats, plasma exposures of Compound II were greater than D-3-OHB at all dose levels tested (Figures 15 and 18).

[0362] Following oral administration of Compound III in rats, the Cmax for Compound II and the Cmax for D-3-OHB were dose dependent but not dose linear (Figures 15 and 18).

[0363] Following oral administration of Compound III in rats, the AUC for Compound II was dose dependent and dose linear. The AUC for D-3-OHB was dose dependent but not dose linear (Figures 15 and 18).

[0364] Following oral administration of equivalent amounts of individual enantiomer salt forms in rats, Cmax was also higher for Compound II as compared to D-3-OHB, and plasma levels of Compound II were higher than D-3-OHB at all timepoints (Figures 16 and 17).

[0365] Following intravenous administration of Compound III in rats, Cl was ~2-fold slower and T1 / ? was ~1.8-fold longer for Compound II as compared to D-3-OHB. Vdss was similar for Compound II and D-3-OHB (Figure 15). Following intravenous administration of Compound III in dogs, Cl was ~2-fold slower and TVi was ~2-fold longer for Compound II as compared to D-3-OHB. Vdss was similar for Compound II and D-3-OHB (Figure 19).

[0366] Following intravenous administration of individual enantiomer salt forms in rats (sodium D-3-OHB vs Compound IV), Cl was ~2-fold slower for Compound II compared to D-3-OHB whereas T1 / ? and Vdss were similar for Compound II and D-3-OHB. (Figures 16 and 17).

[0367] Following intravenous administration of individual enantiomer salt forms in dogs, Cl was ~1.5 fold slower and T1 / ? was -2.5 -fold longer for Compound II as compared to D-3- OHB. Vdss was similar between Compound II and D-3-OHB (Figures 20 and 21).

[0368] In all studies in rats and dogs, plasma exposures of Compound II were greater than D-3-OHB at all timepoints following oral administration.

[0369] In all studies Compound II showed slower Cl and higher bioavailability than D-3- OHB (Figures 15, 16, 17, 18, 19, 20, and 21).

[0370] Comparing dogs and rats, bioavailability of Compound II is greater in dogs.

[0371] Together, the higher bioavailability, slower clearance, and the dose linearity of plasma Compound II following oral administration of Compound IV and Compound III makes L-3-OHB ketone salts more desirable drug candidates as compared to D-3-OHB ketone salts and Compound II a more desirable active metabolite than D-3-OHB.Example 4: Plasma exposures of 3-OHB with Ketone Esters. Example 4 demonstrates plasma exposures and AUC for Compound II and D-3-OHB in rats following a single dose oral administration of ketone esters: Compound XIII, Compound XV, Compound XVII, Compound XVIII, and Compound XIX.

[0372] Separate groups of 3 Sprague-Dawley rats each were orally administered Compound XIII at 1500 mg / kg, Compound XV at 1500 mg / kg, and Compound XVII, Compound XVIII, and Compound XIX at 750 mg / kg.

[0373] Blood samples were collected at 0, 0.5, 1, 2, 4, 8 and 24 hours from the start of administration.

[0374] Plasma levels of D-3-OHB and L-3-OHB (Compound II) were increased to different extents in rats following oral administration of ketone esters Compound XIII, Compound XV, Compound XVII, Compound XVIII, and Compound XIX (Figures 22, 23, 24, 25, and 26).

[0375] AUCo-8hrs for each enantiomer were calculated for each ketone ester and Compound III using plasma exposures of D-3-OHB and Compound II at each time point from 0-8 hours.

[0376] Following oral administration of 1500 mg / kg each of Compounds VIII and XV, the AUCL 3 OHB to AUCD 3 OHB ratio from 0-8 hours was ~1 (Figures 22 and 23), unlike the ratio for Compound III, which was ~4.5 for the same dose over the same time frame.

[0377] Following oral administration of 750 mg / kg each of Compound XVII, Compound XVIII and Compound XIX, Compound XVII showed the highest ratio of AUCL- 3-0HB to AUCD-3-OHB compared to Compound XVIII and Compound XIX (Figures 24, 25, and 26).

[0378] Together, and considering the pharmacology and plasma exposures of Compound II and D-3-OHB for orally administered 3-OHB sodium salt forms, oral administration of ketone esters are also expected to confer unique dose dependent and enantiomer-specific pharmacological responses.Example 5: ADME properties of Compound II and D-3-OHB using Caco-2 cells

[0379] Example 5 demonstrates concentration dependent cell permeability of D-3-OHB and L-3-OHB (Compound II) following incubation of Caco-2 cells with increasing concentrations of Compound III, Compound IV, and sodium D-3-OHB.

[0380] Caco-2 cells were administered Compound III, Compound IV, and sodium D-3- OHB at concentrations of 2, 20, 200, and 2000 pM. For the racemic mixture, concentrations of each enantiomer were 1, 10, 100, and 1000 uM. Nadolol and Metoprolol were used as permeability markers. Digoxin was used as a substrate for P-glycoprotein efflux transporter. The results are presented in Figure 22.

[0381] Compound II showed high permeability at 2 uM, moderate permeability at 20 uM and low permeability at 200 and 2000 uM

[0382] D-3-OHB showed high permeability at 2 and 20 uM, moderate permeability at 200 uM and low permeability at 2000 uM

[0383] Compound I showed similar permeability for D- and Compound II at all concentrations. Compound II and D-3-OHB showed showed high permeability at 1 and 10 uM, moderate permeability at 100 uM, and low permeability at 1000 uM.

[0384] Results show Compound II and D-3-OHB are highly permeable at low concentrations and poorly permeable at high concentrations in Caco-2 cells.Example 6: Metabolic Stability of Compound II in Primary Hepatocytes

[0385] Example 6 demonstrates the hepatocyte stability of Compound II in primary human, rat and dog hepatocytes following incubation of cells with increasing concentrations of Compound IV.

[0386] Hepatocytes were incubated with Compound IV concentrations of 2, 20, 200, and 2000 micromolar for 0, 15, 30, 60, 90 and 120 min. The cells were incubated at each concentration for a total of 120 minutes and samples were drawn at the described time points to measure stability and T' / i. 3 micromolar of 7-ethoxycoumarin and 7-hydroxy coumarin were used separately as control standards.

[0387] The metabolic stability results are presented in Figure 23. The data shown in Figure 23 reveal low rates of metabolism of Compound II in primary hepatocytes. Across all conditions, results show that greater than 90% of Compound II remained at 120 minutes with a calculated T1 / 2 of approximately 24 hours for 20, 200, and 2000 uM and greater than 96 hours at 2 uM (Figure 23) for rat, dogs and humans.

[0388] In addition, calculated estimations of in vitro and in vivo clearance (CLint(hep) and CLint(iiver), respectively) were also lower than the standards. In contrast, the control standards were completely metabolized by hepatocytes, Compound II was metabolically stable in human, dog, and rat hepatocytes at all concentrations tested and with long half-lives in hepatocytes.Example 7: Method of Preparing Compounds of the Disclosure

[0389] All the specific and generic compounds, and the intermediates disclosed for making these compounds, are considered to be part of the disclosure.

[0390] Should the name of a compound conflict with the structure of the compound anywhere in the present application, the structure supersedes the name and is intended to be controlling.

[0391] Compound III (enantiomerically enriched or enantiomerically pure) can be synthesized according to Scheme 1.Scheme 1 step 1 : step 2:

[0392] To a mixture of Compound III ((3S)-3-hydroxybutanoyl]oxysodium, 150 g, 1.19 mol, 1 eq, purchased from Chembon (Chongqing) Pharmaceutical Co., Ltd.) in dimethylformamide (DMF, 1500 mL) and cooled to 0 °C, bromomethylbenzene (BnBr, 203.47 g, 1.19 mol, 141.30 mL, 1 eq) was added dropwise and the mixture was stirred at 25 °C for 12 hr under a nitrogen atmosphere. This mixture was then combined with another 50 g batch and 5 other 150 g batches. The combined mixtures were diluted with ethyl acetate (3000 mL) and extracted with water (5000 mL*3). The organic phase was dried with anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCF. Petroleum Ether / Ethyl Acetate under gradient conditions of 50:1 to 5:1). Then the product Intermediate A was purified by prep-HPLC (column: Welch Xtimate C18 250*100mm, lOum); mobile phase: [A: H2O (lOmM NH4HCO3); B: Acetonitrile]; gradient: 85: 15 to 50:50 A:B over 20.0 min) and further purified by SFC (column: DAICEL CHIRALPAK AD-3, 250mm*50mm, lOum); mobile phase: [CC -EtOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to get benzyl (3S)-3- hydroxybutanoate Intermediate A, 950 g, 99.63% purity as a colorless oil. HPLC: 99.48% purity, Rt = 1.541 min; SFC: 100% ee, Rt = 2.088 min.B. Step 2

[0393] To a solution of benzyl (3S)-3-hydroxybutanoate Intermediate A, 150 g, 772.29 mmol, 1 eq) in tetrahydrofuran (THF, 1500 mL) was added Pd / C (30 g, 10% Palladium on activated carbon, 50% wet with water for safety) under an argon atmosphere. The mixture was stirred under hydrogen gas (15 Psi) at 25 °C for 12 hr. This mixture was then combined with another 50 g batch and 5 other 150 g batches. The combined mixtures were filtered by Celite, washed with THF (2000 mL) and the filtrate was concentrated under reduced pressure to get (3S)-3-hydroxybutanoic acid, L-3-OHB (Compound II), 520 g, crude) as a yellow oil.C. Step 3

[0394] To a solution of (3S)-3-hydroxybutanoic acid, L-3-OHB (250 g, 2.40 mol, 1 eq) in water (H2O, 1250 mL), sodium bicarbonate (NaHCCL, 181.56 g, 2.16 mol, 0.9 eq was added in portions. The mixture was stirred at 25 °C for 1 hr. This mixture was then combined with a 20 g batch and a 250 g batch. The mixtures were filtered, and the filtrate was extracted with ethyl acetate (EtOAc, 2000 mL*3), the aqueous phase was dried by lyophilization to get a white soapy solid. The solid was triturated in THF:ethanol (5: 1, 2000 mL) for 4 h. Then the mixture was filtered, and the filter cake was washed with THF (2000 mL). The white solid was collected and dried under reduced pressure to get Compound III (510 g) as a white solid. ’H NMR: (400 MHz, DMSO-d6), 5 = 6.48 (br s, 1H), 3.81 - 3.43 (m, 1H), 2.03 (dd, 7 = 14.8, 3.6 Hz, 1H), 1.87 (dd, 7 = 14.8, 6.0 Hz, 1H), 0.98 (d, 7 = 6.0 Hz, 3 H) ppm. LCMS: Retention time 0.158 minutes, LCMS Method: Agilent 1260 HPLC MSD: 6120 single quadrupole MSD; Kinetex Cl 8, 2.1 *50 mm, 5 pM column; gradient run from 5-95% B over 3 minutes, and 5% B from 4.01 minutes to 4.5 minutes. Mobile phase A = water (0.04 % CF3CO2H). Mobile phase B = acetonitrile (0.02 % CF3CO2H). Optical rotation: [a]199589 = (±)34.64 (<? 1.0278, MeOH). SFC (as determined by a derivative compound): 100% ee, Rt = 1 .948 min.D. Derivatization of Compound III

[0395] A small sample of Compound III from Example 8 was subjected to conditions of Example 6 to afford Compound XIII. Compound XIII was then used to measure ee on the SFC.

[0396] EQUIVALENTS

[0397] Those skilled in the art will recognize many equivalents to the specific embodiments of the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the claims.

Claims

CLAIMSWe claim:1 . A method of modulating or enhancing cardiovascular function in a subject in need thereof, comprising administering to the subject an effective amount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).

2. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of modulating or enhancing cardiovascular function in a subject in need thereof.

3. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for modulating or enhancing cardiovascular function in a subject in need thereof.

4. The method or compound for use of any one of claims 1-3, wherein the pharmaceutically acceptable salt is selected a sodium salt, a magnesium salt, a calcium salt, a lithium salt, and a potassium salt.

5. The method or compound for use of any one of claims 1-4, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound VII), (Compound (Compound IX), (Compound X),(Compound XI), (Compound XII), (Compound XIII),(Compound XVIII), and (Compound XIX).

6. The method or compound for use of any of claims 1 -3, wherein the compound is selected from Compound I.

7. The method or compound for use of any of claims 1-3, wherein the compound is Compound II.

8. The method or compound for use of claim 5, wherein the compound is selected from Compound III.

9. The method or compound for use of claim 5, wherein the compound is selected from Compound IV.

10. The method or compound for use of claim 5, wherein the compound is selected from Compound V.

11. The method or compound for use of claim 5, wherein the compound is selected from Compound VI.

12. The method or compound for use of claim 5, wherein the compound is selected from Compound VII.

13. The method or compound for use of claim 5, wherein the compound is selected from Compound VIII.

14. The method or compound for use of claim 5, wherein the compound is selected from Compound IX.

15. The method or compound for use of claim 5, wherein the compound is selected from Compound X.

16. The method or compound for use of claim 5, wherein the compound is selected from Compound XI.

17. The method or compound for use of claim 5, wherein the compound is selected from Compound XII.

18. The method or compound for use of claim 5, wherein the compound is selected from Compound XIII.

19. The method or compound for use of claim 5, wherein the compound is selected from Compound XIV.

20. The method or compound for use of claim 5, wherein the compound is selected from Compound XV.

21. The method or compound for use of claim 5, wherein the compound is selected from Compound XVI.

22. The method or compound for use of claim 5, wherein the compound is selected from Compound XVII.

23. The method or compound for use of claim 5, wherein the compound is selected from Compound XVIII.

24. The method or compound for use of claim 5, wherein the compound is selected from Compound XIX.

25. The method or compound for use of claim 1, wherein the compound selected from Compounds II, IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

26. The method or compound for use of claim 25, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

27. The method or compound for use of claim 25, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

28. The method or compound for use of claim 25, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

29. The method or compound for use of claim 25, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

30. The method or compound for use of claim 25, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

31. The method or compound for use of claim 25, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

32. The method or compound for use of claim 25, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

33. The method or compound for use of claim 25, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

34. The method or compound for use of claim 25, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

35. The method or compound for use of claim 25, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

36. The method or compound for use of claim 25, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

37. The method or compound for use of any one of claims 1-36, wherein the subject is a human or a veterinary animal.

38. The method or compound for use of any one of claims 1-36, wherein the subject is human.

39. The method or compound for use of any one of claims 1-36, wherein the subject is the veterinary animal.

40. The method or compound for use of any one of claims 1-39, wherein administration of the compound is oral.

41. The method or compound for use of any one of claims 1-39, wherein administration of the compound is intravenous.

42. The method or compound for use of any one of claims 1-41, wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.

43. The method or compound for use of any one of claims 1-42, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.

44. The method or compound for use of any one of claims 1-43, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.

45. The method or compound for use of any one of claims 1-44, wherein the subject is exposed to 1 pM to 4000 uM of Compound II.

46. The method or compound for use of any one of claims 1-45, wherein the subject is exposed to 10 pM to 3000 M of Compound II.

47. The method or compound for use of any one of claims 1-46, wherein the subject is exposed to 100 pM to 2900 uM, or 200 pM to 2800 pM, or 300 M to 2700 uM, or 400 pM to 2600 pM, or 300 pM to 2500 pM, or 400 pM to 2400 pM, or 500 pM to 2300 pM, or 600 pM to 2200 pM, or 700 pM to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.

48. The method or compound for use of any one of claims 1-47, wherein the compound is administered once per day.

49. The method or compound for use of any one of claims 1-47, wherein the compound is administered twice per day.

50. The method of compound for use of any one of claims 1-47, wherein the compound is administered three times a day.

51. The method or compound for use of any one of claims 1-50, wherein the subject is administered a composition comprising a therapeutically effective amount of the compound.

52. The method or compound for use of claim 51 , wherein the composition is a pharmaceutical composition.

53. The method or compound for use of claim 52, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

54. The method or compound for use of claim 52, wherein the composition is a dietary supplement.

55. The method or compound for use of claim 54, wherein the dietary supplement comprises one or more nutrients to increase the amount of said nutrient consumed by a subject.

56. The method or compound for use of claim 54 or 55, wherein the dietary supplement comprises one or more nutrients to increase the amount of said nutrient already within the body.

57. The method or compound for use of any one of claims 54-56, wherein the dietary supplement is provided in addition to food consumed by the subject.

58. The method or compound for use of any one of claims 54-57, wherein the dietary supplement is provided as a pill, a capsule, a tablet, a powder, or a liquid.

60. The method or compound for use of any one of claims 1-58, wherein the subject has an acute, sub-acute, sub-chronic, or chronic disease.

61. The method or compound for use of claim 60, wherein the acute, sub-acute, subchronic, or chronic disease is selected from cardiovascular, metabolic, renal, skeletal muscle, liver or neurological diseases.

62. The method or compound for use of claim 60 or 61 , the acute, sub-acute, sub-chronic, or chronic disease includes congestive heart failure, HFpEF, diastolic dysfunction, diastolic heart failure, hypertrophic cardiomyopathy, HFrEF, systolic heart dysfunction, systolic heart failure, dilated cardiomyopathy, HFmEF, AHF, ADHF, right heart failure, right heart hypertrophy, restrictive cardiomyopathy, disorders related decreased coronary blood flow, vascular disorder resulting from cardiac and renal complications, stroke, ischemia / reperfusion damage, ischemia / reperfusion associated with organ transplant, lung transplant, pulmonary transplant or cardiac transplant, reperfusion injury, endothelial dysfunction, myocardial infarction, myocardial ischemia, diabetic cardiomyopathy, migraine, vascular cognitive impairment, cerebral vasospasm, peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, Raynaud’s syndrome or phenomenon, critical limb ischemia, intermittent claudication, microcirculation abnormalities, and cardiogenic shock.

63. A method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof, comprising administering to the subject an effective amount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).

64. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

65. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for treating an acute, sub-acute, sub-chronic, or chronic disease in a subject in need thereof.

66. The method or compound for use of any one of claims 63-65, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound VII), (Compound (Compound IX), (Compound X),VIII),(Compound XVIII), and (Compound XIX).

67. The method or compound for use of any one of claims 63-65, wherein the compound is selected from Compound I.

68. The method or compound for use of any one of claims 63-65, wherein the compound is Compound II.

69. The method or compound for use of claim 65, wherein the compound is selected from Compound III.

70. The method or compound for use of claim 65, wherein the compound is selected from Compound IV.

71. The method or compound for use of claim 65, wherein the compound is selected from Compound V.

72. The method or compound for use of claim 65, wherein the compound is selected from Compound VI.

73. The method or compound for use of claim 65, wherein the compound is selected from Compound VII.

74. The method or compound for use of claim 65, wherein the compound is selected from Compound VIII.

75. The method or compound for use of claim 65, wherein the compound is selected from Compound IX.

76. The method or compound for use of claim 65, wherein the compound is selected from Compound X.

77. The method or compound for use of claim 65, wherein the compound is selected from Compound XI.

78. The method or compound for use of claim 65, wherein the compound is selected from Compound XII.

79. The method or compound for use of claim 65, wherein the compound is selected from Compound XIII.

80. The method or compound for use of claim 65, wherein the compound is selected from Compound XIV.

81. The method or compound for use of claim 65, wherein the compound is selected from Compound XV.

82. The method or compound for use of claim 65, wherein the compound is selected from Compound XVI.

83. The method or compound for use of claim 65, wherein the compound is selected from Compound XVII.

84. The method or compound for use of claim 65, wherein the compound is selected from Compound XVIII.

85. The method or compound for use of claim 65, wherein the compound is selected from Compound XIX.

86. The method or compound for use of claim 65, wherein the compound selected from Compounds IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

87. The method or compound for use of any one of claims 63-65, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

88. The method or compound for use of claim 86, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

89. The method or compound for use of claim 86, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

90. The method or compound for use of claim 86, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

91. The method or compound for use of claim 86, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

92. The method or compound for use of claim 86, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

93. The method or compound for use of claim 86, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

94. The method or compound for use of claim 86, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

95. The method or compound for use of claim 86, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

96. The method or compound for use of claim 86, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

97. The method or compound for use of claim 86, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

98. The method or compound for use of any one of claims 63-97, wherein the subject is a human or a veterinary animal.

99. The method or compound for use of any one of claims 63-97, wherein the subject is human.

100. The method or compound for use of any one of claims 63-97, wherein the subject is the veterinary animal.

101. The method or compound for use of any one of claims 63-100, wherein administration of the compound is oral.

102. The method or compound for use of any one of claims 63-100, wherein administration of the compound is intravenous.

103. The method or compound for use of any one of claims 63-101 , wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.

104. The method or compound for use of any one of claims 63-102, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.

105. The method or compound for use of any one of claims 63-104, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to 2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.

106. The method or compound for use of any one of claims 63-105, wherein the subject is exposed to 1 M to 4000 M of Compound II.

107. The method or compound for use of any one of claims 63-106, wherein the subject is exposed to 10 M to 3000 iiM of Compound II.

108. The method or compound for use of any one of claims 63-107, wherein the subject is exposed to 100 M to 2900 pM, or 200 pM to 2800 pM, or 300 pM to 2700 pM, or 400 pM to 2600 pM, or 300 pM to 2500 pM, or 400 pM to 2400 pM, or 500 pM to 2300 pM, or 600 M to 2200 pM, or 700 pM to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.

109. The method or compound for use of any one of claims 63-108, wherein the compound is administered once per day.

110. The method or compound for use of any one of claims 63-108, wherein the compound is administered twice per day.

111. The method of compound for use of any one of claims 63-108, wherein the compound is administered three times a day.

112. A method of increasing plasma exposure of Compound II in a subject in need thereof, comprising administering to the subject an effective amount of Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof(Compound I) (Compound II).

113. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in a method of increasing plasma exposure of Compound II in a subject in need thereof.

114. A compound selected from Compound I or Compound II, a pharmaceutically acceptable salt thereof, and an ester thereof for use in the manufacture of a medicament for increasing plasma exposure of Compound II in a subject in need thereof.

115. The method or compound for use of any one of claims 112-114, wherein the pharmaceutically acceptable salt or ester is selected the group consisting of:(Compound III), (Compound IV), (Compound V), (Compound VI),(Compound XVIII), and (Compound XIX).

116. The method or compound for use of any one of claims 112-115, wherein the compound is selected from Compound I.

117. The method or compound for use of any one of claims 112-115, wherein the compound is Compound II.

118. The method or compound for use of claim 115, wherein the compound is selected from Compound III.

119. The method or compound for use of claim 115, wherein the compound is selected from Compound IV.

120. The method or compound for use of claim 115, wherein the compound is selected from Compound V.

121. The method or compound for use of claim 115, wherein the compound is selected from Compound VI.

122. The method or compound for use of claim 1 15, wherein the compound is selected from Compound VII.

123. The method or compound for use of claim 115, wherein the compound is selected from Compound VIII.

124. The method or compound for use of claim 1 15, wherein the compound is selected from Compound IX.

125. The method or compound for use of claim 115, wherein the compound is selected from Compound X.

126. The method or compound for use of claim 115, wherein the compound is selected from Compound XI.

127. The method or compound for use of claim 115, wherein the compound is selected from Compound XII.

128. The method or compound for use of claim 115, wherein the compound is selected from Compound XIII.

129. The method or compound for use of claim 115, wherein the compound is selected from Compound XIV.

130. The method or compound for use of claim 115, wherein the compound is selected from Compound XV.

131. The method or compound for use of claim 1 15, wherein the compound is selected from Compound XVI.

132. The method or compound for use of claim 115, wherein the compound is selected from Compound XVII.

133. The method or compound for use of claim 1 15, wherein the compound is selected from Compound XVIII.

134. The method or compound for use of claim 115, wherein the compound is selected from Compound XIX.

135. The method or compound for use of claim 115, wherein the compound selected from Compounds IV, VI, VIII, X, XII, XIV, XVI, XVII, XVIII, and XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

136. The method or compound for use of any one of claims 112-115, wherein Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

137. The method or compound for use of claim 135, wherein Compound IV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

138. The method or compound for use of claim 135, wherein Compound VI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

139. The method or compound for use of claim 135, wherein Compound VIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

140. The method or compound for use of claim 135, wherein Compound X is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

141. The method or compound for use of claim 135, wherein Compound XII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

142. The method or compound for use of claim 135, wherein Compound XIV is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

143. The method or compound for use of claim 135, wherein Compound XVI is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

144. The method or compound for use of claim 135, wherein Compound XVII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

145. The method or compound for use of claim 135, wherein Compound XVIII is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

146. The method or compound for use of claim 135, wherein Compound XIX is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

147. The method or compound for use of any one of claims 112-146, wherein the subject is a human or a veterinary animal.

148. The method or compound for use of any one of claims 112-147, wherein the subject is human.

149. The method or compound for use of any one of claims 112-147, wherein the subject is the veterinary animal.

150. The method or compound for use of any one of claims 112-149, wherein administration of the compound is oral.

151. The method or compound for use of any one of claims 112-149, wherein administration of the compound is intravenous.

152. The method or compound for use of any one of claims 112-151, wherein the subject is administered 1 mg / kg to 4000 mg / kg of the compound.

153. The method or compound for use of any one of claims 112-152, wherein the subject is administered 1 mg / kg to 3000 mg / kg of the compound.

154. The method or compound for use of any one of claims 112-153, wherein the subject is administered 10 mg / kg to 3000 mg / kg, or 100 mg / kg to 2900 mg / kg, or 200 mg / kg to2800 mg / kg, or 300 mg / kg to 2700 mg / kg, or 400 mg / kg to 2600 mg / kg, or 300 mg / kg to 2500 mg / kg, or 400 mg / kg to 2400 mg / kg, or 500 mg / kg to 2300 mg / kg, or 600 mg / kg to 2200 mg / kg, or 700 mg / kg to 2100 mg / kg, or 800 mg / kg to 2000 mg / kg, or 900 mg / kg to 1900 mg / kg, or 1000 mg / kg to 1800 mg / kg, or 1100 mg / kg to 1700 mg / kg, or 1200 mg / kg to 1600 mg / kg, or 1300 mg / kg to 1500 mg / kg.

155. The method or compound for use of any one of claims 112-154, wherein the subject is exposed to I is M to 4000 M of Compound II.

156. The method or compound for use of any one of claims 112-155, wherein the subject is exposed to 10 M to 3000 pM of Compound II.

157. The method or compound for use of any one of claims 112-156, wherein the subject is exposed to 100 pM to 2900 pM, or 200 pM to 2800 pM, or 300 pM to 2700 pM, or 400 pM to 2600 pM, or 300 M to 2500 M, or 400 pM to 2400 M, or 500 M to 2300 pM, or 600 pM to 2200 pM, or 700 pM to 2100 pM, or 800 pM to 2000 pM, or 900 pM to 1900 pM, or 1000 pM to 1800 pM, or 1100 pM to 1700 pM, or 1200 pM to 1600 pM, or 1300 pM to 1500 pM of Compound II.

158. The method or compound for use of any one of claims 112-157, wherein the compound is administered once per day.

159. The method or compound for use of any one of claims 112-157, wherein the compound is administered twice per day.

160. The method of compound for use of any one of claims 112-157, wherein the compound is administered three times a day.

161. A process of preparing a pharmaceutically acceptable salt of Compound II:Compound II, wherein a pharmaceutically acceptable salt of Compound II is 97% to less than 100% enantiomerically enriched or is enantiomerically pure, wherein the process comprises:(a) reacting a pharmaceutically acceptable salt of Compound II that is less than 97% enantiomerically enriched with a first reagent to produce Intermediate A:(Intermediate A);(b) reacting Intermediate A with a second reagent to produce Compound II:(Compound II); and(c) reacting Compound II with a third reagent to produce a pharmaceutically acceptable salt of Compound II that is 97% to less than 100% enantiomerically enriched or is enantiomerically pure.

162. The process according to claim 161, wherein the pharmaceutically acceptable salt is selected a sodium salt, a magnesium salt, a calcium salt, a lithium salt, and a potassium salt.

163. The process according to claim of 162, wherein when the pharmaceutically acceptable salt of Compound I is a sodium salt.

164. The process according to claim of 87, wherein when the pharmaceutically acceptable salt of Compound I is a magnesium salt.

165. The process according to claim of 162, wherein when the pharmaceutically acceptable salt of Compound I is a calcium salt.

166. The process according to claim of 162, wherein when the pharmaceutically acceptable salt of Compound I is a lithium salt.

167. The process according to claim of 162, wherein when the pharmaceutically acceptable salt of Compound I is a potassium salt.

Images