Salts and polymorphs of CX3CR1 modulators

Abstract

The present disclosure provides meglumine salts of CX3CR1 modulators, polymorphs and pharmaceutical compositions thereof. Also disclosed are methods of treatment using the meglumine salts of CX3CR1 modulators, polymorphs and pharmaceutical compositions thereof and methods of making salt compounds of CX3CR1 modulators and polymorphs thereof.

Description

SALTS AND POLYMORPHS OF CX3CR1 MODULATORS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 635,192, filed April 17, 2024, and U.S. Provisional Application No.63 / 646,608, filed May 13, 2024, each of which is incorporated by reference herein in its entirety for all purposes. BACKGROUND Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including cardiovascular and respiratory diseases such as asthma, atherosclerosis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, lupus nephritis and inflammatory myopathy. Chemokines are classified into four subfamilies, CC, CXC, C, and CX3C, based on the sequence of their first two cysteine residues. The CX3C chemokine, also known as fractalkine (FKN) receptor, is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells. The CX3C chemokine also functions as an adhesion molecule on immune active cells, such as monocytes and others for infiltration of cells from the blood to the tissue. Blocking the adhesion of the CX3C chemokine to cells has been proven to reduce atherosclerosis progression and plaque growth (Poupel et al., Arterioscler. Thromb. Vasc. Biol.33, 2297-2305 (2013). CX3C chemokine neutralization improves cardiac function in mouse myocardial infarction (MI) models by enhanced systolic function, ventricular remodeling and decreased infarct size (Xuan et al., Cardiovascular Research 92, 385 (2011) and left ventricular ejection fraction (LVEF) and survival rate in myocardial infraction-induced mice two weeks post treatment (Gu et al., Exp Physiol 100, 805 (2015). CX3CR1is a 7-transmembrane receptor for the CX3C chemokine and mediates both its adhesive and migratory functions (Murphy, Pharmacological Reviews 54(2):227-229 (2002). CX3CR1activity has been linked to the treatment of cardiovascular diseases (CVD) including heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, stable coronary artery disease and atherosclerosis related conditions. Current treatment of cardiovascular and respiratory diseases use agents that modulate CX3C receptors as targets for drug development. For example, WO 2005 / 070903 A1 discloses certain triazine derivatives for use in the treatmentof chemokine mediated diseases and disorders. WO 2006 / 107258 A1 discloses certain 5- substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives as antagonists of the CX3CR1 receptor. WO 2006 / 107257 A1 and WO 2009 / 120140 A1 disclose certain 5,7-disubstituted [l,3]thiazolo[4,5- d]pyrimidin-2(3H)one derivatives as antagonists of the CX3CR1 receptor. WO 2013039057 A1 discloses certain pyrrolidine-3-ylacetic acid derivatives having an inhibitory pathway in the fractalkine-CX3CR1pathway. Drug delivery has been a persistent challenge in the pharmaceutical arts. Active pharmaceutical ingredients (API) are often chemically made into their salt forms to aid in formulation of dosage forms, enhance how the API dissolves, boost API absorption, and increase its effectiveness. SUMMARY OF THE INVENTION In some embodiments, the present disclosure provides a compound of Formula I ,wherein MEG is a both Y and X are not N, R1, R2, R3, R4, and R5are independently H, halogen or -methoxy, wherein when Y is N, then R3is not present, and when Z is N, then R2is not present, and # represents the R enantiomer, S enantiomer, or racemic mixture. In some embodiments, # represents the R enantiomer. In some embodiments, # represents the S enantiomer. In some embodiments, # represents a racemic mixture. In some embodiments, the halogen is F or Cl. In some embodiments, one or more of R1, R2, R4, and R5 is F.In some embodiments, Z is N and Y is C. In some embodiments, Z is C and Y is N. In some embodiments, Z is C and Y is C. In some embodiments, one of R1, R2, R3, R4, and R5is methoxy. In some embodiments, R3 is methoxy. In some embodiments, Z is N and R3 is methoxy. In some embodiments, two of R1, R2, R3, R4, and R5 are halogen. In some embodiments, one of R1, R2, R3, R4, and R5 is halogen and one if methoxy. In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2and R3are H, and (iv) R4and R5are F. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1 is F, (iv) R3 is methoxy (v) R4 and R5are H. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R3is methoxy and (iv) R1, R4and R5are H. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R5is F, (iv) R3is methoxy, and (v) R1and R4 are H. In some embodiments, (i) Z is C, (ii) Y is N, (iii) R1, R2 and R5 are H, and (iv) R4 is Cl. In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2 and R5 are H, (iv) R3 is methoxy and v) R4is F. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1and R5are H, (iv) R3is - methoxy and (v) R4 is F. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1 and R5 are H, (iv) R3 is -methoxy, and (v) R4 is F. In some embodiments, the disclosure provides a Form 1 polymorph of the compound of Formula I, in which (i) Z is C, (ii) Y is C, (iii) R1, R2and R3are H, and (iv) R4and R5are F, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.8± 0.2, 16.1± 0.2, and 19.8± 0.2 degrees. In some embodiments, the XPRD of Form 1 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.7± 0.2, 18.6± 0.2, 20.2± 0.2, 21.8± 0.2 and 24.7± 0.2. In some embodiments, the Form 1 polymorph has an XRPD pattern substantially as shown in Fig.1. In some embodiments, the Form 1 polymorph comprises a mono-meglumine salt. In some embodiments, the disclosure provides a Form 2 polymorph of the compound of Formula I, in which (i) Z is N, (ii) Y is C, (iii) R1is F, (iv) R3is methoxy (v) R4and R5are H, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 4.9± 0.2, 8.5± 0.2, 19.5± 0.2, and 20.7± 0.2 degrees. In some embodiments, the XRPD of Form 2 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.5± 0.2, 12.9± 0.2, 22.1± 0.2, 23.2± 0.2, 23.6±0.2 and 24.1± 0.2. In some embodiments, the Form 2 polymorph has an XRPD pattern substantially as shown in Fig.2. In some embodiments, the Form 2 polymorph comprises a mono-meglumine salt. In some embodiments, the disclosure provides a Form 3 polymorph of the compound of Formula I, in which (i) Z is N, (ii) Y is C, (iii) R3 is methoxy and (iv) R1, R4 and R5 are H, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 19.8± 0.2, and 20.6± 0.2 degrees. In some embodiments, the XPRD of Form 3 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.8± 0.2, 15.9± 0.2, 22.5± 0.2, 24.2± 0.2 and 26.3± 0.2. In some embodiments, the Form 3 polymorph has an XRPD pattern substantially as shown in Fig.3. In some embodiments, the Form 3 polymorph comprises a mono-meglumine salt. In some embodiments, the disclosure provides a Form 4 polymorph of the compound of Formula I, in which (i) Z is N, (ii) Y is C, (iii) R5 is F, (iv) R3 is methoxy, and (v) R1 and R4 are H, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.4± 0.2, 20.0± 0.2, and 24.0± 0.2 degrees. In some embodiments, the XPRD of Form 4 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 12.9± 0.2, 15.7± 0.2, 22.4± 0.2, 24.5± 0.2 and 26.5± 0.2. In some embodiments, the Form 4 polymorph has an XRPD pattern substantially as shown in Fig.4. In some embodiments, the Form 4 polymorph comprises a mono-meglumine salt. In some embodiments, the disclosure provides a Form 5 polymorph of the compound of Formula I, in which (i) Z is C, (ii) Y is N, (iii) R1, R2 and R5 are H, and (iv) R4 is Cl, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 20.0± 0.2, 20.6± 0.2, and 24.3± 0.2 degrees. In some embodiments, the XPRD of Form 5 further comprises at least one additional peak expressed in degrees 2-theta selected from 8.6± 0.2, 11.4± 0.2, 12.9± 0.2, 17.7± 0.2, 18.6± 0.2 and 22.0± 0.2. In some embodiments, the Form 5 polymorph has an XRPD pattern substantially as shown in Fig.5. In some embodiments, the Form 5 polymorph comprises a mono-meglumine salt.In some embodiments, the disclosure provides a Form 6 polymorph of the compound of Formula I, in which (i) Z is C, (ii) Y is C, (iii) R1, R2 and R5 are H, (iv) R3 is methoxy and v) R4 is F, wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 12.7± 0.2, 19.5± 0.2, and 20.6± 0.2 degrees. In some embodiments, the XPRD of Form 6 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.2± 0.2, 15.7± 0.2, 20.0± 0.2, 21.6± 0.2, and 22.6± 0.2. In some embodiments, the Form 6 polymorph has an XRPD pattern substantially as shown in Fig.6. In some embodiments, the Form 6 polymorph comprises a mono-meglumine salt. In some embodiments, the disclosure provides a Form 7 polymorph of the compound of Formula I, in which (i) Z is N, (ii) Y is C, (iii) R1 and R5 are H, (iv) R3 is -methoxy, and (v) R4 is F, and (vi), wherein the polymorph has a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.6± 0.2, 12.8± 0.2, and 19.6± 0.2 degrees. In some embodiments, the XPRD of Form 7 further comprises at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 20.1± 0.2, 20.6± 0.2, 21.8± 0.2, 23.5± 0.2, and 26.3± 0.2. In some embodiments, the Form 7 polymorph has an XRPD pattern substantially as shown in Fig.7. In some embodiments, the Form 7 polymorph comprises a mono-meglumine salt. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or polymorph described herein and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure is directed to a method of treating cardiovascular disease comprising administering a therapeutically effective amount of the pharmaceutical composition described herein to a person suffering from or at risk of the disease. In some embodiments, the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. In some embodiments, the compound is administered orally.In some embodiments, the present disclosure provides a process for the preparation of the compounds described herein, the method comprising forming a slurry of (2R,3R,4R,5S)-6- (methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXX. , mixing the slurry forand collecting the retentate, and washing the retentate with water; and drying the retentate to obtain the compounds. In some embodiments, the mixing is for about 2 hours to about 24 hours. In some embodiments, the mixing at about 20°C to about 30°C. In some embodiments, the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol is about 2:1 to about 1:2. In some embodiments, the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane- 1,2,3,4,5-pentaol is about 2:1 to about 1:2. In some embodiments, the present disclosure provides a process for the process for the preparation of a polymorph described herein, the method comprising forming a slurry of (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXXX) mixing the slurry olating the particles from the slurry by filtration, and washing the particles with water, and drying the particles to obtain the polymorph. In some embodiments, the mixing is for about 2 hours to about 24 hours. In some embodiments, the mixing is for about 2 hours to about 24 hours. In some embodiments, the mixing at about 20°C to about 30°C. In some embodiments, the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol is about 2:1 to about 1:2. In some embodiments, the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane- 1,2,3,4,5-pentaol is about 2:1 to about 1:2. BRIEF DESCRIPTION OF THE FIGURES FIG.1 is the XPRD spectrum of Form 1 polymorph of Compound A. FIG.2 is the XPRD spectrum of Form 2 polymorph of Compound B. FIG.3 is the XPRD spectrum of Form 3 polymorph of Compound C. FIG.4 is the XPRD spectrum of Form 4 polymorph of Compound D. FIG.5 is the XPRD spectrum of Form 5 polymorph of Compound E. FIG.6 is the XPRD spectrum of Form 6 polymorph of Compound F. FIG.7 is the XPRD spectrum of Form 7 polymorph of Compound G. DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates to pharmaceutically acceptable meglumine salt compounds of Formula I(I) and methods suitable for t ascular diseases. The present disclosure provides for salts of CX3C modulators. In some embodiments, the present disclosure provides an orally active modulator of CX3CR1 for the treatment cardiovascular diseases (CVD), e.g., heart failure, cardiac muscle diseases and coronary artery disease related conditions. Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, “a” or “an” may mean one or more. A used herein, when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one. As used herein, “another” or “a further” may mean at least a second or more. Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the method / device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term “about” is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% variability, depending on the situation. The use of the term “or” in the claims is used to mean “and / or”, unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein, the terms “comprising” (and any variant or form of comprising, such as “comprise” and “comprises”), “having” (and any variant or form of having, such as “have” and“has”), “including” (and any variant or form of including, such as “includes” and “include”) or “containing” (and any variant or form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. The use of the term “for example” and its corresponding abbreviation “e.g.,” (whether italicized or not) means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. As used herein, “between” is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y. As used herein, where the nomenclature of a chemical compound uses “(R)” or “(S)” to denote specific stereochemistry, the use of “(R*)” can indicate that specific chemistry could be either“(R)” or “(S)”. Likewise, the use of “(S*)” can indicate that specific chemistry could be either“(S)” or “(R)”. For example, while Compound A, the second eluting isomer from the chiral separation of N-(4-(2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, is named “N-(4-((R*)-2-(2,3- Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide,” it could be N-(4-((R)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-((S)-2-(2,3- Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide: Compound AUnless specified otherwise, the term “alkoxy” refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “methoxy” refers to afunctional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula R−O−CH3. In some embodiments, one or more of R1, R2, R3, R4, and R5 in the compound of Formula (I) is methoxy. In some embodiments, one of R1, R2, R3, R4, and R5is methoxy. In some embodiments, two of R1, R2, R3, R4, and R5 is methoxy. In some embodiments, R3 is methoxy. In some embodiments, R4 is methoxy. In some embodiments, R2 is methoxy. Unless specified otherwise, the term “halogen” refers to fluorine, chlorine, bromine, and iodine. In some embodiments, the halogen is fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, two of R1, R2, R3 R4, and R5 is halogen. In some embodiments, one of R1, R2, R3 R4, and R5 is halogen. In some embodiments, the halogen is chlorine, i.e., Cl. In some embodiments, one or more of R1, R2, R3 R4, and R5 is Cl. In some embodiments, one of R1, R2, R3 R4, and R5 is Cl. In some embodiments, two of R1, R2, R3 R4, and R5 is Cl. In some embodiments, R1 and R2 are Cl. In some embodiments, R1 is Cl. In some embodiments, R5 is Cl. In some embodiments, R2 is Cl. In some embodiments, R4 is Cl. In some embodiments, the halogen is fluorine, i.e., F. In some embodiments, one or more of R1, R2, R3 R4, and R5 is F. In some embodiments, one of R1, R2, R3 R4, and R5 is F. In some embodiments, two of R1, R2, R3 R4, and R5 is F. In some embodiments, R1 and R2 are F. In some embodiments, R1 is F. In some embodiments, R5 is F. In some embodiments, R2 is F. In some embodiments, R4 is F. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and one of R1, R2, R3, R4, and R5 is a halogen. One of skill in the art will appreciate that one variable, e.g., R1, can only contain one substituent. Thus, when describing that one of R1, R2, R3, R4, and R5 is methoxy and one of R1, R2, R3, R4, and R5 is a halogen, the skilled artisan will appreciate that both methoxy and halogen cannot both exist at the same R1 position in the same compound. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and two of R1, R2, R3, R4, and R5 is a halogen. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and three of R1, R2, R3, R4, and R5 is a halogen. In some embodiments, two of R1, R2, R3, R4, and R5 is methoxy and one or two of R1, R2, R3, R4, and R5 is a halogen. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and two of R1, R2, R3, R4, and R5 is a Cl. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and three of R1, R2, R3, R4, and R5 isa Cl. In some embodiments, two of R1, R2, R3, R4, and R5 is methoxy and one or two of R1, R2, R3, R4, and R5 is a Cl. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and two of R1, R2, R3, R4, and R5 is a F. In some embodiments, one of R1, R2, R3, R4, and R5 is methoxy and three of R1, R2, R3, R4, and R5 is a F. In some embodiments, two of R1, R2, R3, R4, and R5 is methoxy and one or two of R1, R2, R3, R4, and R5 is a F. In some embodiments, R3 is methoxy and one of R1, R2, R4, and R5 is a halogen. In some embodiments, R3 is methoxy and two of R1, R2, R4, and R5 is a halogen. In some embodiments, R3 is methoxy and three of R1, R2, R4, and R5 is a halogen. In some embodiments, R3 is methoxy and each of R1, R2, R3, R4, and R5 is a halogen. In some embodiments, R3 is methoxy and one of R1, R2, R4, and R5 is a Cl. In some embodiments, R3 is methoxy and two of R1, R2, R4, and R5 is a Cl. In some embodiments, R3 is methoxy and three of R1, R2, R4, and R5 is a Cl. In some embodiments, R3 is methoxy and each of R1, R2, R3, R4, and R5 is a Cl. In some embodiments, R3 is methoxy and one of R1, R2, R4, and R5 is a F. In some embodiments, R3 is methoxy and two of R1, R2, R4, and R5 is a F. In some embodiments, R3 is methoxy and three of R1, R2, R4, and R5 is a F. In some embodiments, R3 is methoxy and each of R1, R2, R3, R4, and R5 is a F. In some embodiments, each of R1, R2, R3, R4, and R5 are attached to an aryl ring, i.e., both Y and Z are carbon, i.e., C. In some embodiments, R1, R2, R3, R4, and R5 are attached to a heteroaryl, i.e., one of Y and Z are nitrogen, i.e., N. However, Y and Z cannot both be N at the same time. The skilled artisan will appreciate that R1 and R5 both in the ortho position, and thus when both Y and Z are C, and the remainder of the aryl ring is symmetrical, then R1 and R5 can be interchangeable. The skilled artisan will appreciate the same for R2 and R4, which are both in the meta position. In some embodiments, both Y and Z are C, and R3 is methoxy. In some embodiments, both Y and Z are C, R3 is methoxy, and at least one of R1, R2, R4, and R5 are halogen. In some embodiments, both Y and Z are C, R3 is methoxy, and at least one of R1, R2, R4, and R5 are Cl. In some embodiments, both Y and Z are C, R3 is methoxy, and at least one of R1, R2, R4, and R5 are F. In some embodiments, both Y and Z are C, R3 is methoxy, and one of R1, R2, R4, andR5 are halogen. In some embodiments, both Y and Z are C, R3 is methoxy, and two of R1, R2, R4, and R5 are halogen. In some embodiments, Z is N and R3 is methoxy. In some embodiments, Z is N, R3 is methoxy, and at least one of R1, R4, and R5 are halogen. In some embodiments, Z is N, R3 is methoxy, and at least one of R1, R4, and R5 are Cl. In some embodiments, Z is N, R3 is methoxy, and at least one of R1, R2, R4, and R5 are F. In some embodiments, Z is N, R3 is methoxy, and one of R1, R4, and R5 are halogen. In some embodiments, Z is N, R3 is methoxy, and two of R1, R4, and R5 are halogen. In some embodiments, Y is N and one of R1, R2, R4, and R5 is methoxy. In some embodiments, Y is N, and at least one of R1, R2, R4, and R5 are halogen. In some embodiments, Y is N, one of R1, R2, R4, and R5 is methoxy, and at least one of R1, R2, R4, and R5 are halogen. In some embodiments, Y is N, and at least one of R1, R2, R4, and R5 are Cl. In some embodiments, Y is N, and at least one of R1, R2, R4, and R5 are F. In some embodiments, Y is N, and one of R1, R2, R4, and R5 are Cl. In some embodiments, Y is N, and two of R1, R2, R4, and R5 are Cl. In some embodiments, Y is N, and one of R1, R2, R4, and R5 are F. In some embodiments, Y is N, and two of R1, R2, R4, and R5 are F. The present disclosure provides for meglumine salts of the compounds described herein. As used herein, the term “salt” refers to a chemical form of a compound that is made when the compound is ionized and forms an ionic interaction with an oppositely charged counterion. In some embodiments, the cationic charge of meglumine can form an ionic bond with the compound of Formula I. A salt of a compound of Formula (I) as disclosed herein, may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. In some embodiments, a salt may be used to aid in the isolation or purification of the compound. In some embodiments, the salt is intended for administration to an animal, e.g. a human, or is a reagent for use in making a compound or salt intended for administration to an animal. In some embodiments, the salt is pharmaceutically acceptable. In some embodiments, the oppositely charged counterion used to form a salt of compound of Formula (I) is meglumine. Meglumine, also known as (2R,3R,4R,5S)-6-(Methylamino)hexane-1,2,3,4,5-pentaol, N- methylglucamine, 1-deoxy-1-(methylamino)-D-glucitol and N-methyl-D-glucamine, has amolecular weight of 195.21 g / mol and a melting point of about 129-131° C. Meglumine is soluble in water (~100 g in 100 mL at 25° C) and is alkaline. The compounds and polymorphs disclosed herein may be pharmaceutically acceptable salts of meglumine. In some embodiments, a compound of Formula I described herein is prepared as a meglumine salt. A preferable molar ratio of the meglumine to Formula I in pharmaceutical compositions and formulations (including any solution formulations, solutions prior to lyophilization, reconstituted solutions after lyophilization, and diluted solutions for oral administration) is about 0.5:1 to about 3:1, about 0.5:1 to about 2:1, about 0.8:1 to about 1.5:1, about 0.9:1 to about 1.1:1, or about 1:1. In some embodiments, the meglumine has a purity of pharmaceutical grade or equivalent. The terms “meglumine salt of Compound X,” “meglumine salt form of Compound X,” “salt form of Compound X is meglumine” and “Compound X meglumine salt” refers to the meglumine salt form of Compound X, wherein X can include any of Compounds A, B, C, D, E, F, or G. In some embodiments, reference to a meglumine salt of Formula I can include the solvent addition forms, i.e., solvates. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. The compounds and polymorphs disclosed herein may have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance), than compounds and polymorphs known in the prior art. In some embodiments, the present disclosure provides a compound of Formula II), wherein MEG is a meglum n both Y and X are not N, R1, R2, R3, R4, and R5are independently H, halogen or -methoxy, wherein when Y is N, then R3is not present, and when Z is N, then R2 is not present, and # represents the R enantiomer, S enantiomer, or racemic mixture. In some embodiments, the compounds presented herein can include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In particular embodiments, certain compounds of Formula (I), may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. In some embodiments, # represents the R enantiomer. In some embodiments, # represents the S enantiomer. In some embodiments, # represents a racemic mixture. In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. Individual stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment,diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981). In some embodiments, stereoisomers are obtained by stereoselective synthesis. Certain compounds of Formula (I) may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring bond or double bond. In some embodiments, Z is N and Y is C in the compound of Formula (I). In some embodiments, Z is C and Y is N in the compound of Formula (I). In some embodiments, Z is C and Y is C in the compound of Formula (I). In some embodiments, Z is N and R3 is methoxy. In some embodiments, two of R1, R2, R3, R4, and R5 are halogen. For example, in some embodiments, two of R1, R2, R3, R4, and R5 are F. In some embodiments, R1 and R2 are F. In some embodiments, one of R1, R2, R3, R4, and R5 is halogen and one is methoxy. For example, in some embodiments, one of R1, R2, R3, R4, and R5 is F and one is methoxy. In some embodiments, one of R1, R2, R3, R4, and R5 is Cl and one is methoxy. In some embodiments, R3 is methoxy, and R1 is a halogen, e.g., F. In some embodiments, R3 is methoxy, and R2 is a halogen, e.g., F. In some embodiments, R3 is methoxy, and R5 is a halogen, e.g., F. In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2 and R3 are H and (iv) R4 and R5 are F in the compound of Formula (I). In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2 and R3 are H, (iv) R4 and R5 are F, and (v) # represents the R enantiomer in the compound of Formula (I). In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2 and R3 are H, (iv) R4 and R5 are F, and (v) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is meglumine salt of N-(4-((R*)-2-(2,3- Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Compound A). In some embodiments, the compound of Formula (I) is meglumine salt of N-(4-((R)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is meglumine salt of N-(4-((S)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide.Compound A , p p y acceptable salt, e.g., a Compound A meglumine salt. In some embodiments, the Compound A meglumine salt is a mono-meglumine salt. In some embodiments, the Compound A meglumine salt can be amorphous. In some embodiments, the Compound A meglumine salt can be crystalline. In some embodiments, the Compound A meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 1 polymorph of the Compound A meglumine salt, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.8± 0.2, 16.1± 0.2, and 19.8± 0.2 degrees. In some embodiments, the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.7± 0.2, 18.6± 0.2, 20.2± 0.2, 21.8± 0.2 and 24.7± 0.2. In some embodiments, the Form 1 polymorph has an XRPD pattern substantially as shown in Fig.1. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1 is F, (iv) R3 is methoxy and (v) R4 and R5 are H in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1is F, (iv) R3is methoxy (v) R4and R5are H, and (vi) # represents the R enantiomer in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1is F, (iv) R3is methoxy (v) R4 and R5 are H, and (vi) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is a meglumine salt of N-(4-((R*)-2-(2- Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide (Compound B). In some embodiments, the compound of Formula (I) is a meglumine salt of N-(4-((R)-2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)- 1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is a meglumine salt of N-(4-((S)-2-(2-Fluoro-6- methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide.d B e.g., a Compound B meglumine salt. In some embodiments, the Compound B meglumine salt is a mono-meglumine salt. In some embodiments, the Compound B meglumine salt can be amorphous. In some embodiments, the Compound B meglumine salt can be crystalline. In some embodiments, the Compound B meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 2 polymorph of the meglumine salt of Compound B, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 4.9± 0.2, 8.5± 0.2, 19.5± 0.2, and 20.7± 0.2 degrees. In some embodiments, the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.5± 0.2, 12.9± 0.2, 22.1± 0.2, 23.2± 0.2, 23.6± 0.2 and 24.1± 0.2. In some embodiments, the Form 2 polymorph has an XRPD pattern substantially as shown in Fig.2. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R3is methoxy and (iv) R1, R4and R5are H in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R3 is methoxy (iv) R1, R4 and R5 are H, and (v) # represents the R enantiomer in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R3is methoxy (iv) R1, R4and R5are H, and (v) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-(((R)-1-Hydroxy-4- methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2- yl)methanesulfonamide (Compound C). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide. In some embodiments, thecompound of Formula (I) is the meglumine salt of N-(4-(((R)-1-Hydroxy-4-methylpentan-2- yl)amino)-6-((S)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide. Compound Cacceptable salt, e.g., a Compound C meglumine salt. In some embodiments, the Compound C meglumine salt is a mono-meglumine salt. In some embodiments, the Compound C meglumine salt can be amorphous. In some embodiments, the Compound C meglumine salt can be crystalline. In some embodiments, the Compound C meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 3 polymorph of the meglumine salt of Compound C, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 19.8± 0.2, and 20.6± 0.2 degrees. In some embodiments, the XPRD further comprises at least one at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.8± 0.2, 15.9± 0.2, 22.5± 0.2, 24.2± 0.2 and 26.3± 0.2. In some embodiments, the Form 3 polymorph has an XRPD pattern substantially as shown in Fig.3. In some embodiments, the Form 3 polymorph comprises a mono-meglumine salt. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R5 is F, (iv) R3 is methoxy, (v) R1 and R4are H in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R5is F, (iv) R3 is methoxy, (v) R1 and R4 are H, and (vi) # represents the R enantiomer in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R5 is F, (iv) R3 is methoxy, (v) R1and R4are H, and (vi) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is meglumine salt of N-(4- ((R*)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound D). In some embodiments, the compound of Formula (I) is meglumine salt of N-(4-((R)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is meglumine salt of N-(4-((S)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. De.g., a Compound D meglumine salt. In some embodiments, the Compound D meglumine salt is a mono-meglumine salt. In some embodiments, the Compound D meglumine salt can be amorphous. In some embodiments, the Compound D meglumine salt can be crystalline. In some embodiments, the Compound D meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 4 polymorph of the meglumine salt of Compound D, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.4± 0.2, 20.0± 0.2, and 24.0± 0.2 degrees. In some embodiments, the XPRD further comprises at least one at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 12.9± 0.2, 15.7± 0.2, 22.4± 0.2, 24.5± 0.2 and 26.5± 0.2. In some embodiments, the Form 4 polymorph has an XRPD pattern substantially as shown in Fig.4. In some embodiments, (i) Z is C, (ii) Y is N, (iii) R1, R2 and R5 are H and (iv) R4 is Cl in the compound of Formula (I). In some embodiments, (i) Z is C, (ii) Y is N, (iii) R1, R2 and R5 are H, (iv) R4is Cl, and (v) # represents the R enantiomer in the compound of Formula (I). In some embodiments, (i) Z is C, (ii) Y is N, (iii) R1, R2and R5are H, (iv) R4is Cl, and (v) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((S*)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound E). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((S)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((R)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Compound Esalt, e.g., a Compound E meglumine salt. In some embodiments, the Compound E meglumine salt is a mono-meglumine salt. In some embodiments, the Compound E meglumine salt can be amorphous. In some embodiments, the Compound E meglumine salt can be crystalline. In some embodiments, the Compound E meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 5 polymorph of the meglumine salt of Compound E, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 20.0± 0.2, 20.6± 0.2, and 24.3± 0.2 degrees. In some embodiments, the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 8.6± 0.2, 11.4± 0.2, 12.9± 0.2, 17.7± 0.2, 18.6± 0.2 and 22.0± 0.2. In some embodiments, the Form 5 polymorph has an XRPD pattern substantially as shown in Fig.5. In some embodiments, (i) Z is C, (ii) Y is C, (iii) R1, R2 and R5 are H, (iv) R3 is methoxy, v) R4 is F in the compound of Formula (I). In some embodiments, wherein (i) Z is C, (ii) Y is C, (iii) R1, R2and R5are H, (iv) R3is methoxy, v) R4is F, and (vi) # represents the R enantiomer in the compound of Formula (I). In some embodiments, wherein (i) Z is C, (ii) Y is C, (iii) R1, R2and R5 are H, (iv) R3 is methoxy, v) R4 is F, and (vi) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound F). In some embodiments, thecompound of Formula (I) is the meglumine salt of N-(4-((R)-2-(3-Fluoro-4- methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((S)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Fe.g., a Compound F meglumine salt. In some embodiments, the Compound F meglumine salt is a mono-meglumine salt. In some embodiments, the Compound F meglumine salt can be amorphous. In some embodiments, the Compound F meglumine salt can be crystalline. In some embodiments, the Compound F meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 6 polymorph of the meglumine salt of Compound F, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 12.7± 0.2, 19.5± 0.2, and 20.6± 0.2 degrees. In some embodiments, the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.2± 0.2, 15.7± 0.2, 20.0± 0.2, 21.6± 0.2, and 22.6± 0.2. In some embodiments, the Form 6 polymorph has an XRPD pattern substantially as shown in Fig.6. In some embodiments, the Form 6 polymorph comprises a mono-meglumine salt. In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1and R5are H, (iv) R3is -methoxy, and (v) R4 is F in the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1 and R5 are H, (iv) R3 is -methoxy, and (v) R4 is F, and (vi) # represents the racemic mixture of the compound of Formula (I). In some embodiments, (i) Z is N, (ii) Y is C, (iii) R1 and R5 are H, (iv) R3 is -methoxy, and (v) R4 is F, and (vi) # represents the R enantiomer in the compound of Formula (I). In someembodiments, (i) Z is N, (ii) Y is C, (iii) R1 and R5 are H, (iv) R3 is -methoxy, and (v) R4 is F, and (vi) # represents the S enantiomer in the compound of Formula (I). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3- yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Compound G). In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((R)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy- 4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. In some embodiments, the compound of Formula (I) is the meglumine salt of N-(4-((S)-2-(5-Fluoro-6-methoxypyridin-3- yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide. GIn some embodiments, Compound G can include a pharmaceutically acceptable salt, e.g., a Compound G meglumine salt. In some embodiments, the Compound G meglumine salt is a mono-meglumine salt. In some embodiments, the Compound G meglumine salt can be amorphous. In some embodiments, the Compound G meglumine salt can be crystalline. In some embodiments, the Compound G meglumine salt can form a polymorph. In some embodiments, the present disclosure provides a Form 7 polymorph of the meglumine salt of Compound G, wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.6± 0.2, 12.8± 0.2, and 19.6± 0.2 degrees. In some embodiments, the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 20.1± 0.2, 20.6± 0.2, 21.8± 0.2, 23.5± 0.2, and 26.3± 0.2. In some embodiments, the Form 7 polymorph has an XRPD pattern substantially as shown in Fig.7.In some embodiments, any of Forms 1, 2, 3, 4, 5, 6 or 7 can be the meglumine salt of Compounds A, B, C, D, E, F, or G, respectively. MEDICAL AND PHARMACEUTICAL USE The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of cardiovascular disease in a mammal, particularly a human. Cardiovascular disease includes, but is not limited to, conditions associated with cardiac dysfunction and / or microvascular dysfunction and / or macrovascular pathology, such as atherosclerosis, arteriosclerosis, coronary artery disease including stable and high risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or by biomarkers of microvascular and cardiac dysfunction), ischemic heart disease, myocardial infarction, restenosis following revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD) including erectile dysfunction due to vascular disease, stroke, cardiomyopathy, including non-ischemic dilated cardiomyopathy, transient ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia, renovascular disease, and renal arterial disease. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of non-ischemic dilated cardiomyopathy. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of cardiovascular disease in a patient having co-morbidities such as renal dysfunction. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies / multisystem diseases such as psoriatic arthropathy. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of cardiovascular disease associated with autoimmune conditions, e.g., rheumatoid arthritis,systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies / multisystem diseases such as psoriatic arthropathy. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of heart failure, including heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of inflammatory bowel disease. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of lupus nephritis. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of patients with remaining risk for a cardiovascular event despite standard of care (SoC) treatment, such as, but not limited to, lipid lowering statins, anti-platelets, ACE inhibitors, mineralocorticoid receptor antagonists, and beta blockers. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of chronic kidney disease. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of type II diabetes mellitus and complications of type II diabetes mellitus in a mammal, particularly a human. This includes, and is not restricted to, diabetic micro and macrovascular pathology, neuropathy and nephropathy. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of renal inflammatory and vascular diseases and complications associated with renal disease in a mammal, particularly a human. Renal inflammatory and vascular disease includes, but is notlimited to chronic kidney disease, drug and toxin induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephritis, reflux nephropathy, focal segmental glomerulosclerosis, Henoch-Schönleins purpura, and diabetic nephropathy. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of autoimmune diseases, such as, but not limited to, dermatomyositis, polymyositis, and systemic lupus erythematosus (SLE). The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and ASH (alcoholic steatohepatitis). The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may lower the cardiovascular and / or cerebrovascular and / or renal and / or peripheral arterial disease morbidity and mortality associated with cardiac dysfunction and / or atherosclerosis, and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology due to their anti-inflammatory properties and influence on vasoactive mechanisms. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may serve to prevent or reduce the risk of developing cardiac dysfunction and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology, as well as for halting or slowing the progression and / or promoting the regression of atherosclerotic cardiovascular disease once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein, to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic cardiovascular disease. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in preventing or reducing the incidence or severity of acute events related to atherosclerotic plaque rupture or erosion, including, but not limited to, myocardial infarction, unstable angina and stroke.The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in preventing or reducing the incidence or severity of acute events by improving microvascular function, macrovascular pathology and / or cardiac function. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in preventing or reducing the progression of abdominal aortic aneurysms (AAA) and incidence of rupture. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be useful in the prevention or treatment of respiratory inflammatory disease and complications associated with respiratory inflammatory disease in a mammal, particularly a human. Respiratory inflammatory disease includes, but is not limited to asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis. Some embodiments disclosed herein provide a method of treating or preventing one or more of the diseases or conditions discussed herein, wherein the method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing non- ischemic dilated cardiomyopathy, wherein the method comprises administering to a person in need thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease in a patient having co-morbidities such as renal dysfunction, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis,systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies / multisystem diseases such as psoriatic arthropathy, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing heart failure wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. In further embodiments the heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. Some embodiments disclosed herein provide a method of treating or preventing respiratory inflammatory disease and complications associated with respiratory inflammatory disease, wherein the method comprises administering to a person in need of thereof, the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein. In further embodiments, the respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and / or rhinitis. Some embodiments disclosed herein provide a compound of formulae (I) or a meglumine salt of Compound A, B, C, D, E, F, or G, or polymorphs thereof for use in a method of prevention or treatment as described herein.Some embodiments disclosed herein provide a compound of formulae (I) or a meglumine salt of Compound A, B, C, D, E, F, or G, or polymorphs thereof for use in the manufacturing of a medicament for prevention or treatment as described herein. The terms “preventing”, “prevention”, and “prevent” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition. The terms "treating”, “treatment”, and “treat” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include (1) diminishing the extent or cause of the condition being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with that condition. Treatment of cardiovascular disease, for example, can include stabilizing (i.e., not worsening), delaying, or slowing the spread or progression of the cardiovascular disease; prolonging survival as compared to expected survival if not receiving treatment; and / or otherwise ameliorating or palliating the severity of the cardiovascular disease, in whole or in part. The compounds disclosed herein may have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance), than compounds known in the prior art. These and other embodiments are described in greater detail herein below, where further aspects will be apparent to one skilled in the art from reading this specification. PHARMACOLOGICAL PROPERTIES The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein are believed to be useful in the prevention or treatment of cardiovascular conditions, including but not limited to coronary artery disease, acute coronary syndrome, cardiomyopathy, non-ischemic dilated cardiomyopathy, heart failure, heartfailure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction in a mammal, particularly a human. When a compound or salt described herein is administered as therapy for treating a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse. The compounds described herein are thus indicated both in the therapeutic and / or prophylactic treatment of these conditions. PHARMACEUTICAL COMPOSITIONS There is provided a method of treatment of a condition where modulation of CX3CR1 is required, which method comprises administration of a therapeutically effective amount of the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein to a person suffering from, or susceptible to, such a condition. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage FormDesigns, M. E. Aulton, Churchill Livingstone, 2ndEd. 2002.The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain / body weight ratio; othermedication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art. According to a further aspect there is thus provided the compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. Some embodiments disclosed herein provide a pharmaceutical composition comprising a compound of formulae (I) or a meglumine salt of Compound A, B, C, D, E, F, or G, or polymorphs thereof and one or more pharmaceutically acceptable excipients for use in a method of prevention or treatment as described herein. The compounds of formulae (I) or the meglumine salts of Compounds A, B, C, D, E, F, or G, or polymorphs thereof, disclosed herein may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation. In some embodiments, the disclosure provides a process for the preparation of the compounds of Formula I disclosed herein, the method comprising forming a slurry of (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXXmixing the slurry for greater than 2 hours, filtering the slurry by filtration and collecting the retentate, and washing the retentate with water, and drying the retentate to obtain the compounds. In some embodiments, the process comprises forming a slurry of compounds of Formula I withacetonitrile and water. In some embodiments, the process comprises forming a slurry of compounds of Formula I with water. In some embodiments, the process comprises forming a slurry of compounds of Formula I with acetonitrile. In some embodiments, the disclosure provides a process for the preparation of the polymorphs disclosed herein, the method comprising forming a slurry of (2R,3R,4R,5S)-6- (methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXX mixing the slurry forparticles from the slurry by filtration, and washing the particles with water, and drying the particles to obtain the polymorph. In some embodiments, the slurry is formed in an acetonitrile / water mixture at a ratio of about 10:90 to about 90:10, about 30:70 to about 70:30, or about 50:50. In some embodiments, the slurry is formed in an acetonitrile / water mixture at a ratio of about 80:20 to about 98:2, about 85:15 to about 95:5, about 88:12 to about 92:8, or about 90:10. In some embodiments, the slurry is formed in an acetonitrile / water mixture at a ratio of about 90:10. In some embodiments, the slurry is formed at a temperature of about 5°C to about 30°C, or about 15°C to about 25°C. In some embodiments, the slurry is mixed for about 10 minutes to about 24 hours, about 20 minutes to about 12 hours, or about 1 hour to about 6 hours. In some embodiments, the compound of Formula XXX is dissolved or mixed in a solvent at 20°C to 70°C to form a solution. In some embodiments, this can be referred to as a “dissolving temperature.” In some embodiments, the compound of Formula XXX is dissolved in a solvent at25° C, 30° C, 35° C, 40° C, 45°C, or 50°C to 70°C to form a solution. In some embodiments, compound of Formula XXX is dissolved in a solvent at 25°C to 30°C, 30°C to 35°C, 35°C to 40°C, 40°C to 45° C, or 45°C to 50 °C, 50 °C to 60°C, 60° C to 70° C, or 70 °C to 80°C to form a solution. In some embodiments, the compound of Formula XXX dissolved in the solution is less than 10% (wt / vol), less than 5% (wt / vol), less than 4% (wt / vol), or less than 3% (wt / vol) of the solvent. In some embodiments, the concentration of compound of Formula XXX is less than the saturation point for a given solvent and temperature, e.g., if the saturation point of compound of Formula XXX for a given solvent and temperature is “X mg / mL,” then the concentration of compound of Formula XXX is less than “X mg / mL”, e.g., 20% less, 50% less, or 80% less. In some embodiments, the compound of Formula XXX is mixed with the solvent to form a slurry, wherein the slurry is mixed for about 2 hours to about 12 hours, about 3 hours to about 8 hours, or about 4 hours to about 7 hours. In some embodiments, the slurry is mixed for greater than 4 hours, greater than 5 hours, or greater than 6 hours. In some embodiments, the mixing is for about 2 hours to about 4 hours. In some embodiments, the mixing occurs at a temperature of about 20 °C to about 30 °C. In some embodiments, the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol is about 2:1 to about 1:2. In some embodiments, the solvent is removed after formation of the slurry by filtration. For example, in some embodiments, the solvent is removed using a membrane or semi- permeable membrane. In some embodiments, when using the semi-permeable membrane, the solvent is replaced by a different solvent, wherein the salt compound of Formula I forms crystals in the different solvent. In some embodiments, the filter has a pore size of less than 50 µm, less than 30 µm, or less than 25 µm. In some embodiments, the filter has a pore size of 22 µm. Various filters are known in the art. In some embodiments, the filter is nonreactive with the polymorph. In some embodiments, the filter is a hydrophobic filter. In some embodiments, the filter is a polytetrafluoroethylene (PTFE) filter, e.g., a PTFE filter with a pore size of 22 µm. All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.EXAMPLES Example 1: General Synthesis Schemes Example I is the general synthetic scheme of providing the non-salt form of the compound of Formula I, i.e., a compound of Formula XXX. As used in Example 1, for compounds of Formula (II)-(XXIX), including IV-a, IXI-a, XX-a, XXI-a, XXII-a, XXIII-a, XXVI-a, and XXVII-a, the following definitions for the variable groups apply: R1is a C3-6 branched alkyl or C3-6 branched haloalkyl; R2is a C1-3alkyl or C1-3haloalkyl; m is 1 or 2; R3and R4are, independently, selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; A is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl; p is 0, 1, 2, 3, or 4; each R5is independently selected from halo, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkoxy-C1-3alkyl, C1-3 hydroxyalkyl, -CN, -(CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, -(CH2)qR8, -C(O)R8, -C(O)OR9,-OC(O)R9, -NR6C(O)R7,-NR6R7, C3-6cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl wherein the C3-6cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 substituents selected from hydroxy, oxy, halo, and -C(O)OR9, the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents, the C1-4 alkoxy can be optionally substituted with a 4-6 member heterocyclyl, each R6and R7are, independently, selected from H and C1-3alkyl, each q is, independently, 1, 2, or 3, each R8is, independently a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy, and each R9is, independently, a C1-5alkyl; The compounds of Formula (XVIIII) may be formed by reacting a compound of Formula (II),with a coupling partner of Formula (I The compounds of Formulaat the hydroxyl moiety with a suitable protecting group, for instance a silyl group such as TBDMS and suitable methods are known to a person skilled in the art (for introduction and removal of such groups see “Protective Groups in Organic Synthesis”, 4thedition, T.W. Greene & P.G.M Wutz, Wiley-Interscience (2007)). The compounds of Formula (III) may be pre-mixed with an organoboron reagent, e.g., 9- BBN dimer or a solution of 9-BBN in an organic solvent, e.g., THF, at rt for 1-24 h or at elevated temperatures, e.g., 35°C to reflux, for 1-2 h, and then a compound of formula (II) as defined above is added together with an inorganic salt e.g. K3PO4 or CsOH, and a catalytic amount of a palladium source e.g. Pd(dppf)Cl2^DCM. The resulting reaction mixture is stirred at temperatures ranging from 35°C to reflux for a prolonged time, e.g., 2-48 hours (h) until the reaction is complete, to give the compound of Formula (I). The compounds of Formula (II) may be prepared by sequentially reacting a compound of Formula (V), and a compound of Formula (VI), with a compound of Formula (IV), as illustrated in Scheme 1.Scheme 1MeTHF, is added to a solution of (IV) in an organic solvent, such as 2-MeTHF, at -35°C to - 10°C and then an organic base such as DIPEA dissolved in an organic solvent, e.g., 2-MeTHF is added to the reaction mixture at -35°C to 0°C and the reaction mixture is stirred until finished before any solids are filtered. The filtrate is added to a compound of Formula (VI) in an organic solvent, such as DMA, and an inorganic base, e.g., K2CO3, and the reaction mixture is stirred at an elevated temperature, e.g., 70°C to 80°C for a prolonged time, e.g., 48 h until the reaction is complete, to give the compound of Formula (II).

[0001] Compounds of Formula (IV), (V) and (VI) are commercially available or can be prepared in a conventional manner by a person skilled in the art. Compounds of Formula (III) may be prepared from compounds of Formula (VII) or (VIII) and (IX), according to Methods illustrated in Scheme 2. Scheme 2a: may a a compound of Formula (VII) and a suitable phosphonium salt, such as methyl triphenylphosphonium bromide, with an appropriate base, such as KOtBu or n-BuLi, in an inert solvent such as Et2O or THF. The base and phosphonium salt may be premixed in the solvent at -10°C to 40°C for 30 min to 1 h before a compound of Formula (VII) is added and the reaction is kept at temperatures ranging from rt to 50°C for reaction times between 1 h and 24 h, until the reaction is complete, to give the compound of Formula (III). Method b: A compound of Formula (VIII) may be reacted with a compound of Formula (IX) to give a compound of Formula (III). The reaction may be performed using a catalytic amount of a palladium source e.g. Pd(dppf)Cl2^DCM or Pd(dtbpf), in the presence of a base, e.g., an inorganic base, such as K2CO3, Cs2CO3or CsOH, using an organic solvent such as THF or 1,4-dioxane together with water, and at elevated temperatures e.g., ranging from 50°C to 95°C for a prolonged time, e.g.2 h to 24 h, until the reaction is finished, to give the compound of Formula (III). Compounds of Formula (VII) may be prepared in a two-step sequence from compounds of Formula (X) as illustrated in Scheme 3. Scheme 3Step 1: A compound of Formula (X) may be reacted with a nucleophilic reagent containing a suitable R3-group, e.g., a Grignard reagent, in an inert solvent, e.g. Et2O to give an alcohol of Formula (XI). Step 2: A compound of Formula (XI) may be reacted with an appropriate oxidizing reagent, e.g., Dess-Martin periodinane, in an inert solvent to give a compound of Formula (VII). Compounds of Formula (VII) may also be prepared in a two-step sequence from compounds of Formula (XII) as illustrated in Scheme 4.Scheme 4hydrochloride using a suitable coupling reagent e.g. TBTU, in the presence of an organic base such as DIPEA, using a solvent such as DCM, to give the corresponding Weinreb amide of Formula (XIII). Step 2: A compound of Formula (XIII), in which A, R5and p are as in step above, may be reacted with a nucleophilic reagent containing a suitable R3-group, where R3is as defined in step 2 above, e.g., a Grignard reagent, in an inert solvent, e.g. THF to give a compound of Formula (VII). Certain compounds of Formula (VII), (VIII), (IX), (X), (X1), (XII) and (XIII) are commercially available or can be prepared in a conventional manner by a person skilled in the art. A compound of Formula (I) may be formed by reacting a compound of Formula (XIV), with a coupling partner of, A compound of Formula (I) may be formed by reacting a compound of Formula (XIV-a),with a coupling partner of Form Catalytic amounts of a phosphine ligand, e.g., X-Phos, and a palladium source, e.g., Pd2dba3, are premixed under inert atmosphere in a suitable solvent such as THF, and then a compound of Formula (XIV) or a compound of Formula (XIV-a) and a compound of Formula (VI) are added together with a base, such as K2CO3, and the reaction is run under inert atmosphere at an elevated temperature, e.g., 70°C, for a prolonged time, such as overnight, until the reaction is finished, to give the compound of Formula (I). A compound of Formula (XIV) may be prepared by reacting a compound of Formula (XV), which can be a cis- or trans-isomer or a mix of both, and a compound of Formula (XVI), in which B is a boron species, e.g., a boronic acid or a boronate ester, as illustrated in Scheme 5. Scheme 52, mixed with a compound of Formula (XV), a compound of Formula (XVI) together with a base, such as KOH, using an organic solvent such as 1,4-dioxane, together with water, at elevated temperatures, e.g., from 50°C to 95°C for a prolonged time, e.g., 2 h to 24 h, until the reaction is finished, to give the compound of Formula (XIV). The compounds of Formula (XV), which can be a cis- or trans-isomer or a mix of both, may be prepared by sequentially reacting a compound of Formula (XVII), in which M is metal ora halo metal, usually MgBr, and a compound of Formula (V), as defined above, with a compound of Formula (IV), as defined above, as illustrated in Scheme 6. Scheme 6A solution of a compound of Formula (XVII) in a suitable organic solvent, e.g., THF, is added to a cold solution of (IV) in an organic solvent, e.g., THF, and the mixture is allowed to reach rt during a short period of time, usually 30 min, and then cooled and a solution of a compound of Formula (V) in a suitable organic solvent, e.g., THF and an organic base, such as DIPEA, are added and the reaction mixture is allowed to reach rt during a prolonged time until finished, to give the compound of Formula (XV). Compounds of Formula (XVI) and (XVII) are commercially available or can be prepared in a conventional manner by a person skilled in the art. A compound of Formula (I) may be prepared by reacting a compound of Formula (XVIII),with a coupling partner of Formula (XVI) as defined above. The reaction may be performed in a similar manner as the preparation of Formula (XIV). A compound of Formula (XIV) may also be prepared by reacting a compound of Formula (XIX),with a compound of Formula (V able solvent, e.g. THF or MeCN, and base, e.g., K2CO3for a prolonged time, e.g., 2 h to 24 h at rt, until the reaction is finished to give the compound of Formula (XIV). Compounds of Formula (XIX) may be prepared in a two-step sequence from compounds of Formula (XX), as illustrated in Scheme 7. Scheme 7compounds of Formula (XII), as illustrated in Scheme 4. Step 1: A compound of Formula (XX) may be reacted with diphenyl iminodicarboxylate in a suitable solvent, e.g., MeCN, in the presence of a base, such as K2CO3, at temperatures ranging from rt to 70°C for a prolonged time, e.g.2 h to 24 h, until the reaction is finished, to give a compound of Formula (XXI). Step 2: A compound of Formula (XXI) may be reacted with a suitable reagent, e.g., POCl3 in excess, with or without an amine base such as N,N-diethyl aniline as an additive, at elevated temperatures ranging from 70°C to reflux for a prolonged reaction time, e.g., 1.5 h to 15 h, until the reaction is finished, to give a compound of Formula (XIX). A compound of Formula (XX), as defined above, may be prepared from a compound of Formula (XXII), according to Methods illustrated in Scheme 8. Scheme 8Method a: A compound of Formula (XX) may be prepared by adding a compound of Formula (XXII) to a mixture of AlMe3and NH4Cl in an inert solvent, e.g., toluene, at temperatures ranging from 70°C to 90°C for prolonged reaction times until the reaction is complete, to give the compound of Formula (XX). Method b: Step 1: A compound of Formula (XXIII), may be prepared by adding AcCl to a cold solution of a compound of Formula (XXII) in a suitable solvent, e.g., EtOH, and allowing the temperature to reach rt during a prolonged time, e.g., 15 h to 24 h. Step 2: A compound of Formula (XX) may be prepared by adding a cold solution of NH3in a solvent such as MeOH, to a compound of Formula (XXIII) and allowing the temperature to reach rt during a prolonged time, e.g., 22 h. A compound of Formula (XXII) may be prepared in a two-step sequence from a compound of Formula (VII), as defined above, as illustrated in Scheme 9. Scheme 9Step 1: A compound of Formula (VII), as defined above, may be reacted with a suitable phosphonate, such as diethyl cyanomethyl phosphonate, with an appropriate base, such as NaOtBu or NaH, using a solvent such as abs EtOH or THF. The base and phosphonate may be premixed in the solvent for a short period of time before a compound of Formula (VII) is added and the reaction is kept at rt for reaction times between 2 h and 24 h, until the reaction iscomplete, to give a compound of Formula (XXIV). Step 2: A compound of Formula (XXIV) may be reduced by either of the methods described below. Method a: A compound of Formula (XXII) may be prepared by reacting a compound of Formula (XXIV) with Pd / C under hydrogen atmosphere, in an inert solvent such as EtOAc, at rt for a prolonged time, until the reaction is complete. Method b: A compound of Formula (XXII) may be prepared by reacting a compound of Formula (XXIV) with NaBH4, in a suitable solvent, such as MeOH at rt for a prolonged time, until the reaction is complete. Method c: A compound of Formula (XXII) may be prepared by adding a compound of Formula (XXIV) to a premixed slurry of diphenylsilane, Cu(OAc)2and DPEphos in a suitable solvent such as toluene at rt, and kept at rt for a prolonged time, until the reaction is complete. A compound of Formula (XIV-a) may be prepared by reacting a compound of Formula (XIX-a), as illustrated in Scheme 10. Scheme 10 with a, or MeCN, and base, e.g., K2CO3 for a prolonged time, e.g., 2 h to 24 h at rt, until the reaction is finished to give the compound of Formula (XIV-a). Compounds of Formula (XIX-a) may be prepared in a two-step sequence from compounds of Formula (XX-a), as illustrated in Scheme 11. Scheme 11Step 1: A compound of Formula (XX-a) may be reacted with diphenyl iminodicarboxylate in a suitable solvent, e.g., MeCN, in the presence of a base, such as K2CO3, at temperatures ranging from rt to 70°C for a prolonged time, e.g.2 h to 24 h, until the reaction is finished, to give a compound of Formula (XXI-a). Step 2: A compound of Formula (XXI-a) may be reacted with a suitable reagent, e.g., POCl3in excess, with or without an amine base such as N,N-diethyl aniline as an additive, at elevated temperatures ranging from 70°C to reflux for a prolonged reaction time, e.g., 1.5 h to 15 h, until the reaction is finished, to give a compound of Formula (XIX-a). A compound of Formula (XX-a), as defined above, may be prepared from a compound of Formula (XXII-a), according to Methods illustrated in Scheme 12. Scheme 12a compound of Formula (XXII-a) to a mixture of AlMe3and NH4Cl in an inert solvent, e.g., toluene, at temperatures ranging from 70°C to 90°C for prolonged reaction times until the reaction is complete, to give the compound of Formula (XX-a). Method b: Step 1: A compound of Formula (XXIII-a), in which A, R3, R4, R5and p are as defined in Formula (I), may be prepared by adding AcCl to a cold solution of a compound of Formula (XXII-a) in a suitable solvent, e.g., EtOH, and allowing the temperature to reach rt during a prolonged time, e.g., 15 h to 24 h. Step 2: A compound of Formula (XX-a) may be prepared by adding a cold solution of NH3 in a solvent such as MeOH, to a compound of Formula (XXIII-a) and allowing the temperature to reach rt during a prolonged time, e.g., 22 h.Certain compounds of Formula (XXII-a) may be prepared in a two-step sequence from compounds of Formula (XXVII-a), as illustrated in Scheme 13. Scheme 13Step 1: A Compound of Formula (XXVI-a) may be prepared from a compound of Formula (XXVII-a) by reacting with oxalyl chloride and catalytical amounts of DMF in a solvent e.g. DCM at low temperature to rt for 30 min to 12 h. The formed product may after concentration at reduced pressure be reacted with NH3 in a solvent e.g. THF at low temperature for a period of time, typically 1 h to 24 h. Step 2: A compound of Formula (XXII-a) may be prepared from a compound of Formula (XXVI-a) by reacting with a PdCl2 in a solvent e.g. a mixture of MeCN and water at rt for a 12 h to 24 h. Compounds of Formula (XXII-a) and (XXVII-a) are commercially available or can be prepared in a conventional manner by a person skilled in the art (for example, see methods described in; Liebigs Annalen 1996, 8, 1289-1294). A compound of Formula (I) in which m is 2, may be formed by reacting a compound of Formula (II), as defined above, with a coupling partner of Formula (XXV), as illustrated in Scheme 14.Scheme 14e.g., 9- BBN dimer or a solution of 9-BBN in an organic solvent, e.g., THF, at rt for 1 h to 24 h or at elevated temperatures, e.g., 35°C to reflux, for 1-2 h, before a compound of Formula (II) as defined above is added together with an inorganic salt e.g. K3PO4 or CsOH, and a catalytic amount of a palladium source e.g. Pd(dppf)Cl2^DCM. The resulting reaction mixture is stirred at temperatures ranging from 35°C to reflux for a prolonged time, e.g., 2-48 h until the reaction is complete, to give the compound of Formula (I). Compounds of Formula (XXV) are commercially available or can be prepared as described in Scheme 11 in a conventional manner by a person skilled in the art (for example, see methods described in; J. Org. Chem.1958, 23, 1658; J. Am. Chem. Soc.2012, 134, 17470; Angew. Chem. Int. Ed.2021, 60, 25746). The below isomer compounds (Compounds A-H) were prepared from reaction intermediates formed in the chemical reactions or mechanism schemes above. Example 2: X-ray Powder Diffraction (XRPD) Analysis X-ray powder diffraction analysis was performed according to standard methods, which can be found in e.g. Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York. Persons skilled in the art of X-ray powder diffraction will understand that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non- unitary aspect ratios, which may affect analysis of samples. The skilled person will also realizethat the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. (Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures). Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately plus or minus 0.2o2-theta, and such a level of measurement error should be taken into account when considering the XRPD pattern in Figures 1-7 and when reading Tables 1-7. Furthermore, peak intensities may fluctuate depending on experimental conditions and sample preparation (preferred orientation). Definition of relative intensity is described in Table 1 below. The XRPD pattern was determined by mounting a sample on a zero-background sample holder with a small depression filled with some of the ground material. A glass slide was used to get an evenly distributed sample with the correct sample height. The X-ray powder diffraction for polymorphs of Compounds C, D, E and F disclosed herein was recorded with a theta-two theta scan axis using a Rigaku Miniflex 600 (wavelength of X-rays 1.5418 Å nickel-filtered Cu K^radiation, 40 kV, 15 mA) equipped with D / Tex Ultra detector operating in one dimensional mode. Fixed divergence and receiving slits were used together with an automatic variable anti-scatter screen. The samples were rotated at 30 revolutions per minute during measurement. Samples were scanned from 3 - 40° or 3 - 50° 2- theta (2^) using a 0.01° and 1° / min step width and scan speed respectively. The X-ray powder diffraction for polymorphs of Compounds A, B and G disclosed herein was recorded with a theta-theta scan axis using a Malvern Panalytical Empyrean (wavelength of X-rays 1.5418 Å nickel-filtered Cu K^radiation, 45 kV, 40 mA) equipped with PIXcel3D detector operating in one dimensional mode. Variable divergence and receiving slits are used. The sample is rotated during measurement. Samples were scanned from 2.4 - 50° 2-theta (2θ) using a 0.013° step width and 45.645 s / step speed. The XRPD pattern in this was obtained in Bragg-Brentano geometryExample 3: Synthesis of Compounds A-G and meglumine salts thereof General conditions General condition include: (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28oC and where needed under an atmosphere of an inert gas such as N2; optionally reactions were carried out using a MBRAUN UNILab Plus ECO or a MBRAUN UNILab SP Eco glovebox workstation, in which case it is indicated; (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g)); (iii) in general, the course of reactions was followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS). (iv) when necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4, or by using ISOLUTE® Phase Separator, and workup procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4or Na2SO4is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer. (v), evaporations were carried out either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (vi) unless otherwise stated, flash column chromatography was performed on straight phase silica, using either Merck Silica Gel (Art.9385) or prep-packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4–330 g), Biotage® Sfär Silica HC D cartridges (20 µm, 10–100 g), Interchim puriFlash™ cartridges (25 µm, 4–120 g), Interchim puriFlash™ cartridges (50 µm, 25–330 g), Grace™ GraceResolv™ Silica Flash Cartridges (4–120 g) or Agela Flash Colum Silica-CS cartridges (80–330g), or on reversed phase silica using AgelaTechnologies C-18, spherical cartridges (20–35µm, 100A, 80–330g), manually or automated using a Grace Reveleris® X2 Flash system or similar system; (vii) preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and / or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section and using one of the following methods: PrepMethod A: The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm, 250×50 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as mobile phase; PrepMethod C: The compound was purified by preparative HPLC on an unspecified column using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as mobile phase; PrepMethod D: The compound was purified by preparative HPLC on a XBridge™ C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as mobile phase; PrepMethod F: The compound was purified by preparative HPLC on a XBridge™ C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / NH3 (0.2%, pH 10) buffer system as mobile phase; relevant fractions were collected, combined and freeze-dried or evaporated to give the purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, the aqueous layer was extracted with DCM or EtOAc, and the organic layer was dried, either over Na2SO4 or by using a phase-separator, and then concentrated at reduced pressure and when needed dried in vacuo, to give the purified compound; (viii) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instruments, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section; (ix) yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required; (x) in general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported whendetected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. It is understood, where the NMR spectra contains residual impurities and / or residual solvent(s), this is not reported unless it partially coincides with peaks of Intermediates and / or Structures of Formula (I), in which case said peaks of Intermediates and / or Structures of Formula (I) are reported as multiplets partially overlapping with said solvent or impurity, and the Integral is omitted. In some cases, the structures of the end-products of the Formula (I) might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported. In some cases, the structures of the end- products of Formula (I) might appear as rotamers in a more equal relationship, in such instances the peaks of such rotamers are either reported as multiplets, if the signals of said rotamers are partially overlapping, or as individual peaks, if the signals of said rotamers are well separated; electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported; (xi) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xii) in general Examples and Intermediate compounds are named using ChemDraw Professional version 20.1.1.125 or version 21.0.0 from PerkinElmer. ChemDraw Professional version 20.1.1.125 or version 21.0.0 generates the names of chemical structures using the Cahn- Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules.ChemDraw is optionally using labels in the graphical representation of stereocenters such as '&' and 'or' to describe the configuration of the stereochemical centers present in the structure. A number following the '&' and 'or' flag is assigned to each stereocenter present in the structure. The numbers are incremented automatically to indicate that stereocenters may vary independently to each other. In general, for chemical structures of Examples and Intermediates where more than one stereocenter is present and said stereocenters have a fixed relative configuration, the same number is used after the label '&' and 'or' to indicate that said stereocenters forms a group. A third stereocenter present in the same chemical structure, that varies independently to the former stereocenters, is designated with a unique new number following the label '&' and 'or'. In general, chemical structures of Examples and Intermediates containing the label '&' at a stereocenter, means the configuration of such Example or Intermediate at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such Example or Intermediate at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure. In general, for structures of Examples and Intermediates where all of the stereocenters are designated as '&', the structure is named with a “rac-” prefix. The descriptors (RS) and (SR) are used to denote general '&' centers for chemical structures with multiple chiral centers where only some are designated as '&'. In general, for structures of Examples and Intermediates where all of the stereocenters are designated as 'or', the structure is named with a “rel-” prefix. The descriptors (R*) and (S*) are used to denote the general 'or' centers for chemical structures with multiple chiral centers where only some are designated as 'or'. It is to be understood that an Example or Intermediate with a stereocenter labled (R*) or (S*) has an absolute configuration at said stereocenter and while said stereocenter in the compound has been designated as (R*) or (S*), the actual stereochemistry of that particular isomer could be the opposite of the label. For example, while Compound A, the second eluting isomer from the chiral separation of N-(4-(2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, is named “N-(4-((R*)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide,” it could be N-(4-((R)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-((S)-2-(2,3- Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide: Compound Athe ones mentioned above, the following abbreviations and units have been used: Aq Aqueous 9-BBN 9-borabicyclo[3.3.1]nonane tBu tert-Butyl KOtBu Potassium tert-butoxide Brine Saturated aqueous sodium chloride solution Calcd Calculated DCM Dichloromethane DEA Diethylamine DIPEA N-ethyl-N-isopropyl-propan-2-amine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DPEphos (oxybis(2,1-phenylene))bis(diphenylphosphane) e.g. for example ESI Electrospray ionization Et2O Diethyl etherEtOAc Ethyl acetate EtOH Ethanol FA Formic acid HPLC High performance liquid chromatography HOAc Acetic acid HRMS High resolution mass spectrometry ID Inner diameter LCMS Liquid chromatography Mass spectrometry MeCN Acetonitrile MeOH Methanol MS Mass spectrometry 2-MeTHF 2-Methyltetrahydrofuran m / z mass spectrometry peak(s) NaOtBu Sodium tert-butoxide NMR Nuclear magnetic resonance OAc O(CO)CH3Pd / C Palladium on charcoal Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2•DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2(1:1) [Rh(COD)Cl]2 Bis(1,5-cyclooctadiene)dirhodium(I) dichloride Rt Room temperature sat Saturated TBDMS tert-butyldimehylsilyl TBTU 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TEA Triethylamine THF Tetrahydrofuran TLC Thin layer chromatography UV ultraviolet X-Phos dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphaneUnits C Celcius g gram h hour(s) mg milligram MHz megaherz min minute(s) mL milliliter mm millimeter mmol millimole(s) µm micrometer ^L microlitre nm nanometer ppm parts per million I. Synthesis of N-(4-((R*)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound A) Oxalyl dichloride (20.8 mL, 246 mmol) was added under nitrogen atmosphere to a stirred suspension of phenyl carbamate (30.7 g, 224 mmol) in DCM (165 mL). The mixture was heated under nitrogen atmosphere to gentle reflux for 18 h to obtain a solution. After evaporation, the residue was treated with toluene (150 mL). The slurry was stirred for 20 min, and the insoluble material was removed by filtration to provide toluene-filtrate containing phenyl carbonisocyanatidate (224 mmol). Phenol (23.2 g, 246 mmol) was added in portions within 10 min to the ice cold toluene- filtrate containing phenyl carbonisocyanatidate (224 mmol). The mixture was stirred with the cooling bath for 30 min and thereafter at rt for 20 h. The mixture was concentrated, the residue was dissolved in DCM and concentrated, after repeated once more the residue solidified. Toluene (200 mL) was added to the solid and the mixture was stirred at rt for 20 min. Heptane (50 mL) was added to the mixture and stirring was continued overnight in order to get a slurry. The crude product was filtered off and the solid was washed with heptane until the filtratebecame clear. The mother liquor and washings were combined and concentrated. Toluene (50 mL) and heptane (20 mL) were added to the residue. The mixture was stirred overnight in order to get a slurry. The residue was filtered off and the solid was washed with heptane until the filtrate became clear. Both crops were combined to yield diphenyl iminodicarbonate (38.8 g, 93%). MS (ESI) m / z [M+H]+257.9. Diethyl cyanomethylphosphonate (4.45 mL, 27.5 mmol) was added at 0°C to a solution of NaOtBu (2.64 g, 27.5 mmol) in abs EtOH (33 mL). After stirring for 15 min, 1-(2,3- difluorophenyl)ethanone (3.90 g, 25.0 mmol) was added and the mixture was stirred at rt for 2 h. 10% Citric acid (33 mL) was added and the mixture was extracted with PE × 3 (bp.40-60) (×3, 100, 50 and 50 mL). The combined colourless extracts were washed with brine, dried over Na2SO4 and concentrated to give (E)-3-(2,3-difluorophenyl)but-2-enenitrile (3.94 g, 88%). According to1H NMR a mixture of E- and Z-isomer (~ 4:1) was obtained;1H NMR (400 MHz, CDCl3) 2.28 – 2.48 (3H, m), 5.54 – 5.66 (1H, m), 7.03 – 7.25 (3H, m).Pd / C 10% (1.20 g, 1.13 mmol) was added under argon atmosphere to a stirred solution of crude (E)-3-(2,3-difluorophenyl)but-2-enenitrile (9.92 g, 55.4 mmol) (E / Z-mixture) in EtOAc (240 mL). The mixture was hydrogenated (atmospheric pressure) at rt for 14 h. The catalyst was removed by filtration through silica and celite. The filtrate was concentrated to give 3-(2,3- Difluorophenyl)butanenitril (9.62, 96%) as a colourless oil which was used without further purification;1H NMR (400 MHz, CDCl3) 1.48 (3H, dd), 2.58 – 2.75 (2H, m), 3.45 – 3.57 (1H, m), 6.94 – 7.15 (3H, m). AlMe3 (2 M in toluene, 4.8 mL, 9.6 mmol) was added dropwise under argon atmosphere to an ice cold suspension of NH4Cl (0.551 g, 10.3 mmol) in toluene (6 mL). The resulting mixture was warmed to rt and stirred for 1 h.3-(2,3-Difluorophenyl)butanenitrile (1.09 g, 6.01 mmol) was added and the mixture was stirred at 80°C overnight. After cooling to rt the mixture was slowly poured into an ice cold slurry of silica (4 g) in CHCl3 (15 mL) and stirred for 15 min. The slurry was filtered and the residue was washed with MeOH (2 × 40 mL). The combined filtrates were concentrated. The residue was stirred for 5 min with HCl (1.25 M in MeOH, 4 mL) and then concentrated. The colourless residue was stirred with IPA / acetone (4 / 1, 16 mL) for 45 min, the insolubles were removed by filtration and the filtrate was concentrated. The crude product was dissolved in IPA (5 mL), HCl (1.25 M in MeOH, 0.5 mL) was added under stirringfollowed by dropwise addition (~10 min) of Et2O (~ 20 mL). The mixture was stirred at rt for 30 min and then cooled to 5°C for 1 h. The colourless precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield the HCl salt of 3-(2,3-difluorophenyl)butanimidamide (0.79 g, 56%);1H NMR (400 MHz, D2O) 1.41 (3H, d), 2.68 – 2.9 (2H, m), 3.53 – 3.66 (1H, m), 7.12 – 7.26 (3H, m). A suspension of K2CO3(462 mg, 3.35 mmol) and 3-(2,3-difluorophenyl)butanimidamide (785 mg, 3.35 mmol) in MeCN (15 mL) was stirred under argon atmosphere for 5 min. Diphenyl iminodicarbonate (862 mg, 3.35 mmol) was added and stirring was continued at rt for 1 h. Another equivalent of K2CO3(462 mg, 3.35 mmol) was added and stirring was continued at rt for 1 h and at 60°C for 2 h. After cooling to rt the resulting thick suspension was dissolved in 1 M HCl (15 mL) and EtOAc (50 mL). The layers were separated, the aqueous phase was extracted with EtOAc (2 × 25 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and the remaining solid was dried in vacuo. The material, containing phenol (~ 20 mol%) as impurity, was stirred for 10 min with PE / Et2O (2 / 1, 30 mL), filtered and dried in vacuo to yield 6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine- 2,4(1H,3H)-dione (791 mg, 88%); MS (ESI) m / z [M+H]+268.4. A mixture of 6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione (0.27 g, 1.0 mmol), POCl3 (0.28 ml, 3.0 mmol) and N,N-diethylaniline (0.16 ml, 1.0 mmol) was heated at 70°C for 1.5 h. After cooling to rt the mixture was diluted with CHCl3(10 mL) and toluene (10 mL). The mixture was concentrated to give 2,4-dichloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5- triazine as an oil used below (yield assumed quantitative). K2CO3(270 mg, 1.95 mmol) was added in 3 portions over 2 h to a stirred solution of 2,4- dichloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine and (R)-2-amino-4-methylpentan-1-ol (150 µl, 1.17 mmol) in dry THF (6 mL). Stirring was continued for another 1 h, additional (R)-2- amino-4-methylpentan-1-ol (100 µl, 0.780 mmol) was added and the mixture was stirred overnight. The mixture was diluted with Et2O (40 mL) and the insolubles were removed by filtration. The filtrate was concentrated and the residue was purified by preparative HPLC, PrepMethod A, (gradient: 40–80%) to yield (2R)-2-((4-Chloro-6-(2-(2,3-difluorophenyl)propyl)- 1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (80 mg, 21%); MS (ESI) m / z [M+H]+385.5Cs2CO3 (132 mg, 0.410 mmol) was added under argon atmosphere to a suspension of methanesulfonamide (39 mg, 0.41 mmol), Pd2(dba)3 (21 mg, 0.020 mmol), X-Phos (21 mg, 0.040 mmol) and (2R)-2-((4-chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)- 4-methylpentan-1-ol (80 mg, 0.21 mmol) in THF (3.1 mL) and the reaction mixture was stirred at 64°C for 6.5 h. After cooling to room temperature the mixture was diluted with THF (7 mL) and filtered through celite. The filtrate was acidified with HOAc (50 µL) and concentrated. The remaining oil was purified by preparative HPLC, PrepMethod F, (gradient: 5-95%), to give the title compound N-(4-(2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (37 mg, 40%); MS (ESI) m / z [M+H]+444.19. The diastereomers of N-(4-(2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 118 (50 mg, 0.11 mmol) were separated by preparative chiral HPLC on a Chiralpak OJ column (5 μm, 250×20 mm ID) using heptane / EtOH / TEA (80 / 20 / 0.1) as mobile phase, at a flow rate of 18 mL / min and detected at 254 nm, to give the first eluted compound N-(4-((S*)-2-(2,3-difluorophenyl)propyl)- 6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) that was purified by preparative HPLC, PrepMethod F, (gradient: 5–95%) to yield (14 mg, 29%); HRMS (ESI) m / z [M+H]+ calcd for C19H28F2N5O3S: 444.1876, found: 444.1896; 1H NMR (600 MHz, DMSO-d6) 0.75 – 0.88 (6H, m), 1.23 – 1.44 (5H, m), 1.46 – 1.59 (1H, m), 2.76 (1H, d), 2.82 – 2.90 (1H, m), 2.97 – 3.18 (3H, m), 3.26 – 3.32 (m, overlap with water signal), 3.60 –3.73 (1H, m), 3.98 – 4.06 (1H, m), 4.62 – 4.74 (1H, m), 7.11 – 7.2 (2H, m), 7.20 – 7.30 (1H, m). The second eluted compound from the chiral separation, N-(4-((R*)-2-(2,3- difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Compound A) was purified by preparative HPLC, PrepMethod F, (gradient: 5–95%) to yield (22 mg, 43%); HRMS (ESI) m / z [M+H]+ calcd for C19 H28 F2N5O3S: 444.1876, found: 444.1870; 1H NMR (600 MHz, DMSO-d6) 0.80 – 0.88 (6H, m), 1.22 – 1.45 (5H, m), 1.47 – 1.60 (1H, m), 2.69 – 2.86 (2H, m), 2.97 – 3.18 (3H, m), 3.23 – 3.29 (m, partial overlap with water signal), 3.61– 3.72 (1H, m), 3.98 – 4.08 (1H, m), 4.63 – 4.72 (1H, m), 7.11 – 7.19 (2H, m), 7.21 – 7.3 (1H, m). II. Synthesis of N-(4-((R*)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound A) mono-meglumine saltAmorphous compound (N-(4-((R*)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (400 mg, 0.90 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (194 mg, 0.99 mmol) were slurried in acetonitrile (5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight and slurry washed in water (2 mL). The resultant sample of mono-meglumine salt was isolated by filtration and dried in vacuo at ambient temperature prior to H-NMR and XRPD analysis. A 25.5% mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-((R*)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 1) is presented in Table 1. An exemplary diffraction pattern of the Form 1 polymorph can be found in FIG.1. Table 1 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.2 100 vs 8.8 24 s 11.3 9 m 12.7 18 s 16.1 25 vs 18.6 11 s 19.8 28 vs 20.2 16 s 21.8 5 m 24.7 16 s III. Synthesis of N-(4-((R*)-2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound B) 2,4,6-Trichloro-1,3,5-triazine (50.0 g, 271.1 mmol) was dissolved in 2-MeTHF (500 mL) under nitrogen atmosphere and the stirred solution was cooled to -30ºC. A solution of (R)-2- amino-4-methylpentan-1-ol (31.1 g, 265.7 mmol) in 2-MeTHF (125 mL) was added dropwise during approximately 45 min. A thick slurry was obtained and DIPEA (47.2 mL, 271.1 mmol) in 2-MeTHF (125 mL) was added at -30ºC during 70 min. The reaction mixture was allowed toreach -5ºC during 30 min and then filtered and used directly, without purification, as described below. DMA (875 mL) was added to methanesulfonamide (77.0 g, 813.5 mmol) followed by K2CO3 (75.0 g, 542.4 mmol) and the mixture was stirred at 50ºC for 10 min and then the filtered reaction solution above was added during 2 min. The reaction mixture was stirred at 75ºC for 48 h and then allowed to reach rt. Water (1 L) was added and pH was adjusted to approximately 3 with the addition of 6 M HCl. The two phases were separated, and the aqueous phase was extracted with 2-MeTHF (2×300 mL). The combined organic extract was washed with sat NH4Cl (aq) (2×500 mL) and concentrated in vacuo. The solid was dissolved in MTBE (250 mL) and the product was extracted with 5% K2CO3(aq) (3×200 mL). The pH of the aqueous phase was adjusted to approximately 4 by the addition of 6 M HCl and extracted with MTBE (2×250 mL). The organic extract was dried over MgSO4, filtered and evaporated to yield (R)-N-(4-Chloro-6- ((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (57.4 g, 67%) as an off-white solid foam; MS (ESI) m / z [M+H]+324.2. n-BuLi (1.6 M in hexane, 44.3 mL, 70.9 mmol) was added to methyltriphenylphosphonium bromide (25.3 g, 70.9 mmol) in THF (150 mL). The reaction mixture was stirred at rt for 10 min and then a solution of 1-(2-fluoro-6-methoxypyridin-3- yl)ethan-1-one (10.0 g, 59.1 mmol) in THF (50 mL) was added and the reaction mixture was stirred at 40ºC for 1 h. Water and Et2O were added and the two phases were separated. The organic extract was washed with water, dried over MgSO4, filtered and evaporated. The residue was dissolved in boiling heptane. The heptane solution was allowed to reach rt and then filtered. The filtrate was evaporated and the residue was purified by straight phase flash chromatography on silica (heptane / EtOAc, 15 / 1) to yield 2-Fluoro-6-methoxy-3-(prop-1-en-2-yl)pyridine compound as a colourless oil (8.5 g, 86%);1H NMR (500 MHz, CDCl3) 2.10 – 2.13 (3H, m), 3.92 (3H, s), 5.19 – 5.21 (1H, m), 5.23 – 5.26 (1H, m), 6.59 (1H, dd), 7.63 (1H, dd). 9-BBN (0.5 M in THF, 56.5 ml, 28.3 mmol) in THF (30 mL) was added to 2-fluoro-6- methoxy-3-(prop-1-en-2-yl)pyridine (2.70 g, 16.2 mmol) and the mixture was stirred at rt overnight. Degassed 3 M K3PO4 (aq, 16.2 mL, 48.4 mmol), (R)-N-(4-chloro-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (2.61 g, 8.07 mmol) and Pd(dppf)Cl2∙DCM (0.989 g, 1.21 mmol) were added to the solution . The reaction mixture waspurged and stirred at 38°C for 20 h. The reaction mixture was poured into sat brine (100 mL), acidified with 0.3 M HCl (to pH 1) and extracted with EtOAc (3 × 150 mL). The pH of the aqueous phase was adjusted to ~7 by the addition of sat NaHCO3and then extracted with EtOAc (2 × 50 mL). The combined organic layers were treated with SiliaMetS Thiol, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase flash chromatography on C18-column [gradient: 0-50% MeCN in water (0.2% FA)] to afford N-(4-(2-(2-Fluoro-6- methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (1.70 g, 46%) as a colourless solid; MS (ESI) m / z [M+H]+457.15 The diastereomers of N-(4-(2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (1.70 g, 3.72 mmol) were separated by preparative chiral HPLC on a CHIRAL ART Cellulose-SC (5 µm, 250 × 20 mm) column using 40 % EtOH in hexane (0.1 % FA), at a flow rate of 20 mL / min and detected at 220 / 254 nm, to yield the first eluted compound N-(4-((R*)-2-(2-fluoro-6- methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 2-yl)methanesulfonamide (Compound B) (0.64 g, 38%) as a white solid; HRMS (ESI) m / z [M+H]+ calcd for C19H30FN6O4S: 457.2028, found: 457.2012; 1H NMR (400 MHz, CDCl3) 0.89 – 0.99 (6H, m), 1.25 – 1.54 (5H, m), 1.54 – 1.73 (1H, m), 2.95 – 3.06 (2H, m), 3.26 – 3.33 (3H, m), 3.52 – 3.81 (3H, m), 3.83 – 3.92 (3H, m), 4.16 – 4.33 (1H, m), 6.53 – 6.62 (1H, m), 7.56 – 7.68 (1H, m), and the second eluted compound N-(4-((S*)-2-(2-fluoro-6-methoxypyridin- 3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 2) Example 86 (0.67 g, 39%) as a white solid; HRMS (ESI) m / z [M+H]+ calcd for C19H30FN6O4S: 457.2028, found: 457.2016; 1H NMR (300 MHz, CDCl3) 0.82 – 1.0 (6H, m), 1.22 – 1.75 (6H, m), 2.88 – 3.05 (2H, m), 3.22 – 3.35 (3H, m), 3.50 – 3.84 (3H, m), 3.88 (3H, s), 4.12 – 4.3 (1H, m), 6.57 (1H, d), 7.54 – 7.72 (1H, m). IV. Synthesis of N-(4-((R*)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound B) mono- meglumine salt Amorphous compound (N-(4-((R*)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (400 mg, 0.88 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (188 mg, 0.96 mmol) wereslurried in acetonitrile (5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight and slurry washed in water (2 mL). The resultant sample of N-(4-((R*)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6- (((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono- meglumine salt was isolated by filtration and dried in vacuo at ambient temperature prior to H- NMR and XRPD analysis. A 64.4% mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-((R*)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 2) is presented in Table 2. An exemplary diffraction pattern of the Form 2 polymorph can be found in FIG.2. Table 2 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 4.9 100 vs 8.5 33 vs 11.5 16 s 12.9 23 s 19.5 41 vs 20.7 29 vs 22.1 12 s 23.2 18 s 23.6 14 s 24.1 11 s V. Synthesis of N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Compound C) Methyltriphenylphosphonium bromide (23.6 g, 66.2 mmol) was added to a suspension of KOtBu (7.42 g, 66.2 mmol) in THF (50 mL) at -20°C under nitrogen atmosphere. The reaction mixture was stirred at -20°C for 1 h.1-(6-Methoxypyridin-3-yl)ethan-1-one (5.0 g, 33 mmol) was added at -20°C and stirring was continued at rt for 14 h. The mixture was concentrated, diluted with EtOAc (200 mL) and washed sequentially with sat NH4Cl (2 × 200 mL), brine (2 × 200 mL), and water (3 × 200 mL). The organic layer was dried over Na2SO4, filtered andevaporated. The residue was purified by straight phase flash chromatography on silica (gradient: 10-20% EtOAc in PE) to afford 2-methoxy-5-(prop-1-en-2-yl)pyridine (3.4 g, 69%) as a dark oil;1H NMR (300 MHz, DMSO-d6) 2.10 (3H, dd), 3.86 (3H, s), 5.00 – 5.10 (1H, m), 5.30 – 5.40 (1H, m), 6.80 (1H, dd), 7.87 (1H, dd), 8.29 (1H, dd). 9-BBN (0.5 M, 72.9 mL, 36.5 mmol) in THF (40 mL) was added to 2-methoxy-5-(prop- 1-en-2-yl)pyridine (3.20 g, 21.4 mmol), and the reaction mixture was stirred at 70°C for 1 h. Degassed (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (3.47 g, 10.7 mmol), Pd(dppf)Cl2∙DCM (1.31 g, 1.61 mmol) and 3 M K3PO4(aq, 21.4 mL, 64.4 mmol) were added to the solution . The resulting mixture was purged and stirred at 40°C for 20 h. The reaction mixture was poured into sat brine (250 mL), acidified with 0.3 M HCl (to pH 1) and extracted with EtOAc (2 × 200 mL). The pH of the aqueous phase was adjusted to ~7 by the addition of sat NaHCO3 (50 mL) and then extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated (40°C). The residue was purified by reversed phase flash chromatography on C18-column (gradient: 10-80% water in CH3CN) to afford the N-(4-(((R)-1-Hydroxy-4-methylpentan-2- yl)amino)-6-(2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (2.80 g, 60%) as a colourless solid; MS (ESI) m / z [M+H]+439.20. The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (2.8 g, 6.38 mmol) were separated by preparative chiral HPLC on a Lux 5 µm Cellulose-4 column (5 µm, 250×30) using 35% MeOH (0.1% 2 M NH3-MeOH) in CO2, 100 bar, at a flow rate of 70 mL / min and detected at 220 nm, to yield the first eluted compound N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 6-((S*)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (1.04 g, 37%) as a white solid; HRMS (ESI) m / z [M+H]+calcd for C19H31N6O4S: 439.2122, found: 439.2116;1H NMR (400 MHz, CDCl3) 0.83 – 1.0 (6H, m), 1.2 – 1.55 (5H, m), 1.55 – 1.78 (1H, m), 2.82 – 3.02 (2H, m), 3.2 – 3.4 (4H, m), 3.52 – 3.82 (2H, m), 3.89 (3H, s), 4.12 – 4.35 (1H, m), 6.69 (1H, d), 6.98 (1H, br s), 7.47 – 7.58 (1H, m), 7.95 – 8.03 (1H, m), and the second eluted compound N- (4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxypyridin-3-yl)propyl)- 1,3,5-triazin-2-yl)methanesulfonamide (Compound C) (0.856 g, 31%) as a white solid; HRMS (ESI) m / z [M+H]+calcd for C19H31N6O4S: 439.2122, found: 439.2122;1H NMR (300 MHz, CDCl3) 0.85 – 1.02 (6H, m), 1.25 – 1.55 (5H, m), 1.55 – 1.78 (1H, m), 2.83 – 3.0 (2H, m),3.25 – 3.48 (4H, m), 3.48 – 3.81 (2H, m), 3.93 (3H, d), 4.15 – 4.33 (1H, m), 6.74 (1H, d), 6.80 – 6.89 (1H, m), 7.48 – 7.65 (1H, m), 8.01 – 8.13 (1H, m). VI. Synthesis of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Compound C) mono- meglumine salt Amorphous compound (N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide) (100 mg, 0.23 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (49.0 mg, 0.25 mmol) were slurried in acetonitrile (1.5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight before it was washed with water. The resultant sample of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6- methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt was isolated by filtration and dried in vacuo at ambient temperature overnight prior to H-NMR and XRPD analysis. A 16.6 % mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxypyridin-3-yl)propyl)- 1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 3) is presented in Table 3. An exemplary diffraction pattern of the Form 3 polymorph can be found in FIG.3. Table 3 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.0 100 vs 8.5 22 s 11.3 14 s 12.8 15 s 15.9 17 s 19.8 25 s 20.6 22 s 22.5 7 m 24.2 11 s 26.3 9 mVII. Synthesis of N-(4-((R*)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound D) Dibromine (56.6 g, 354.0 mmol) in HOAc (100 mL) was added dropwise during 15 min to a solution of 4-fluoro-2-methoxypyridine (30.0 g, 236.0 mmol) in HOAc (150 mL) and the reaction mixture was stirred at rt overnight. EtOAc and water were added followed by the addition of Na2S2O5(aq) until bromine colour disappeared, and the two phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic extract was washed with 2 M NaOH and water, dried over MgSO4, filtered and evaporated. The residue was purified by straight phase flash chromatography on silica (heptane / EtOAc:10 / 1 as eluent) to yield 5- bromo-4-fluoro-2-methoxypyridine as a colourless oil that solidified upon standing (25.6 g, 53%);1H NMR (500 MHz, CDCl3) 3.93 (3H, s), 6.52 (1H, d), 8.23 (1H, d). 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (27.4 ml, 145.6 mmol) was added to a mixture of 5-bromo-4-fluoro-2-methoxypyridine (25.0 g, 121.4 mmol), K2CO3(41.9 g, 303.4 mmol) and Pd(dtbpf)Cl2 (4.75 g, 7.28 mmol) in THF (240 mL) and water (60 mL) under nitrogen atmosphere. The reaction mixture was stirred at 50ºC for 2 h and then it was allowed to reach rt. Water and Et2O were added and the two phases were separated. The aqueous phase was extracted with Et2O and the combined organic extract was washed with water (×2) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by straight phase flash chromatography on silica (heptane / MTBE:20 / 1 as eluent) to yield 4-fluoro-2-methoxy-5-(prop- 1-en-2-yl)pyridine as an oil (17.1 g, 84%);1H NMR (500 MHz, CDCl3) 2.10 – 2.12 (3H, m), 3.94 (3H, s), 5.19 – 5.21 (1H, m), 5.22 – 5.24 (1H, m), 6.42 (1H, d), 8.10 (1H, d). A solution of 0.5 M 9-BBN in THF (7.41 mL, 3.71 mmol) was added to 4-fluoro-2- methoxy-5-(prop-1-en-2-yl)pyridine (341 mg, 2.04 mmol) under nitrogen atmosphere and the reaction mixture was stirred at rt for 1 h. The reaction mixture was added to (R)-N-(4-chloro-6- ((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (from Example 3 -III) (600 mg, 1.85 mmol), Pd(dppf)Cl2^DCM (151 mg, 0.19 mmol) and K3PO4(1.57 g, 7.41 mmol) and the reaction mixture was stirred at 50°C for 1 h under nitrogen atmosphere. Water and EtOAc were added and the two phases were separated. The organic extract was washed with water and brine. The combined aqueous phase was acidified by the addition of 1 M HCl and extracted with EtOAc (×3). The combined organic extract was dried over MgSO4, filtered andevaporated. The residue was purified by straight phase flash chromatography on silica (EtOAc as eluent) to yield N-(4-(2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (498 mg, 59%); MS (ESI) m / z [M+H]+457.4. The diastereomers of N-(4-(2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (494 mg, 1.08 mmol) were separated by preparative chiral HPLC on a Lux C3 (OJ) column (250×30 mm, 5 µm), eluted with 20% MeCN:MeOH / DEA (85:15 / 20mM) in CO2, at 120 bar, and at a flow rate of 140 mL / min and detected at 240 nm, to give the first eluting compound N-(4-((S*)-2-(4- fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide (227 mg, 46%); HRMS (ESI) m / z [M+H]+calcd for C19H30FN6O4S: 457.2028, found: 457.2002;1H NMR (500 MHz, DMSO) 0.77 – 0.89 (6H, m), 1.24 – 1.46 (5H, m), 1.47 – 1.60 (1H, m), 2.74 – 2.88 (2H, m), 3.02 – 3.16 (3H, m), 3.23 – 3.54 (m, partial overlap with solvent residues), 3.80 – 3.86 (3H, m), 3.96 – 4.06 (1H, m), 4.57 – 4.78 (1H, m), 6.67 (1H, dd), 8.10 (1H, dd), and the second eluting compound N-(4-((R*)-2-(4-fluoro- 6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide (Compound D) (217 mg, 44%); HRMS (ESI) m / z [M+H]+calcd for C19H30FN6O4S: 457.2028, found: 457.2030;1H NMR (500 MHz, DMSO) 0.77 – 0.90 (6H, m), 1.23 – 1.46 (5H, m), 1.46 – 1.60 (1H, m), 2.75 – 2.87 (2H, m), 3.04 – 3.17 (3H, m), 3.25 – 3.41 (m, partial overlap with solvent residues), 3.45 – 3.54 (1H, m), 3.83 (3H, d), 3.97 – 4.08 (1H, m), 4.63 – 4.71 (1H, m), 6.67 (1H, dd), 8.07 – 8.13 (1H, m). VIII. Synthesis of N-(4-((R*)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound D) mono- meglumine salt Amorphous compound (N-(4-((R*)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (5.0 mg, 10.95 mmol) was dissolved in 20 mL acetonitrile. (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5- pentaol (2.35 g, 12.0 mmol) was dissolved in 20 mL of water and was slowly added (30 minutes) to the solution of N-(4-((R*)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide at ambient temperature.Another 10 ml of water was then added and slurring continued at ambient temperature overnight. The resultant solid was collected by filtration and the solid was slurry washed with 10 mL of water. The resultant sample of N-(4-((R*)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt was isolated by filtration and dried in vacuo vacuo at 40°C for 48 hours prior to H-NMR and XRPD analysis. A 77.3 % mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-((R*)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 4) is presented in Table 4. An exemplary diffraction pattern of the Form 4 polymorph can be found in FIG.4. Table 4 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.2 100 vs 8.4 33 vs 11.4 13 s 12.9 12 s 15.7 7 m 20.0 21 s 22.4 4 m 24.0 15 s 24.5 6 m 26.5 5 m IX. Synthesis of N-(4-((R*)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound E) KOtBu (0.620 g, 5.53 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (1.98 g, 5.53 mmol) in Et2O (4 mL) and the reaction mixture was stirred at rt for 30 min. A solution of 1-(2-chloropyridin-4-yl)ethan-1-one (0.43 g, 2.76 mmol) in Et2O (1.5 mL) was added, and stirring was continued at rt for 30 min. The reaction mixture was filtered, the solid was washed with Et2O and the combined filtrate was carefully evaporated (product is volatile). The residue was purified by straight phase flash chromatography on silica (pentane / Et2O:4 / 1 as eluent) to yield 2-chloro-4-(prop-1-en-2-yl)pyridine (350 mg, 82%) as a colourless oil;1H NMR (400 MHz, CDCl3) 2.11 – 2.14 (3H, m), 5.29 – 5.33 (1H, m), 5.56 – 5.60 (1H, m), 7.25 (1H, dd), 7.35 (1H, dd), 8.32 (1H, dd). A solution of 0.5 M 9-BBN in THF (2.16 mL, 1.08 mmol) was added to 2-chloro-4- (prop-1-en-2-yl)pyridine (89 mg, 0.58 mmol) under nitrogen atmosphere. The reaction mixture was stirred at rt overnight and then a degassed solution of 3 M K3PO4 (aq, 0.62 mL, 1.85 mmol) was added followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (from Example 3 -III) (100 mg, 0.31 mmol) and Pd(dppf)Cl2^DCM (25.0 mg, 0.03 mmol). The reaction mixture was stirred at 35°C under nitrogen atmosphere for 20 h. EtOAc and water were added and the two phases were separated. The aqueous phase was acidified with dilute HCl and extracted with EtOAc. SiliaMetS Thiolwas added to the organic phase and stirred for a few min, then was filtered. The filtrate was collected and evaporated and the residue was purified by preparative HPLC, PrepMethod A, (gradient: 20- 75%). Repurified by preparative HPLC, PrepMethod D, (gradient: 0-50%) to yield N-(4-(2-(2- Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 2yl)methanesulfonamide (23 mg, 17%);1H NMR (500 MHz, CDCl3) 0.88 – 0.98 (6H, m), 1.21 – 1.77 (8H, m), 2.85 – 3.06 (2H, m), 3.29 – 3.46 (4H, m), 3.54 – 3.85 (2H, m), 4.15 – 4.30 (1H, m), 7.15 (1H, dd), 7.24 – 7.27 (m, partially overlapping with solvent), 8.31 (1H, dd). The diastereomers of N-(4-(2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (23 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250×30 mm, 5 µm), eluted with 20% EtOH / TEA (100 / 0.5) in CO2, 120 bar at a flow rate of 87.5 mL / min and detected at 230 nm, to give the first eluting compound N-(4-((S*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy- 4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide that was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod C, (gradient: 20-60%) to yield (4.6 mg, 20%); HRMS (ESI) m / z [M+H]+calcd for C18H28ClN6O3S: 443.1626, found: 443.1626;1H NMR (400 MHz, CDCl3) 0.87 – 0.99 (6H, m), 1.30 – 1.54 (5H, m), 1.55 – 1.71 (1H, m), 2.82 – 3.02 (2H, m), 3.29 – 3.45 (m, partial overlap with byproduct), 3.56 – 3.64 (1H, m), 3.66 – 3.83 (1H, m), 4.13 – 4.28 (1H, m), 7.12 (1H, dd), 7.20 – 7.24 (1H, m), 8.24 – 8.32 (1H, m). The second eluting compound from the chiral separation, N-(4-((R*)-2-(2- chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound E) was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered and evaporated to yield (5.6 mg, 24%); HRMS (ESI) m / z [M+H]+calcd for C18H28ClN6O3S: 443.1626, found: 443.1618;1H NMR (500 MHz, CDCl3) 0.87 – 0.98 (6H, m), 1.28 – 1.52 (5H, m), 1.55 – 1.71 (1H, m), 2.82 – 3.02 (2H, m), 3.25 – 3.45 (4H, m), 3.53 – 3.61 (1H, m), 3.63 – 3.81 (1H, m), 4.16 – 4.26 (1H, m), 7.09 – 7.14 (1H, m), 7.22 (1H, d), 8.26 (1H, d). X. Synthesis of N-(4-((R*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound E) mono-meglumine salt Amorphous compound (N-(4-((R*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (100 mg, 0.23 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (48.5 mg, 0.25 mmol) were slurried in acetonitrile (1.5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight before it was washed with water. The resultant sample of N-(4-((R*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt was isolated by filtration and dried in vacuo at ambient temperature overnight prior to H-NMR and XRPD analysis. A 13.2 % mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-((R*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 5) is presented in Table 5. An exemplary diffraction pattern of the Form 5 polymorph can be found in FIG.5. Table 5 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.2 100 vs 8.6 19 s 11.4 10 s 12.9 21 s 17.7 9 m 18.6 9 m 20.0 30 vs 20.6 33 vs22.0 20 s 24.3 24 s XI. Synthesis of N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound F) (E)-Prop-1-en-1-ylmagnesium bromide (35.8 mL, 17.9 mmol, 0.5 M in THF) was added to a stirred suspension of 2,4,6-trichloro-1,3,5-triazine (3.0 g, 16.3 mmol) in THF (10 mL) at 0ºC during 10 min. The reaction mixture was allowed to reach rt during 30 min and then cooled again to 0ºC. DIPEA (2.98 mL, 17.1 mmol) and a solution of (R)-2-amino-4-methylpentan-1-ol (1.91 g, 16.3 mmol) in THF (5 mL) were added and the reaction mixture was stirred at rt for 2 h. Water and MTBE were added and the two phases were separated. The aqueous phase was acidified by the addition of 1 M HCl and extracted twice with EtOAc. The organic extract was evaporated to yield (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol (2.23 g, 51%); MS (ESI) m / z [M+H]+271.3. NMR indicates a mix of E- and Z-isomers. 1,4-Dioxane (1.11 mL) and water (0.19 mL) were added to (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)- 1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (70 mg, 0.26 mmol), (3-fluoro-4- methoxyphenyl)boronic acid (132 mg, 0.78 mmol), [Rh(COD)Cl]2 (6.4 mg, 0.01 mmol) and KOH (43.5 mg, 0.78 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 65°C for 3.5 h. EtOAc and water were added and the two phases were separated. The organic layer was washed with brine and evaporated. The residue was purified by preparative HPLC, PrepMethod A, (gradient: 30-80%) to yield (2R)-2-((4-chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol (70 mg, 68%) as a colourless solid; MS (ESI) m / z [M+H]+397.4. THF (0.25 mL) was added to Pd2dba3(6.5 mg, 7.1 µmol) and X-Phos (13.5 mg, 0.03 mmol) under nitrogen atmosphere. The mixture was stirred for 10 min and then (2R)-2-((4- chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (56 mg, 0.14 mmol) in THF (0.75 mL), methanesulfonamide (32 mg, 0.34 mmol) and K2CO3 (44 mg, 0.32 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere at 70°C overnight. EtOAc was added and the mixture was washed with dilute HCl and brine. Thecombined aqueous phase was extracted with EtOAc. The combined organic extract was dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC, PrepMethod A, (gradient: 30-80%) to yield N-(4-(2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)- 1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (54 mg, 84%) as a colorless solid; MS (ESI) m / z [M+H]+456.4. The diastereomers of N-(4-(2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (64 mg, 0.14 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 µm), eluted with 30% EtOH / DEA (100 / 0.5) in CO2, 120 bar at a flow rate of 80 mL / min and detected at 254 nm, to give the first eluting compound N-(4-((R*)-2-(3-fluoro-4-methoxyphenyl)propyl)-6- (((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound F) that was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered and evaporated to yield (30 mg, 47%); HRMS (ESI) m / z [M+H]+calcd for C20H31FN5O4S: 456.2076, found: 456.2088;1H NMR (400 MHz, CDCl3) 0.87 – 0.98 (6H, m), 1.22 – 1.54 (m, partial overlap with solvent residues), 1.55 – 1.73 (1H, m), 2.86 – 2.98 (2H, m), 3.19 – 3.40 (4H, m), 3.52 – 3.89 (5H, m), 4.16 – 4.31 (1H, m), 6.80 – 7.01 (3H, m). The second eluting compound from the chiral separation, N-(4-((S*)-2-(3-fluoro-4- methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered and evaporated to yield (28 mg, 44%); HRMS (ESI) m / z [M+H]+calcd for C20H31FN5O4S: 456.2076, found: 456.2092;1H NMR (400 MHz, CDCl3) 0.88 – 0.98 (6H, m), 1.22 – 1.54 (m, partial overlap with solvent residues), 1.55 – 1.73 (1H, m), 2.81 – 2.95 (2H, m), 3.18 – 3.36 (4H, m), 3.53 – 3.87 (5H, m), 4.17 – 4.29 (1H, d), 6.80 – 7.02 (3H, m). XII. Synthesis of N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound F) mono- meglumine salt Amorphous compound (N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (100 mg, 0.22 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (47.1 mg, 0.24 mmol) wereslurried in acetonitrile (1.5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight before it was washed with water. The resultant sample of N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt was isolated by filtration and dried in vacuo at ambient temperature overnight prior to H- NMR and XRPD analysis. A 53.2 % mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 6) is presented in Table 6. An exemplary diffraction pattern of the Form 6 polymorph can be found in FIG.6. Table 6 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.0 100 vs 8.5 16 s 11.2 5 m 12.7 12 s 15.7 7 m 19.5 18 s 20.0 9 m 20.6 12 s 21.6 4 m 22.6 7 m XIII. Synthesis of N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound G) KOtBu (0.663 g, 5.91 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (2.11 g, 5.91 mmol) in Et2O (4 mL) at rt and the reaction mixture was stirred at rt for 30 min. A solution of 1-(5-fluoro-6-methoxypyridin-3-yl)ethan-1- one (0.50 g, 2.96 mmol) in THF (1.5 mL) was added and stirring was continued at rt for 30 min. The reaction mixture was filtered, and the solid was washed with Et2O. The combined filtrate was carefully evaporated (product is volatile) and the residue was purified by straight phase flashchromatography on silica (pentane:Et2O, 4:1 as eluent) to yield 3-fluoro-2-methoxy-5-(prop-1- en-2-yl)pyridine (530 mg, 107%), containing some residual solvents;1H NMR (500 MHz, CDCl3) 2.11 – 2.13 (3H, m), 4.03 (3H, s), 5.08 – 5.10 (1H, m), 5.30 – 5.32 (1H, m), 7.45 (1H,dd), 8.01 (1H, d). 9-BBN dimer (224 mg, 0.93 mmol) was added to a solution of 3-fluoro-2-methoxy-5- (prop-1-en-2-yl)pyridine (112 mg, 0.67 mmol) in THF (2 mL) under nitrogen atmosphere and the reaction mixture was stirred at rt for 1 h. A degassed solution of 3 M K3PO4(aq, 0.74 mL, 2.22 mmol) was added, followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (120 mg, 0.37 mmol) and Pd(dppf)Cl2^DCM (44.9 mg, 0.06 mmol). The reaction mixture was diluted with THF (1 mL) and stirred at 35°C for 15 h. EtOAc and water were added and the two phases were separated. The aqueous phase was neutralised and extracted several times with EtOAc and the combined organic extract was evaporated. The residue was filtered through silica eluted with DCM, EtOAc and MeOH. The solvents were evaporated and the residue was purified by preparative HPLC, PrepMethod C, (gradient: 15-60%). Repurified by straight phase flash chromatography on silica (gradient: 35-100% EtOAc / MeOH:20 / 1 in DCM as eluent) to yield N-(4-(2-(5-Fluoro-6- methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 2yl)methanesulfonamide (33 mg, 20%); MS (ESI) m / z [M+H]+457.3. The diastereomers of N-(4-(2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (33 mg, 0.07 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 µm), eluted with 20% EtOH / DEA (100 / 0.5) in CO2, 120 bar at a flow rate of 70 mL / min and detected at 230 nm, to give the first eluting compound N-(4-((R*)-2-(5-fluoro-6- methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 2-yl)methanesulfonamide (Compound G) that was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered and evaporated to yield (15 mg, 45%); HRMS (ESI) m / z [M+H]+calcd for C19H30FN6O4S: 457.2028, found: 457.2020;1H NMR (400 MHz, MeOD) 0.84 – 0.99 (6H, m), 1.31 – 1.54 (5H, m), 1.54 – 1.71 (1H, m), 2.67 – 2.98 (m, partial overlap with citric acid residues), 3.16 (3H, d), 3.37 – 3.63 (3H, m), 3.95 (3H, d), 4.18 – 4.28 (1H, m), 7.44 (1H, ddd), 7.77 (1H, dd). The second eluting compound from the chiral separation, N-(4-((S*)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered and evaporated to yield (13 mg, 39%); HRMS (ESI) m / z [M+H]+calcd for C19H30FN6O4S: 457.2028, found: 457.2010;1H NMR (400 MHz, MeOD) 0.87 – 0.99 (6H, m), 1.31 – 1.53 (5H, m), 1.55 – 1.71 (1H, m), 2.68 – 2.97 (m, partial overlap with citric acid residues), 3.16 (3H, d), 3.34 – 3.61 (3H, m), 3.95 (3H, d), 4.15 – 4.27 (1H, m), 7.44 (1H, dt), 7.74 – 7.79 (1H, m). XIV. Synthesis of N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Compound G) mono- meglumine salt Amorphous compound (N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)- 1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) (400 mg, 0.88 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (188 mg, 0.96 mmol) were slurried in acetonitrile (5 mL) at ambient temperature overnight. The resultant solid was collected by filtration and dried in vacuo at ambient temperature overnight and slurry washed in water (2 mL). The resultant N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt was isolated by filtration and dried in vacuo at ambient temperature prior to H-NMR and XRPD analysis. A 53.1% mass recovery was obtained. The ten most prominent peaks from the X-ray powder diffraction pattern of a polymorph of N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide mono-meglumine salt (Form 7) is presented in Table 7. An exemplary diffraction pattern of the Form 7 polymorph can be found in FIG.7. Table 7 PEAK POSITION RELATIVE DEFINITION (°2^) INTENSITY (%) 5.0 100 vs 8.6 34 vs 11.4 16 s 12.8 30 vs 19.6 34 vs

Claims

CLAIMS What is claimed is:

1. A compound of Formula I , wherein:MEG is a meglumine salt; Y is C or N; Z is C or N, wherein both Y and X are not N; R1, R2, R3, R4, and R5are independently H, halogen or -methoxy,wherein when Y is N, then R3 is not present, and when Z is N, then R2 is not present; and # represents the R enantiomer, S enantiomer, or racemic mixture.

2. The compound of claim 1, wherein # represents the R enantiomer.

3. The compound of claim 1, wherein # represents the S enantiomer.

4. The compound of claim 1, wherein # represents a racemic mixture.

5. The compound of claim 1 or 2, wherein the halogen is F or Cl.

6. The compound of any one of claims 1 to 3, wherein Z is N and Y is C.

7. The compound of any one of claims 1 to 3, wherein Z is C and Y is N.

8. The compound of any one of claims 1 to 3, wherein Z is C and Y is C.

9. The compound of any one of claims 1 to 6, wherein one of R1, R2, R3, R4, and R5 is methoxy.

10. The compound of any one of claims 1 to 8, wherein R3 is methoxy.

11. The compound of any one of claims 1 to 8, wherein one or more of R1, R2, R3, R4, and R5is F.

12. The compound of any one of claims 1 to 7, wherein Z is N and R3is methoxy.

13. The compound of any one of claims 1 to 7, wherein two of R1, R2, R3, R4, and R5 are halogen, or one of R1, R2, R3, R4, and R5is halogen and one if methoxy.

14. The compound of any one of claims 1 to 4, wherein (i) Z is C, (ii) Y is C, (iii) R1, R2and R3 are H, and (iv) R4 and R5 are F.

15. The compound of any one of claims 1 to 4, wherein (i) Z is N, (ii) Y is C, (iii) R1 is F, (iv) R3is methoxy and (v) R4and R5are H.

16. The compound of any one of claims 1 to 4, wherein (i) Z is N, (ii) Y is C, (iii) R3 is methoxy and (iv) R1, R4 and R5 are H.

17. The compound of any one of claims 1 to 4, wherein (i) Z is N, (ii) Y is C, (iii) R5is F, (iv) R3is methoxy and (v) R1and R4are H.

18. The compound of any one of claims 1 to 4, wherein (i) Z is C, (ii) Y is N, (iii) R1, R2 and R5are H and (iv) R4is Cl.

19. The compound of any one of claims 1 to 4, wherein (i) Z is C, (ii) Y is C, (iii) R1, R2and R5 are H, (iv) R3 is methoxy and v) R4 is F.

20. The compound of any one of claims 1 to 4, wherein (i) Z is N, (ii) Y is C, (iii) R1and R5are H, (iv) R3is -methoxy and (v) R4is F.

21. A polymorph of the compound of claim 14, wherein the polymorph is Form 1 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.8± 0.2, 16.1± 0.2, and 19.8± 0.2 degrees.

22. The polymorph of claim 21, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.7± 0.2, 18.6± 0.2, 20.2± 0.2, 21.8± 0.2 and 24.7± 0.

2.

23. The polymorph of the compound of claim 14, wherein the polymorph has an XRPD pattern substantially as shown in Fig.

1.

24. A polymorph of the compound of claim 15, wherein the polymorph is Form 2 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 4.9± 0.2, 8.5± 0.2, 19.5± 0.2, and 20.7± 0.2 degrees.

25. The polymorph of claim 24, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.5± 0.2, 12.9± 0.2, 22.1± 0.2, 23.2± 0.2, 23.6± 0.2 and 24.1± 0.

2.

26. The polymorph of the compound of claim 15, wherein the polymorph has an XRPD pattern substantially as shown in Fig.

2.

27. A polymorph of the compound of claim 16, wherein the polymorph is Form 3 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 19.8± 0.2, and 20.6± 0.2 degrees.

28. The polymorph of claim 27, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.3± 0.2, 12.8± 0.2, 15.9± 0.2, 22.5± 0.2, 24.2± 0.2 and 26.3± 0.

2.

29. The polymorph of the compound of claim 16, wherein the polymorph has an XRPD pattern substantially as shown in Fig.3.

30. A polymorph of the compound of claim 17, wherein the polymorph is Form 4 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 8.4± 0.2, 20.0± 0.2, and 24.0± 0.2 degrees.

31. The polymorph of claim 30, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 12.9± 0.2, 15.7± 0.2, 22.4± 0.2, 24.5± 0.2 and 26.5± 0.

2.

32. The polymorph of the compound of claim 17, wherein the polymorph has an XRPD pattern substantially as shown in Fig.

4.

33. A polymorph of the compound of claim 18, wherein the polymorph is Form 5 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.2± 0.2, 20.0± 0.2, 20.6± 0.2, and 24.3± 0.2 degrees.

34. The polymorph of claim 33, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 8.6± 0.2, 11.4± 0.2, 12.9± 0.2, 17.7± 0.2, 18.6± 0.2 and 22.0± 0.

2.

35. The polymorph of the compound of claim 18, wherein the polymorph has an XRPD pattern substantially as shown in Fig.

5.

36. A polymorph of the compound of claim 19, wherein the polymorph is Form 6 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 5.0± 0.2, 8.5± 0.2, 12.7± 0.2, 19.5± 0.2, and 20.6± 0.2 degrees.

37. The polymorph of claim 36, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.2± 0.2, 15.7± 0.2, 20.0± 0.2, 21.6± 0.2, and 22.6± 0.

2.

38. The polymorph of the compound of claim 19, wherein the polymorph has an XRPD pattern substantially as shown in Fig.6.

39. A polymorph of the compound of claim 20, wherein the compound is the R isomer of Compound G, and wherein the polymorph is Form 7 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2- theta selected from 5.0± 0.2, 8.6± 0.2, 12.8± 0.2, and 19.6± 0.2 degrees.

40. The polymorph of claim 36, wherein the XPRD further comprises at least one additional peak expressed in degrees 2-theta selected from 11.4± 0.2, 20.1± 0.2, 20.6± 0.2, 21.8± 0.2, 23.5± 0.2, and 26.3± 0.

2.

41. The polymorph of the compound of claim 20, wherein the polymorph has an XRPD pattern substantially as shown in Fig.

7.

42. The polymorph of any one of claims 21 to 41, wherein the XRPD is recorded using Cu radiation.

43. The polymorph of any one of claims 21 to 41, wherein the polymorph comprises a mono-meglumine salt. ` 44. A method of treating cardiovascular disease comprising administering a therapeutically effective amount of a compound of any of one of claims 1 to 20 or a polymorph of any one of claims 21 to 43.

45. A pharmaceutical composition comprising (i) a compound of any of one of claims 1 to 20 or a polymorph of any one of claims 21 to 43, and (ii) one or more pharmaceutically acceptable excipients.

46. A method of treating cardiovascular disease comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 44 to a person suffering from or at risk of the disease.

47. The method of claim 45, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

48. The method of claim 46 or 47, wherein the compound is administered orally.

49. A compound of any of one of claims 1 to 20 or a polymorph of any one of claims 21 to 43, or a pharmaceutical composition comprising (i) a compound of any of one of claims 1 to 20 or a polymorph of any one of claims 21 to 43, and (ii) one or more pharmaceutically acceptable excipients for use in treating cardiovascular disease.

50. The compound of claim 49 wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

51. A process for the preparation of the compounds of any one of claims 1 to 20, the method comprising: a. forming a slurry of (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXXb. mixing the c. filtering the slurry by filtration and collecting the retentate; and d. washing the retentate with water; and e. drying the retentate to obtain the compounds.

52. A process for the preparation of a polymorph of any one of claims 21 to 43, the method comprising: a. forming a slurry of (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol, a solvent selected from acetonitrile, water or combinations thereof, and a compound of Formula XXX b. mixing thec. isolating the particles from the slurry by filtration; and d. washing the particles with water; and e. drying the particles to obtain the polymorph.

53. The process of claim 51 or 52, wherein the mixing is for about 2 hours to about 24 hours.

54. The process of claim any one of claims 51 to 53, wherein the mixing at about 20oC to about 30oC.

55. The process of any one of claims 51 to 53, wherein the molar ratio of the compound to (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol is about 2:1 to about 1:2.

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