Crystalline GPR40 agonist and methods of making

Abstract

Disclosed herein are crystalline GPR40 agonists and methods of producing the same, said crystalline GPR40 agonists being useful for the treatment of diseases and disorders.

Description

CRYSTALLINE GPR40 AGONIST AND METHODS OF MAKING CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No.63 / 613,861, filed on December 22, 2023, and US Provisional Application No.63 / 613,884, filed on December 22, 2023, each of which is incorporated herein by reference in its entirety. SUMMARY OF THE DISCLOSURE

[0002] The present disclosure relates to various solid state forms of the GPR40 agonist sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 2). Such forms of sodium (S)-(2- cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinate are useful for modulating the activity of GPR40 in mammals that would benefit from such activity. In some embodiments, the present disclosure describes a solid state form of the GPR40 agonist sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4- dimethylpentyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate hemiheptahydrate (Compound 3).

[0003] In some embodiments, the crystalline Compound 2 is Crystalline Form 1 of Compound 2. In some embodiments, Crystalline Form 1 of Compound 2 is crystalline Compound 3. In some embodiments, described herein is a composition comprising Crystalline Form 1 of Compound 2. In some embodiments, Crystalline Form 1 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 1; (b) an XRPD pattern with peaks at about 4.4º 2-Theta, about 6.6 º 2-Theta, about 13.2 º 2- Theta, about 17.7 º 2-Theta, about 21.0 º 2-Theta, about 22.8 º 2-Theta, and about 24.7 º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 2; (d) a DSC thermogram with two endothermic events having: i. an onset at about 88.3 °C and peak at about 111.7 °C; and ii. an onset at about 265.6 °C and peak at about 267.0 °C; (e) a TGA pattern substantially the same as shown in Figure 2; (f) a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C; (g) unit cell parameters substantially equal to the following at 100 K: Crystal System Monoclinic Space Group C2 a (Å) 10.0187(2) b (Å) 8.6317(2)c (Å) 36.9014(8) ;(h) reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; (i) reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C; (j) an unchanged XRPD after DVS analysis up to 90% RH and 25 °C; (k) an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days; or a combination thereof.

[0004] In some embodiments, the crystalline Compound 2 is Crystalline Form 2 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 2 of Compound 2. In some embodiments, Crystalline Form 2 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 3; (b) an XRPD pattern with peaks at about 3.89º 2-Theta, about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.76º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 4; (d) a DSC thermogram with two endothermic events having: i. an onset at about 120.9 °C and peak at about 130.4 °C; and ii. an onset at about 264.5 °C and peak at about 266.0 °C; (e) a TGA pattern substantially the same as shown in Figure 4; (f) a TGA pattern with an about 2.1% w / w loss from about 48 °C to about 208 °C; or a combination thereof.

[0005] In some embodiments, the crystalline Compound 2 is Crystalline Form 3 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 3 of Compound 2. In some embodiments, Crystalline Form 3 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 5;(b) an XRPD pattern with peaks at about 3.64º 2-Theta, about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 6; (d) a DSC thermogram with two endothermic events having: i. an onset at about 167.1 °C and peak at about 169.4 °C; and ii. an onset at about 268.3 °C and peak at about 269.5 °C; (e) a TGA pattern substantially the same as shown in Figure 6; (f) a TGA pattern with substantially no loss in weight from about 50 °C to about 200 °C; or a combination thereof.

[0006] In some embodiments, the crystalline Compound 2 is Crystalline Form 4 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 4 of Compound 2. In some embodiments, Crystalline Form 4 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 7; (b) an XRPD pattern with peaks at about 3.87º 2-Theta, about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 8; (d) a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C; or a combination thereof.

[0007] In one aspect, described herein is a process for the preparation of Compound 2, comprising treating Compound 1:(Compound 1) or a salt thereof, or the alkyl ester of Compound 1:wherein R1isC1-C6alkyl; with a sodium hydroxide solution in the presence of a suitable solvent to provide Compound 2. In some embodiments, the process further comprises a process for the preparation of Compound 1, comprising contacting compound 4:Compound 4; with a suitable acid in a suitable solvent to provide Compound 1.

[0008] In one aspect, described herein is a process for the preparation of Crystalline Form 1 of Compound 2, comprising dissolving Compound 2 or a crystalline form thereof in a first suitable solvent to form a solution; and adding a second suitable solvent to the solution to provide Crystalline Form 1 of Compound 2.

[0009] In one aspect, described herein is a process for the preparation of Crystalline Form 1 of Compound 2, comprising dissolving Compound 2 or a crystalline form thereof in a solvent toform a solution; and evaporating the solution to provide the Crystalline Form 1 of Compound 2.

[0010] In one aspect, disclosed herein is a compound selected from:a pharmaceutically acceptable solvate thereof; and.

[0011] In one aspect, described herein is a pharmaceutical composition comprising crystalline Compound 2 and at least one pharmaceutically acceptable excipient. In some embodiments, crystalline Compound 2 is Crystalline Form 1 of Compound 2.

[0012] Also described herein are methods of making the GPR40 agonist ((S)-2-cyclopropyl-2- (3-((1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 1), and pharmaceutically acceptable salts thereof (e.g., the potassium salt, Compound 4, potassium (S)-(2-cyclopropyl-2- (3-((1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinate).

[0013] In one aspect, described herein is a process for the preparation of Compound 1:Compound 1; comprising: contacting a com ound of Formula A:Formula A; wherein M+is an alkali metal cation or an alkylammonium cation; with a suitable acid in a suitable solvent to provide Compound 1.

[0014] In another aspect, described herein is a process for the preparation of Formula A, comprising: contacting a compound of Formula B:Formula B; wherein X is a suitable leaving group; with a compound of Formula C-I:Formula C-I; wherein M+is an alkali metal cation or an alkylammonium cation; in a suitable solvent to provide a compound of Formula A.

[0015] In another aspect, described herein is a process for the preparation of Formula G:Formula G; wherein PG1is a suitable protecting group; comprising: contacting a compound of Formula B:wherein X is halogen or a suitable leaving group; with a compound of Formula C-II:Formula C-II; wherein M+is an alkali metal cation or an alkylammonium cation, and wherein PG1is a suitable protecting group; in a suitable solvent to provide a compound of Formula G.

[0016] In some embodiments, described herein is a process for the preparation of Formula B, comprising: contacting Compound D:Compound D; to a suitable activating agent and a suitable base in a suitable solvent to provide the compound of Formula B.

[0017] In some embodiments, described herein is a process for the preparation of Formula C-I, comprising: contacting Compound E:Compound E; to a suitable base in a suitable solvent to provide the compound of Formula C-I.

[0018] In some embodiments, described herein is a process for the preparation of Formula C- II, comprising: contacting a compound of Formula H:Formula H; wherein PG1is a suitable protecting group; to a suitable base in a suitable solvent to provide the compound of Formula C-II.

[0019] In some embodiments, described herein is a process for the preparation of Compound E, comprising: contacting a compound of Formula F:wherein PG1and PG2are each independently a suitable protecting group; to a suitable deprotection reagent in a suitable solvent to provide Compound E.

[0020] In some embodiments, described herein is a process for the preparation of Formula H, comprising: contacting a compound of Formula H:Formula H; wherein PG1is a suitable protecting group; to a suitable deprotection reagent in a suitable solvent to provide Compound E.

[0021] In some embodiments, described herein is a process for the preparation of Formula H, comprising: contacting a com d f F l FFormula F; wherein PG1and PG2are each independently a suitable protecting group; to a suitable hydrogen source and a suitable hydrogenation catalyst in a suitable solvent to provide the compound of Formula H.

[0022] In some embodiments, described herein is a process for the preparation of Formula F, comprising: contacting a compound of Formula I:Formula I; wherein PG1and PG2are each independently a suitable protecting group, and Y is halogen; to a suitable methylation reagent in a suitable solvent to provide the compound of Formula F.

[0023] In some embodiments, described herein is a process for the preparation of Formula I, comprising: contacting a compound of Formula J:Formula J; wherein PG1and PG2are each independently a suitable protecting group, and R1is hydrogen or C1-6alkyl; to a suitable halogenation reagent and a suitable organocatalyst in a suitable solvent to provide the compound of Formula I.

[0024] In some embodiments, described herein is a process for the preparation of Formula J, comprising: contacting a compound of Formula K:Formula K; wherein PG1and PG2are each independently a suitable protecting group, andR1is hydrogen or C1-6alkyl; to a suitable hydrogen source and a suitable metal catalyst in a suitable solvent to provide the compound of Formula I; wherein the suitable metal catalyst generated by combining a suitable ligated metal salt with a suitable chiral phosphine ligand.

[0025] In some embodiments, described herein is a process for the preparation of Compound D, comprising: contacting Compound P:Compound P; to a suitable acid, a suitable hydrogen source, and a suitable hydrogenation catalyst in a suitable solvent to provide Compound D.

[0026] In some embodiments, described herein is a process for the preparation of Compound P, comprising: contacting Compound Q:Compound Q; to pivalaldehyde and a suitable base in a suitable solvent to provide Compound P; wherein Compound Q is prepared by a process comprising: contacting Compound R:Compound R; to piperidin-4-ylmethanol and a suitable base in a suitable solvent to provide Compound Q.

[0027] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. INCORPORATION BY REFERENCE

[0028] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, orpatent application was specifically and individually indicated to be incorporated by reference. Tothe extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0030] FIG.1 illustrates a representative XRPD pattern for Crystalline Form 1 of Compound 2.

[0031] FIG.2 illustrates a representative DSC thermogram and a representative TGA pattern for Crystalline Form 1 of Compound 2.

[0032] FIG.3 illustrates a representative XRPD pattern for Crystalline Form 2 of Compound 2.

[0033] FIG.4 illustrates a representative DSC thermogram and a representative TGA pattern for Crystalline Form 2 of Compound 2.

[0034] FIG.5 illustrates a representative XRPD pattern for Crystalline Form 3 of Compound 2.

[0035] FIG.6 illustrates a representative DSC thermogram and a representative TGA pattern for Crystalline Form 3 of Compound 2.

[0036] FIG.7 illustrates a representative XRPD pattern for Crystalline Form 4 of Compound 2.

[0037] FIG.8 illustrates a representative DSC thermogram for Crystalline Form 4 of Compound 2.

[0038] FIG.9 illustrates a representative DVS mass plot for Crystalline Form 1 of Compound 2.

[0039] FIG.10 illustrates a representative DVS mass plot for Crystalline Form 2 of Compound 2.

[0040] FIG.11 illustrates a representative DVS mass plot for Crystalline Form 3 of Compound 2.

[0041] FIG.12 illustrates a representative DVS mass plot for Crystalline Form 4 of Compound 2.

[0042] FIG.13 provides a non-limiting exemplary embodiment of a process for making a compound of Formula A. In FIG.13: CSTR = continuously stirred tank reactor; and holding time is equivalent to retention time. DETAILED DESCRIPTION OF THE DISCLOSURE

[0043] This disclosure is directed, at least in part, to solid state forms of a GPR40 agonist, and to methods of making GPR40 agonists, which are useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR40 agonists are gut restrictedcompounds. In some embodiments, the GPR40 agonists are full agonists or partial agonists.Certain Terminology

[0044] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0045] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0046] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or withinstatistical experimental error), and thus the number or numerical range, in some instances, willvary up to 10% of the stated number or numerical range. For example, an XRPD peak (e.g., about 5.00º 2-Theta, about 10.00º 2-Theta, about 15.00º 2-Theta) can vary within a range of ±0.1º2-Theta, ±0.2º 2-Theta, ±0.3º 2-Theta, ±0.4º 2-Theta, or ±0.5º 2-Theta. In some embodiments of XRPD peaks, about means ± 0.2 ° 2-Theta. For example, a temperature (e.g., about 80.0 °C, about 100.0 °C, about 120.0 °C) associated with a feature in a TGA pattern or a DCS thermogram can vary within a range of ±1.0 °C, ±2.0 °C, ±3.0 °C, ±4.0 °C, or ±5.0 °C.

[0047] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like,described herein, “consist of” or “consist essentially of” the described features.

[0048] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the G protein-coupled receptor.

[0049] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0050] The term “agonist” as used herein refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. By way of example, “GPR40 agonist” can be used to refer to a compound that exhibits an EC50with respect to GPR40 activity of no more than about 100 μM, as measured in the as measured in the inositol phosphate accumulation assay. In some embodiments, the term “agonist” includes full agonists or partial agonists.

[0051] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an agonist can elicit at the receptor or enzyme.

[0052] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.

[0053] The term “moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0054] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0055] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes.

[0056] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates suchas chimpanzees, and other apes and monkey species. In one aspect, the mammal is a human.

[0057] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0058] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0059] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1-C5alkyl, a C1-C4alkyl, a C1-C3alkyl, a C1-C2alkyl, or a C1alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, - OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, - OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), - S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0060] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon or an sp3-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10alkenyl, a C2-C9alkenyl, a C2-C8alkenyl, a C2-C7alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or a C2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0061] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp3-hybridized carbon of the alkynyl residue is attached tothe rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2 -propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10alkynyl, a C2-C9alkynyl, a C2-C8alkynyl, a C2-C7alkynyl, a C2-C6alkynyl, a C2-C5alkynyl, a C2-C4alkynyl, a C2-C3alkynyl, or a C2alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0062] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0063] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms unless otherwise specified (i.e., from 6 to 18 carbon atoms), where at least one of the rings in the ring system is fully unsaturated, (i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory). The ring system from which aryl groups are derivedinclude, but are not limited to, groups such as benzene, f luorene, indane, indene, tetralin andnaphthalene. In some embodiments, the aryl is a C6-C10aryl. In some embodiments, the aryl is a phenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo,haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalky l,heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionallysubstituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0064] An “arylene” refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group. The arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the arylene is a phenylene. Unless stated otherwise specifically in thespecification, an arylene group is optionally substituted as described above for an aryl group.

[0065] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0066] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0067] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0068] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0069] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups includerings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo -fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrof uranyl,dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1- onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)- onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0070] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nit ro,aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb- ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, R f is independentlyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0071] “Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule throughany atom of the ring(s). Unless stated otherwise specifically in the specification, the term“heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl,heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0072] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible. Gut-Brain Axis

[0073] The gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.

[0074] In some instances, the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis). The gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.

[0075] The gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components ofthese hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior.

[0076] Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need. Diseases and conditions affected by the gut-brain axis, include central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency, binge eating disorder, and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis. GPR40 in the Gut-Brain Axis

[0077] Free fatty acid receptor 1 (FFA1, FFAR1), also known as GPR40, is a class A G-protein coupled receptor. This membrane protein binds free fatty acids, acting as a nutrient sensor for regulating energy homeostasis. In some instances, GPR40 is expressed in enteroendocrine cells and pancreatic islet β cells. In some instances, GPR40 is expressed in enteroendocrine cells. Several naturally-occurring medium to long-chain fatty acids act as ligands for GPR40. GPR40 agonists or partial agonists may be useful in the treatment of metabolic diseases such as obesity, diabetes, and NASH, and other diseases involving the gut-brain axis.

[0078] In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce insulin secretion. In some instances, modulators of GPR40, for example, GPR40agonists or partial agonists, induce an increase in cytosolic Ca2+. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce higher levels of intracellular cAMP. In some instances, GPR40 modulation is in enteroendocrine cells. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce the secretion of GLP-1, GLP-2, GIP, PYY, CCK, or other hormones. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1, GIP, CCK or PYY. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1.

[0079] Described herein are methods of making a GPR40 receptor modulator useful for methods of treating a condition or disorder involving the gut-brain axis in an individual in need thereof, the method comprising administering to the individual the GPR40 receptor modulator. In some embodiments, the GPR40 receptor modulator is a GPR40 agonist or partial agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 partial agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 positive allosteric modulator. In some embodiments, the GPR40 modulator is a gut-restricted GPR40 modulator. In some embodiments, the GPR40 modulator is a soft drug. In some embodiments, the GPR40 modulator is Compound 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the GPR40 modulator is Compound 2 or a pharmaceutically acceptable solvate thereof.

[0080] In some embodiments, the condition or disorder involving the gut-brain axis is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency, binge eating disorder, and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, andopioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis. In some embodiments, the condition is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension. In some embodiments, the metabolic disorder is diabetes. In other embodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is nonalcoholic steatohepatitis. In some embodiments, the condition involving the gut-brain axis is a nutritional disorder. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome. In some embodiments, the condition involving the gut-brain axis is enteritis. In some embodiments, the condition involving the gut-brain axis is chemotherapy-induced enteritis or radiation-induced enteritis. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain post- bariatric surgery. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery. Gut-Restricted Modulators

[0081] In some instances, differentiation of systemic effects of a GPR40 agonist from beneficial, gut-driven effects would be critical for the development of a GPR40 agonist for the treatment of disease.

[0082] In some instances, activation of GPR40 by a GPR40 agonist recapitulates the lipotoxicity of free fatty acids on pancreatic beta-cells. In some instances, activation of GPR40 by a GPR40 agonist leads to beta-cell degeneration, islet insulin depletion, glucose intolerance and hyperglycemia. In some instances, the detrimental effects on beta-cells by a GPR40 agonist may be mediated through ER stress and NF-kB signaling pathways. In some instances, differentiation of deleterious systemic effects of a GPR40 agonist on beta-cell function and viability from beneficial, gut-driven effects would be critical for the development of a GPR40 agonist for the treatment of disease.

[0083] In some embodiments, the GPR40 agonist is gut-restricted. In some embodiments, the GPR40 agonist is designed to be substantially non-permeable or substantially non-bioavailable in the blood stream. In some embodiments, the GPR40 agonist is designed to activate GPR40 activity in the gut and is substantially non-systemic. In some embodiments, the GPR40 agonist has low systemic exposure. In some embodiments, low oral bioavailability of a GPR40 agonist indicates that the GPR40 agonist is gut-restricted. In some embodiments, low oral bioavailability of a GPR40 agonist indicates that the GPR40 agonist has low systemic exposure.Compound 1, Compound 2, Compound 3, and Compound 4

[0084] Compound 1 refers to ((S)-2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid, which has the chemical structure shown below:

[0085] In one aspect, Compound 1 is a GPR40 agonist that is useful in the methods of treatment described herein. In CHO-K1 cells expressing human GPR40, Compound 1 is a potent GPR40 agonist (EC50< 50 nM). Compound 1 displays low oral bioavailability (< 2%; 1 mg / kg) in in vivo mice studies.

[0086] The preparation and uses of Compound 1 have been previously described (see, PCT / US2021 / 019975, US 17 / 745126, PCT / US2023 / 068729, and US 18 / 387170, each of which is incorporated by reference in its entirety).

[0087] Compound 2 refers to sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate, which has the chemical structure shown below:Compound 2.

[0088] Compound 2 is a salt of Compound 1 that can be obtained according to the methods disclosed herein. In one aspect, Compound 2 is useful in methods for producing Compound 1. In another aspect, Compound 2 or a pharmaceutically acceptable solvate thereof is useful in the methods of treatment described herein.

[0089] Compound 3 refers to sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate hemiheptahydrate, which has the chemical structure shown below:Compound 3.

[0090] Compound 3 is a salt of Compound 1 that can be obtained according to the methods disclosed herein. Compound 3 is a hydrate of Compound 2 that can be obtained according to the methods disclosed herein. In one aspect, Compound 3 is useful in methods for producing Compound 1. In another aspect, Compound 3 is useful in the methods of treatment described herein.

[0091] Compound 4 refers to potassium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)- 5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate, which has the chemical structure shown below:Compound 4.

[0092] Compound 4 is a salt of Compound 1 that can be obtained according to the methods disclosed herein. In one aspect, Compound 4 is useful in methods for producing Compound 1. In another aspect, Compound 4, or a pharmaceutically acceptable solvate thereof, is useful in the methods of treatment described herein. Crystalline Compound 2

[0093] In one aspect, provided herein is crystalline Compound 2. In some embodiments, provided herein is crystalline Compound 3.

[0094] In some embodiments, the crystalline Compound 2 is solvated. In some embodiments, the crystalline Compound 2 is hydrated. In some embodiments, the crystalline Compound 2 is ahydrate. In some embodiments, the crystalline Compound 2 is a hemiheptahydrate. In so meembodiments, crystalline Compound 2 that is a hemiheptahydrate is crystalline Compound 3. Insome embodiments, the crystalline Compound 2 is unsolvated.

[0095] In some embodiments, crystalline Compound 2 is substantially free of impurities. In some embodiments, crystalline Compound 2 is at least about 90% pure. In some embodiments, crystalline Compound 2 is at least about 95%, about 96%, about 97%, about 98%, or about 99%pure. In some embodiments, crystalline Compound 2 is at least about 95% pure. In some embodiments, crystalline Compound 2 is at least about 96% pure. In some embodiments, crystalline Compound 2 is at least about 97% pure. In some embodiments, crystalline Compound 2 is at least about 98% pure. In some embodiments, crystalline Compound 2 is at least about 99% pure. In some embodiments, crystalline Compound 2 is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100% pure. In some embodiments, crystalline Compound 3 is substantially free of impurities. In some embodiments, crystalline Compound 3 is at least about 90% pure. In some embodiments, crystalline Compound 3 is at least about 95%, about 96%, about 97%, about 98%, or about 99% pure. In some embodiments, crystalline Compound 3 is at least about 95% pure. In some embodiments, crystalline Compound 3 is at least about 96% pure. In some embodiments, crystalline Compound 3 is at least about 97% pure. In some embodiments, crystalline Compound 3 is at least about 98% pure. In some embodiments, crystalline Compound 3 is at least about 99% pure. In some embodiments, crystalline Compound 3 is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100% pure. Crystalline Form 1 of Compound 2

[0096] In some embodiments, the crystalline Compound 2 is Crystalline Form 1 of Compound 2. In some embodiments, Crystalline Form 1 of Compound 2 is crystalline Compound 3. In some embodiments, described herein is a composition comprising Crystalline Form 1 of Compound 2. In some embodiments, Crystalline Form 1 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 1; (b) an XRPD pattern with peaks at about 4.35 º 2-Theta, about 6.56 º 2-Theta, about 13.22 º 2-Theta, about 17.67 º 2-Theta, about 21.01 º 2-Theta, about 22.80 º 2-Theta, and about 24.66 º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 2; (d) a DSC thermogram with two endothermic events having: i. an onset at about 88.3 °C and peak at about 111.7 °C; and ii. an onset at about 265.6 °C and peak at about 267.0 °C; (e) a TGA pattern substantially the same as shown in Figure 2; (f) a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C; (g) unit cell pa 0 K:. b (Å) 8.6317(2)c (Å) 36.9014(8) ^^90^^97.521(2) ^ ^ 90 V (Å3) 3163.72(12) Z 4 Calculated Density (Mg / m3) 1.137 Absorption coefficient (mm-1) 1.034 F(000) 1176 ; (h) reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; (i) reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C; (j) an unchanged XRPD after DVS analysis up to 90% RH and 25 °C; (k) an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days; or (l) a combination thereof.

[0097] In some embodiments, the Crystalline Form 1 of Compound 2 has an XRPD pattern substantially the same as shown in Figure 1. In some embodiments, the Crystalline Form 1 of Compound 2 has an XRPD pattern with peaks at about 4.35 º 2-Theta, about 6.56 º 2-Theta, about 13.22 º 2-Theta, about 17.67 º 2-Theta, about 21.01 º 2-Theta, about 22.80 º 2-Theta, and about 24.66 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 has an XRPD pattern with peaks at 4.35 ± 0.2 º 2-Theta, 6.56 ± 0.2 º 2- Theta, 13.22 ± 0.2 º 2-Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2-Theta,and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation . In some embodiments, theCrystalline Form 1 of Compound 2 has a DSC thermogram substantially the same as shown in Figure 2. In some embodiments, the Crystalline Form 1 of Compound 2 has a DSC thermogram with two endothermic events having: an onset at about 88.3 °C and a peak at about 111.7 °C; and an onset at about 265.6 °C and a peak at about 267.0 °C. In some embodiments, the Crystalline Form 1 of Compound 2 has a TGA pattern substantially the same as shown in Figure 2. In some embodiments, the Crystalline Form 1 of Compound 2 has a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C. In some embodiments, the Crystalline Form 1 of Compound 2 has unit cell parameters substantially equal to the following at 100 K: Crystal System Monoclinic Space Group C2 a (Å) 10.0187(2) b (Å) 8.6317(2) c (Å) 36.9014(8). In some embodiments, the Crystalline Form 1 of Compound 2 has reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C. In some embodiments, the Crystalline Form 1 of Compound 2 has reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C. In some embodiments, the Crystalline Form 1 of Compound 2 has an unchanged XRPD after DVS analysis up to 90% RH and 25 °C. In some embodiments, the Crystalline Form 1 of Compound 2 has an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days. In some embodiments, the Crystalline Form 1 of Compound 2 has a combination of the properties detailed above.

[0098] In some embodiments, the Crystalline Form 1 of Compound 2 has an XRPD pattern reflection at about 4.35º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterized by XRPD pattern reflections at about 6.56 º 2-Theta, about 13.22 º 2-Theta, about 17.67 º 2-Theta, about 21.01 º 2-Theta, about 22.80 º 2-Theta, and about 24.66 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from: about 6.56 º 2-Theta, about 13.22 º 2-Theta, about 17.67 º 2-Theta, about 21.01 º 2-Theta, about 22.80 º 2-Theta, and about 24.66 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterized by at least three XRPD pattern reflections selected from: about 6.56 º 2-Theta, about 13.22 º 2-Theta, about 17.67 º 2-Theta, about 21.01 º 2-Theta, about 22.80 º 2-Theta, and about 24.66 º 2-Theta as measured using Cu Kα radiation.

[0099] In some embodiments, the Crystalline Form 1 of Compound 2 has an XRPD pattern reflection at 4.35 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterized by XRPD pattern reflections at 6.56 ± 0.2 º 2-Theta, 13.22 ± 0.2 º 2-Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2- Theta, and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from: 6.56 ± 0.2 º 2-Theta, 13.22 ± 0.2 º 2-Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2-Theta, and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 1 of Compound 2 is further characterizedby at least three XRPD pattern reflections selected from: 6.56 ± 0.2 º 2-Theta, 13.22 ± 0.2 º 2- Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2-Theta, and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation .

[0100] In some embodiments, Crystalline Form 1 of Compound 2 has an unchanged XRPD pattern and about the same water content after being stored in a sealed container for up to 6months under external conditions of 40±2 °C and 75±5% relative humidity. In someembodiments, Crystalline Form 1 of Compound 2 has an unchanged XRPD pattern and about the same water content after being stored in a sealed container for up to 24 months under external conditions of 25±2 °C and 60±5% relative humidity. Crystalline Form 2 of Compound 2

[0101] In some embodiments, the crystalline Compound 2 is Crystalline Form 2 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 2 of Compound 2. In some embodiments, Crystalline Form 2 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 3; (b) an XRPD pattern with peaks at about 3.89º 2-Theta, about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 4; (d) a DSC thermogram with two endothermic events having: i. an onset at about 120.9 °C and peak at about 130.4 °C; and ii. an onset at about 264.5 °C and peak at about 266.0 °C; (e) a TGA pattern substantially the same as shown in Figure 4; (f) a TGA pattern with an about 2.1% w / w loss from about 48 °C to about 208 °C; or a combination thereof.

[0102] In some embodiments, the Crystalline Form 2 of Compound 2 has an XRPD pattern substantially the same as shown in Figure 3. In some embodiments, the Crystalline Form 2 of Compound 2 has an XRPD pattern with peaks at about 3.89º 2-Theta, about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 has an XRPD pattern with peaks at about 3.89 ± 0.2 º 2-Theta, about 6.96 ± 0.2 º 2-Theta, about 7.82 ± 0.2 º 2-Theta, about 10.57 ± 0.2 º 2-Theta, about 14.17 ± 0.2 º 2-Theta, about 19.00 ± 0.2 º 2-Theta, and about 20.81 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 has a DSC thermogram substantially the same as shown in Figure 4. In some embodiments, the Crystalline Form 2 ofCompound 2 has a DSC thermogram with two endothermic events having: an onset at about 120.9 °C and peak at about 130.4 °C; and an onset at about 264.5 °C and peak at about 266.0 °C. In some embodiments, the Crystalline Form 2 of Compound 2 has a TGA pattern substantially the same as shown in Figure 4. In some embodiments, the Crystalline Form 2 of Compound 2 has a TGA pattern with an about 2.1% w / w loss from about 48 °C to about 208 °C. In some embodiments, the Crystalline Form 2 of Compound 2 has a combination of the properties detailed above.

[0103] In some embodiments, the Crystalline Form 2 of Compound 2 has an XRPD pattern reflection at about 3.89º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by XRPD pattern reflections at about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2- Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by at least three XRPD pattern reflections selected from about 6.96º 2-Theta, about 7.82º 2- Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation .

[0104] In some embodiments, the Crystalline Form 2 of Compound 2 has an XRPD pattern reflection at 3.89 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by XRPD pattern reflections at 6.96 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, 10.57 ± 0.2 º 2-Theta, 14.17 ± 0.2 º 2-Theta, 19.00 ± 0.2 º 2- Theta, and 20.81 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from 6.96 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, 10.57 ± 0.2 º 2-Theta, 14.17 ± 0.2 º 2-Theta, 19.00 ± 0.2 º 2-Theta, and 20.81 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 2 of Compound 2 is further characterized by at least three XRPD pattern reflections selected from 6.96 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2- Theta, 10.57 ± 0.2 º 2-Theta, 14.17 ± 0.2 º 2-Theta, 19.00 ± 0.2 º 2-Theta, and 20.81 ± 0.2 º 2-Theta as measured using Cu Kα radiation .Crystalline Form 3 of Compound 2

[0105] In some embodiments, the crystalline Compound 2 is Crystalline Form 3 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 3 ofCompound 2. In some embodiments, Crystalline Form 3 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 5; (b) an XRPD pattern with peaks at about 3.64º 2-Theta, about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 6; (d) a DSC thermogram with two endothermic events having: i. an onset at about 167.1 °C and peak at about 169.4 °C; and ii. an onset at about 268.3 °C and peak at about 269.5 °C; (e) a TGA pattern substantially the same as shown in Figure 6; (f) a TGA pattern with substantially no loss in weight from about 50 °C to about 200 °C; or a combination thereof.

[0106] In some embodiments, the Crystalline Form 3 of Compound 2 has an XRPD pattern substantially the same as shown in Figure 5. In some embodiments, the Crystalline Form 3 of Compound 2 has an XRPD pattern with peaks at about 3.64º 2-Theta, about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 has an XRPD pattern with peaks at 3.64 ± 0.2 º 2-Theta, 4.02 ± 0.2 º 2-Theta, 5.52 ± 0.2 º 2-Theta, 8.12 ± 0.2 º 2-Theta, 9.03 ± 0.2 º 2-Theta, 13.41 ± 0.2 º 2-Theta, and 16.83 ± 0.2º 2-Theta as measured using Cu Kα radiation . In some embodiments, the Crystalline Form 3 ofCompound 2 has a DSC thermogram substantially the same as shown in Figure 6. In some embodiments, the Crystalline Form 3 of Compound 2 has a DSC thermogram with two endothermic events having: an onset at about 167.1 °C and peak at about 169.4 °C; and an onset at about 268.3 °C and peak at about 269.5 °C. In some embodiments, the Crystalline Form 3 of Compound 2 has a TGA pattern substantially the same as shown in Figure 6. In some embodiments, the Crystalline Form 3 of Compound 2 has a TGA pattern with substantially no loss in weight from about 50 °C to about 200 °C. In some embodiments, the Crystalline Form 3 of Compound 2 has a combination of the properties detailed above.

[0107] In some embodiments, the Crystalline Form 3 of Compound 2 has an XRPD pattern reflection at about 3.64º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by XRPD pattern reflections at about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2- Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by at least one XRPD patternreflection selected from about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by at least three XRPD pattern reflections selected from about 4.02º 2-Theta, about 5.52º 2- Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation.

[0108] In some embodiments, the Crystalline Form 3 of Compound 2 has an XRPD pattern reflection at 3.64 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by XRPD pattern reflections at 4.02 ± 0.2 º 2-Theta, 5.52 ± 0.2 º 2-Theta, 8.12 ± 0.2 º 2-Theta, 9.03 ± 0.2 º 2-Theta, 13.41 ± 0.2 º 2- Theta, and 16.83 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from 4.02 ± 0.2 º 2-Theta, 5.52 ± 0.2 º 2-Theta, 8.12 ± 0.2 º 2-Theta, 9.03 ± 0.2 º 2-Theta, 13.41 ± 0.2 º 2-Theta, and 16.83 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 3 of Compound 2 is further characterized by at least three XRPD pattern reflections selected from 4.02 ± 0.2 º 2-Theta, 5.52 ± 0.2 º 2- Theta, 8.12 ± 0.2 º 2-Theta, 9.03 ± 0.2 º 2-Theta, 13.41 ± 0.2 º 2-Theta, and 16.83 ± 0.2 º 2-Theta as measured using Cu Kα radiation. Crystalline Form 4 of Compound 2

[0109] In some embodiments, the crystalline Compound 2 is Crystalline Form 4 of Compound 2. In some embodiments, described herein is a composition comprising Crystalline Form 4 of Compound 2. In some embodiments, Crystalline Form 4 of Compound 2 is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 7; (b) an XRPD pattern with peaks at about 3.87º 2-Theta, about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 8; (d) a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C; or a combination thereof.

[0110] In some embodiments, the Crystalline Form 4 of Compound 2 has an XRPD pattern substantially the same as shown in Figure 7. In some embodiments, the Crystalline Form 4 of Compound 2 has an XRPD pattern with peaks at about 3.87º 2-Theta, about 6.75º 2-Theta, about7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation . In someembodiments, the Crystalline Form 4 of Compound 2 has an XRPD pattern with peaks at 3.87 ±0.2 º 2-Theta, 6.75 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, and 10.38 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 has a DSC thermogram substantially the same as shown in Figure 8. In some embodiments, the Crystalline Form 4 of Compound 2 has a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C. In some embodiments, the Crystalline Form 4 of Compound 2 has a combination of the properties detailed above.

[0111] In some embodiments, the Crystalline Form 4 of Compound 2 has an XRPD pattern reflection at about 3.87º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by XRPD pattern reflections at about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by at least two XRPD pattern reflections selected from about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation.

[0112] In some embodiments, the Crystalline Form 4 of Compound 2 has an XRPD pattern reflection at 3.87 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by XRPD pattern reflections at 6.75 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, and 10.38 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by at least one XRPD pattern reflection selected from 6.75 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, and 10.38 ± 0.2 º 2-Theta as measured using Cu Kα radiation. In some embodiments, the Crystalline Form 4 of Compound 2 is further characterized by at least two XRPD pattern reflections selected from 6.75 ± 0.2 º 2-Theta, 7.82 ± 0.2 º 2-Theta, and 10.38 ± 0.2 º 2-Theta as measured using Cu Kα radiation. Synthesis

[0113] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0114] Compounds are prepared using standard organic chemistry techniques such as thosedescribed in, for example, March’s Advanced Organic Chemistry, 6 th Edition, John Wiley andSons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0115] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy or amino groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0116] In some embodiments, the compounds are synthesized following the procedures in the Examples. Synthesis of Compound 1 and Compound 4

[0117] Disclosed herein are methods for the synthesis of Compound 1 and Compound 4 as outlined in Scheme A. Scheme A

[0118] As disclosed herein, variables in Scheme A are defined as follows: X is a suitable leaving group; and each M+is independently at each occurrence an alkali metal cation or an alkylammonium cation. In some embodiments, X is halogen or a sulfonate group. In some embodiments, X is halogen. In some embodiments, the halogen is selected from fluoro, chloro, bromo, and iodo. In some embodiments, X is a sulfonate group. In some embodiments, the sulfonate group is -OS(=O)2Z, wherein Z is C1-10alkyl, C1-10fluoroalkyl, or C3-10carbocycle optionally substituted with 1-5 groups selected from C1-6alkyl and fluoro. In some embodiments, the sulfonate group is selected from mesylate (-OMs, methanesulfonate), esylate (-OEs, ethanesulfonate), tosylate (-OTs, para-toluenesulfonate), triflate (-OTf, trifluoromethanesulfonate), besylate (-OBs, benzenesulfonate), nonaflate (-ONf,perfluorobutanesulfonate), or the like. In some embodiments, X is tosylate. In some embodiments, X is mesylate. In some embodiments, each M+is independently selected from lithium, sodium, potassium, rubidium, and cesium. In some embodiments, each M+is potassium. In some embodiments, each M+is sodium. In some embodiments, each M+is independently an alkyl ammonium cation. In some embodiments, an alkyl ammonium cation comprises a tetracoordinate nitrogen atom bound to 1-4 C1-10alkyl groups, 0-3 hydrogen atoms, and 0-3 groups selected from C1-10heteroalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocycle, and 3- to 10- membered heterocycle. In some embodiments, the alkyl ammonium cation is triethylammonium, diisopropylethylammonium, a 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.2.2]octan-1-ium. Scheme A Step 1: S nthesis of a Compound of Formula C-I

[0119] As disclosed herein, a compound of Formula C-I is prepared from Compound E. In some embodiments, Compound E is contacted to a suitable base in a suitable solvent to yield the compound of Formula C-I.

[0120] In some embodiments, the suitable base in Scheme A, Step 1 is selected from an alkoxide base, a carbonate base, an amine base, a hydride base, a silanolate base, a hydroxide base, a bis(silyl)amide base, a dialkylamide base, or a phosphate base. In some embodiments, the alkoxide base is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium 2-methylbutan-2-olate, or potassium 2- methylbutan-2-olate. In some embodiments, the carbonate base is sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the hydride base is sodium hydride or potassium hydride. In some embodiments, the amine base is triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the silanolate base is sodium trimethylsilanolate or potassium trimethylsilanolate. In some embodiments, the hydroxide base is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide. In some embodiments, the dialkylamide base is lithium diisopropylamide. In some embodiments, the phosphate base is sodium phosphate or potassium phosphate. In some embodiments, the bis(silyl)amide base is lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In some embodiments, the suitable solvent in Scheme A, Step 1 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2- pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, methanol, ethanol, isopropanol, tert-butanol, n-butanol, or a combination thereof. In some embodiments, the suitable base in Scheme A, Step 1 is potassium tert-butoxide, and the suitable solvent in Scheme A, Step 1 is dimethyl sulfoxide.

[0121] In some embodiments, the amount of the suitable base used in Scheme A, Step 1 is about 2.0 equiv. In some embodiments, the amount of the suitable base used in Scheme A, Step 1 is greater than 2.0 equiv. In some embodiments, the amount of the suitable base used in Scheme A, Step 1 is about 2.2 equiv. In some embodiments, the amount of the suitable base used in Scheme A, Step 1 is about 2.1 equiv. In some embodiments, the amount of the suitable base used in Scheme A, Step 1 is about 2.05 equiv.

[0122] In some embodiments, the compound of Formula C-I is isolated. In some embodiments, the compound of Formula C-I is prepared as a solution according to Scheme A, Step 1, and the solution is used directly in a subsequent step.

[0123] In some embodiments, the compound of Formula C-I is Compound 5: Sc

[0124] As disclosed herein, a compound of Formula A is prepared from a compound of Formula C-I and a Compound of Formula B. In some embodiments, a compound of Formula C-I is contacted with a Compound of Formula B in a suitable solvent to yield the compound of Formula A.

[0125] In some embodiments, the suitable solvent of Scheme A, Step 2 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2- imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or acombination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide. In some embodiments, the suitable solvent is tetrahydrofuran. In some embodiments, the suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran.

[0126] In some embodiments of Scheme A, Step 2, the molar ratio of the quantity of the compound of Formula B used to the quantity of the compound of Formula C-I used is about 1:1. In some embodiments, the molar ratio is 1:1. In some embodiments, the molar ratio is about 0.7:1, 0.8:1, 0.9:1, 1:1, 1:0.9, 1:0.8, or 1:0.7.

[0127] In some embodiments, Scheme A, Step 2 is conducted by: a) providing a first solution comprising the compound of Formula B and a first suitable solvent; b) providing a second solution comprising the compound of Formula C-I and a second suitable solvent; and c) combining the first solution and the second solution to form a reaction mixture, thereby contacting the compound of Formula B with the compound of Formula C-I to provide the compound of Formula A.

[0128] In some embodiments, the first suitable solvent is dimethyl sulfoxide, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4- dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the first suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof. In some embodiments, the first suitable solvent is dimethyl sulfoxide. In some embodiments, the first suitable solvent is tetrahydrofuran. In some embodiments, the first suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran. In some embodiments, the second suitable solvent is dimethyl sulfoxide, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4- dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the second suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide. In some embodiments, the second suitable solvent is tetrahydrofuran. In some embodiments, the second suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran.

[0129] In some embodiments, Scheme A, Step 2 is conducted in one or more flow reactors. In some embodiments, Scheme A, Step 2 is conducted in one flow reactor. In some embodiments, Scheme A, Step 2 is conducted in two flow reactors in series. In some embodiments, Scheme A, Step 2 is conducted in three flow reactors in series. In some embodiments, each of the one ormore flow reactors is a coil reactor. In some embodiments, each of the one or more f low reactorsis a continuously stirred tank reactor.

[0130] In some embodiments, c) comprises combining the first solution and the second solution in a flow reactor, thereby forming the reaction mixture. In some embodiments, the flow reactor is a first continuously stirred tank reactor. In some embodiments, the first continuously stirred tank reactor is configured to pass the reaction mixture to a second continuously stirred tank reactor in series with the first continuously stirred tank reactor. In some embodiments, the second continuously stirred tank reactor is configured to pass the reaction mixture to a third continuously stirred tank reactor in series with the first continuously stirred tank reactor and the second continuously stirred tank reactor. In some embodiments, the first continuously stirred tank reactor, the second continuously stirred tank reactor, the third continuously stirred tank reactor, or a combination thereof is configured to maintain the reaction mixture at the suitable temperature. In some embodiments, the first continuously stirred tank reactor, the second continuously stirred tank reactor, the third continuously stirred tank reactor, or a combination thereof is configured to maintain the reaction mixture at the suitable temperature for the suitable quantity of time, wherein the suitable quantity of time is the cumulative residence time of the reaction mixture in the first continuously stirred tank reactor, the second continuously stirred tank reactor, the third continuously stirred tank reactor, or a combination thereof. In some embodiments, the compound of Formula A is Compound 4; the compound of Formula B is Compound 6-I; and the compound of Formula C-I is Compound 5. In some embodiments, b) comprises contacting Compound E to potassium tert-butoxide in dimethyl sulfoxide, thereby providing the second solution.

[0131] In some embodiments, Scheme A, Step 2 further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, Scheme A, Step 2 further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 100° Celsius. In someembodiments, the suitable temperature is about 40° Celsius to about 90° Celsius. In someembodiments, the suitable temperature is about 50° Celsius to about 80° Celsius. In someembodiments, the suitable temperature is about 60° Celsius to about 70° Celsius. In someembodiments, the suitable temperature is about 65° Celsius. In some embodiments, the suitable temperature is 60±5° Celsius, 65±5° Celsius, 70±5° Celsius, 75±5° Celsius, or 80±5° Celsius. In some embodiments, the suitable quantity of time is about 30 minutes to about 10 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 10 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 5 hours. In someembodiments, the suitable quantity of time is about 2 hours to about 4 hours. In some embodiments, the suitable quantity of time is about 3 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0132] In some embodiments, the compound of Formula C-I is Compound 5.

[0133] In some embodiments, the compound of Formula B is Compound 6-I: ).

[0134] In some embodiments, the compound of Formula B is Compound 6-II:).

[0135] In some embodiments, the compound of Formula A is Compound 4.Sc

[0136] As disclosed herein, Compound 1 is prepared from a compound of Formula A. In some embodiments, a compound of Formula A is contacted with a suitable acid in a suitable solvent to yield Compound 1.

[0137] In some embodiments, the suitable acid of Scheme A, Step 3 is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, nitric acid, trifluoroacetic acid, citric acid, or a combination thereof. In some embodiments, the suitable acid is trifluoroacetic acid or citric acid. In some embodiments, the suitable acid is trifluoroacetic acid. In some embodiments, the suitable acid is citric acid.

[0138] In some embodiments, the suitable solvent of Scheme A, Step 3 is tetrahydrofuran, 2 -methyl tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, or a combination thereof. In some embodiments, the suitablesolvent is 2-methyl tetrahydrofuran, water, or a combination thereof. In some embodiments, the suitable solvent is 2-methyl tetrahydrofuran. In some embodiments, the suitable solvent is water. In some embodiments, the suitable solvent is a combination of 2-methyl tetrahydrofuran and water.

[0139] In some embodiments of Scheme A, Step 3, a molar excess of the suitable acid with respect to the compound of Formula A. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, 20.0, or 50.0 molar equivalents of the suitable acid with respect to the compound of Formula A are used. In some embodiments of Scheme A, Step 3, the concentration of the suitable acid in the suitable solvent is about 0.01 M, 0.05 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, or more than 0.5 M.

[0140] In some embodiments, the compound of Formula A is Compound 4. Synthesis of A Compound of Formula G

[0141] Disclosed herein are methods for the synthesis of a compound of Formula G as outlined in Scheme B. Scheme B

[0142] As disclosed herein, variables in Scheme B are defined as follows: PG1is a suitable protecting group; X is a suitable leaving group; and each M+is independently at each occurrence an alkali metal cation or an alkylammonium cation. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10- membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In someembodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2-trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2-trifluoroethyl. In some embodiments, X is halogen or a sulfonate group. In some embodiments, X is halogen. In some embodiments, the halogen is selected from fluoro, chloro, bromo, and iodo. In some embodiments, X is a sulfonate group. In some embodiments, the sulfonate group is -OS(=O)2Z, wherein Z is C1-10alkyl, C1-10fluoroalkyl, or C3-10carbocycle optionally substituted with 1-5 groups selected from C1-6alkyl and fluoro. In some embodiments, the sulfonate group is selected from mesylate (-OMs, methanesulfonate), esylate (-OEs, ethanesulfonate), tosylate (-OTs, para- toluenesulfonate), triflate (-OTf, trifluoromethanesulfonate), besylate (-OBs, benzenesulfonate), or nonaflate (-ONf, perfluorobutanesulfonate). In some embodiments, X is tosylate. In some embodiments, X is mesylate. In some embodiments, each M+is independently selected from lithium, sodium, potassium, rubidium, and cesium. In some embodiments, each M+is potassium. In some embodiments, each M+is independently an alkyl ammonium cation. In some embodiments, an alkyl ammonium cation comprises a tetracoordinate nitrogen atom substituted with 1-4 C1-10alkyl groups, 0-3 hydrogen atoms, and 0-3 groups selected from C1-10heteroalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle. In some embodiments, the alkyl ammonium cation is triethylammonium, diisopropylethylammonium, a 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.2.2]octan- 1-ium. Sc

[0143] As disclosed herein, a compound of Formula C-II is prepared from a compound of Formula H. In some embodiments, a compound of Formula H is contacted to a suitable base in a suitable solvent to yield the compound of Formula C-II.

[0144] In some embodiments, the suitable base in Scheme B, Step 1 is selected from an alkoxide base, a carbonate base, an amine base, a hydride base, a silanolate base, a hydroxide base, a bis(silyl)amide base, a dialkylamide base, or a phosphate base. In some embodiments, the alkoxide base is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium 2-methylbutan-2-olate, or potassium 2- methylbutan-2-olate. In some embodiments, the carbonate base is sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the hydride base is sodium hydride or potassium hydride. In some embodiments, the amine base is triethylamine,diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the silanolate base is sodium trimethylsilanolate or potassium trimethylsilanolate. In some embodiments, the dialkylamide base is lithium diisopropylamide. In some embodiments, the phosphate base is sodium phosphate or potassium phosphate. In some embodiments, the bis(silyl)amide base is lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In some embodiments, the suitable solvent in Scheme B, Step 1 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, methanol, ethanol, isopropanol, tert-butanol, n- butanol, or a combination thereof. In some embodiments, the suitable base in Scheme B, Step 1 is potassium tert-butoxide, and the suitable solvent in Scheme B, Step 1 is dimethyl sulfoxide.

[0145] In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is about 1.0 equiv. In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is about 1.2 equiv. In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is greater than 1.0 equiv. In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is about 1.1 equiv. In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is about 1.05 equiv. In some embodiments, the amount of the suitable base used in Scheme B, Step 1 is about 1.025 equiv.

[0146] In some embodiments, the compound of Formula C-II is isolated. In some embodiments, the compound of Formula C-II is prepared as a solution according to Scheme B,Step 1, and the solution is used directly in a subsequent step.

[0147] In some embodiments, the compound of Formula H is Compound 7:(Compound 7). Scheme B, Step 2: Synthesis of a Compound of Formula G

[0148] As disclosed herein, a compound of Formula G is prepared from a compound of Formula C-II and a Compound of Formula B. In some embodiments, a compound of Formula C- II is contacted with a Compound of Formula B in a suitable solvent to yield the compound of Formula G.

[0149] In some embodiments, the suitable solvent of Scheme B, Step 2 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2- imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide. In some embodiments, the suitable solvent is tetrahydrofuran. In some embodiments, the suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran.

[0150] In some embodiments of Scheme B, Step 2, the molar ratio of the quantity of the compound of Formula B used to the quantity of the compound of Formula C-II used is about 1:1. In some embodiments, the molar ratio is 1:1. In some embodiments, the molar ratio is about 0.7:1, 0.8:1, 0.9:1, 1:1, 1:0.9, 1:0.8, or 1:0.7.

[0151] In some embodiments, Scheme B, Step 2 is conducted by: a) providing a first solution comprising the compound of Formula B and a first suitable solvent; b) providing a second solution comprising the compound of Formula C-II and a second suitable solvent; and c) combining the first solution and the second solution to form a reaction mixture, thereby contacting the compound of Formula B with the compound of Formula C-II to provide the compound of Formula G.

[0152] In some embodiments, the first suitable solvent is dimethyl sulfoxide, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4- dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the first suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof. In some embodiments, the first suitable solvent is dimethyl sulfoxide. In some embodiments, the first suitable solvent is tetrahydrofuran. In some embodiments, the first suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran. In some embodiments, the second suitable solvent is dimethyl sulfoxide, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4- dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the second suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent is dimethyl sulfoxide. In some embodiments, the second suitable solvent is tetrahydrofuran. In some embodiments, the second suitable solvent is a combination of dimethyl sulfoxide and tetrahydrofuran.

[0153] In some embodiments, Scheme B, Step 2 is conducted in one or more flow reactors. In some embodiments, Scheme B, Step 2 is conducted in one flow reactor. In some embodiments, Scheme B, Step 2 is conducted in two flow reactors in series. In some embodiments, Scheme B, Step 2 is conducted in three flow reactors in series. In some embodiments, each of the one or more flow reactors is a coil reactor. In some embodiments, each of the one or more flow reactors is a continuously stirred tank reactor.

[0154] In some embodiments, Scheme B, Step 2 further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, Scheme B, Step 2 further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 90° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 80° Celsius. In someembodiments, the suitable temperature is about 60° Celsius to about 70° Celsius. In someembodiments, the suitable temperature is about 65° Celsius. In some embodiments, the suitable temperature is 60±5° Celsius, 65±5° Celsius, 70±5° Celsius, 75±5° Celsius, or 80±5° Celsius. In some embodiments, the suitable quantity of time is about 30 minutes to about 10 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 10 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 5 hours. In some embodiments, the suitable quantity of time is about 2 hours to about 4 hours. In some embodiments, the suitable quantity of time is about 3 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0155] In some embodiments the compound of Formula C-II is Compound 8:(Compound 8).

[0156] In some embodiments, the compound of Formula B is Compound 6-I. In some embodiments, the compound of Formula B is Compound 6-II.

[0157] In one aspect, a compound of Formula G is useful in the preparation of Compound 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula G is contacted with a suitable base in a suitable solvent to yield Compound 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula G is contacted with a suitable hydroxide base in a suitable solvent to yield Compound 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula G is contacted with sodium hydroxide or potassium hydroxide in a suitable solvent to yield Compound 1 or a pharmaceutically acceptable salt or solvate thereof; wherein the suitable solvent is water, ethanol, methanol, or a combination thereof.

[0158] In some embodiments, the compound of Formula G is Compound 9:(Compound 9). Synthesis of a Compound of Formula B

[0159] Disclosed herein are methods for the synthesis of a compound of Formula B as outlined in Scheme C. Scheme C

[0160] As disclosed herein, variables in Scheme C are defined as follows: X is a suitable leaving group. In some embodiments, X is halogen or a sulfonate group. In some embodiments, X is halogen. In some embodiments, the halogen is selected from fluoro, chloro, bromo, and iodo. In some embodiments, X is a sulfonate group. In some embodiments, the sulfonate group is -OS(=O)2Z, wherein Z is C1-10alkyl, C1-10fluoroalkyl, or C3-10carbocycle optionally substituted with 1-5 groups selected from C1-6alkyl and fluoro. In some embodiments, the sulfonate group is selected from mesylate (-OMs, methanesulfonate), esylate (-OEs, ethanesulfonate), tosylate (-OTs, para-toluenesulfonate), triflate (-OTf, trifluoromethanesulfonate), besylate (-OBs, benzenesulfonate), or nonaflate (-ONf, perfluorobutanesulfonate). In some embodiments, X is tosylate. In some embodiments, X is mesylate. Scheme C, Step 1: Synthesis of Compound Q

[0161] As disclosed herein, Compound Q is prepared from Compound R. In some embodiments, Compound R is contacted to piperidin-4-ylmethanol and a suitable base in a suitable solvent to yield Compound Q.

[0162] In some embodiments, the suitable base in Scheme C, Step 1 is a carbonate base or a bicarbonate base. In some embodiments, the suitable base is a bicarbonate base. In some embodiments, the suitable base is a carbonate base. In some embodiments, the carbonate base is lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the bicarbonate base is lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or cesium bicarbonate. In some embodiments, the suitable base is potassium bicarbonate. In some embodiments, the suitable solvent in Scheme C, Step 1 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2- methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2- imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, methanol, ethanol, isopropanol, tert-butanol, n-butanol, or a combination thereof. In some embodiments, the suitable solvent is N,N-dimethylacetamide. In some embodiments, the suitable base is potassium bicarbonate and the suitable solvent is N,N-dimethylacetamide.

[0163] In some embodiments of Scheme C, Step 1, 1.2 molar equivalents of piperidin-4- ylmethanol with respect to the quantity of Compound R are used. In some embodiments ofScheme C, Step 1, 1.5 molar equivalents of the suitable base (e.g., potassium bicarbonate) withrespect to the quantity of Compound R are used. In some embodiments of Scheme C, Step 1, 0.6 molar equivalents of the suitable base (e.g., potassium bicarbonate) with respect to the quantity of Compound R are used. In some embodiments, Scheme C, Step 1 is carried out at about 100° Celsius. In some embodiments, Scheme C, Step 1 is carried out at 100±5° Celsius. In some embodiments, Scheme C, Step 1 is carried out at 105±5° Celsius. In some embodiments, SchemeC, Step 1 is carried out at 80±5° Celsius, 85±5° Celsius, 90±5° Celsius, 95±5° Celsius, 100±5°Celsius, 105±5° Celsius, 110±5° Celsius, 115±5° Celsius, or 120±5° Celsius.Scheme C, Step 2: Synthesis of Compound P

[0164] As disclosed herein, Compound P is prepared from Compound Q. In some embodiments, Compound Q is contacted to pivalaldehyde and a suitable base in a suitable solvent to yield Compound P.

[0165] In some embodiments, the suitable base in Scheme C, Step 2 is a hydroxide base or an alkoxide base. In some embodiments, the suitable base is a hydroxide base. In some embodiments, the suitable base is an alkoxide base. In some embodiments, the alkoxide base is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert- butoxide, potassium tert-butoxide, sodium 2-methylbutan-2-olate, or potassium 2-methylbutan-2- olate. In some embodiments, the hydroxide base is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide. In some embodiments, the suitable base is potassium hydroxide. In some embodiments, the suitable solvent in Scheme C, Step 2 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2- pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′-dimethylpropyleneurea, tert-amyl alcohol, water, methanol, ethanol, isopropanol, tert-butanol, n-butanol, or a combination thereof. In some embodiments, the suitable solvent is 2-methyl tetrahydrofuran. In some embodiments, thesuitable base is potassium hydroxide and the suitable solvent is 2 -methyl tetrahydrofuran.

[0166] In some embodiments of Scheme C, Step 2, 1.2 molar equivalents of p ivalaldehydewith respect to the quantity of Compound Q are used. In some embodiments of Scheme C, Step 2, about 0.8, 1.0, 1.2, 1.4 or 1.6 molar equivalents of pivalaldehyde with respect to the quantity of Compound Q are used. In some embodiments of Scheme C, Step 2, 1.05 molar equivalents of the suitable base (e.g., potassium hydroxide) with respect to the quantity of Compound Q are used. In some embodiments of Scheme C, Step 2, 3.0 molar equivalents of the suitable base (e.g., potassium hydroxide) with respect to the quantity of Compound Q are used. In some embodiments of Scheme C, Step 2, about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the suitable base (e.g., potassium hydroxide) with respect to the quantity ofCompound Q are used. In some embodiments, Scheme C, Step 2 is carried out at about 25° Celsius. In some embodiments, Scheme C, Step 2 is carried out at 25±5° Celsius. In some embodiments, Scheme C, Step 2 is carried out at 5±5° Celsius, 10±5° Celsius, 15±5° Celsius, 20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, 40±5° Celsius, or 45±5° Celsius. Scheme C, Step 3: Synthesis of Compound D

[0167] As disclosed herein, Compound D is prepared from Compound P. In some embodiments, Compound P is contacted to a suitable acid, a suitable hydrogen source and a suitable hydrogenation catalyst in a suitable solvent to yield Compound P.

[0168] In some embodiments, the suitable acid in Scheme C, Step 3 is sulfuric acid or a sulfonic acid. In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the suitable acid is a sulfonic acid. In some embodiments, the sulfonic acid is methanesulfonic acid (MsOH), ethanesulfonic acid (EsOH), para-toluenesulfonic acid (TsOH), trifluoromethanesulfonic acid (TfOH), benzenesulfonic acid (BsOH), or perfluorobutanesulfonic acid (NfOH). In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the suitable hydrogen source in Scheme C, Step 3 is dihydrogen (H2) or ammonium formate. In some embodiments, the suitable hydrogen source is dihydrogen. In some embodiments, the suitable hydrogenation catalyst in Scheme C, Step 3 is a palladium catalyst or a platinum catalyst. In some embodiments, the suitable hydrogenation catalyst is palladium on carbon (Pd / C) or platinum on carbon (Pt / C). In some embodiments, the suitable hydrogenation catalyst is palladium on carbon. In some embodiments, the suitable hydrogenation catalyst is platinum on carbon. In some embodiments, the weight percentage (i.e., % w / w) of palladium in the palladium on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the weight percentage (i.e., % w / w) of platinum in the platinum on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the suitable solvent in Scheme C, Step 3 is methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol, water, or a combination thereof. In some embodiments, the suitable solvent is a combination of water andethanol. In some embodiments, the suitable acid is methanesulfonic acid, the suitable hydrogen source is dihydrogen, and the suitable hydrogenation catalyst is platinum on carbon.

[0169] In some embodiments, the amount of the suitable hydrogenation catalyst used in Scheme C, Step 3 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments of Scheme C, Step 3, a molar excess of the suitable acid (e.g., MsOH) with respect to the quantity of Compound P are used. In some embodiments of Scheme C, Step 3, more than 1.0, more than 5.0, more than 10, more than 15 or more than 20 molar equivalents of the suitable acid (e.g., MsOH) with respect to the quantity of Compound P are used. In some embodiments of Scheme C, Step 3, a molar excess of the suitable hydrogen source with respect to the quantity of Compound P is used. In some embodiments of Scheme C, Step 3, the suitable hydrogen source is dihydrogen at a pressure of about 0.5 MPa, 0.75 MPa, 1.0 MPa,1.5 MPa, 2.0 MPa, 2.2 MPa, 2.5 MPa, 3.0 MPa, 3.5 MPa, 4.0 MPa, 4.5 MPa, or 5.0 MPa. Insome embodiments of Scheme C, Step 3, the suitable hydrogen source is dihydrogen at a pressure of about 2.2 MPa. In some embodiments of Scheme C, Step 3, the suitable hydrogen source is dihydrogen at a pressure of 2.2±0.2 MPa. In some embodiments, Scheme C, Step 3 is carried out at about 90° Celsius. In some embodiments, Scheme C, Step 3 is carried out at 90±5° Celsius. In some embodiments, Scheme C, Step 3 is carried out at 95±5° Celsius. In some embodiments, Scheme C, Step 3 is carried out at 70±5° Celsius, 75±5° Celsius, 80±5° Celsius, 85±5° Celsius, 90±5° Celsius, 95±5° Celsius, 100±5° Celsius, 105±5° Celsius, or 110±5° Celsius. Scheme C, Step 4: Synthesis of a Compound of Formula B

[0170] As disclosed herein, a compound of Formula B is prepared from Compound D. In some embodiments, Compound D is contacted to a suitable activating agent and a suitable base in a suitable solvent to yield a compound of Formula B.

[0171] In some embodiments, the suitable activating agent in Scheme C, Step 4 is a phosphorus halide, a thionyl halide, a sulfonyl halide, or a sulfonyl anhydride. In some embodiments, the suitable activating agent is a sulfonyl halide. In some embodiments, the suitable activating agent is a sulfonyl chloride. In some embodiments, the suitable activating agent is methanesulfonyl chloride (MsCl), ethanesulfonyl chloride (EsCl), para-toluenesulfonyl chloride (TsCl), trifluoromethanesulfonyl chloride (TfCl), benzenesulfonyl chloride (BsCl), orperfluorobutanesulfonyl chloride (NfCl). In some embodiments, the suitable activating agent is para-toluenesulfonyl chloride. In some embodiments, the suitable activating agent is methanesulfonyl chloride. In some embodiments, the suitable base in Scheme C, Step 4 is a pyridine, an amine, or a combination thereof. In some embodiments, the suitable base is pyridine, 4-dimethylaminopyridine, triethylamine, or a combination thereof. In some embodiments, the suitable base is 4-dimethylaminopyridine. In some embodiments, the suitable base is triethylamine. In some embodiments, the suitable base is a combination of 4- dimethylaminopyridine and triethylamine. In some embodiments, the suitable solvent in Scheme C, Step 4 is dichloromethane or 1,2-dichloroethane. In some embodiments, the suitable activating agent is para-toluenesulfonyl chloride, the suitable base is 4-dimethylaminopyridine, and the suitable solvent is dichloromethane.

[0172] In some embodiments of Scheme C, Step 4, about 1.5 molar equivalents of the suitable activating agent (e.g., MsCl, TsCl) with respect to the quantity of Compound D are used. In some embodiments of Scheme C, Step 4, about 1.3 molar equivalents of the suitable activating agent (e.g., MsCl, TsCl) with respect to the quantity of Compound D are used. In some embodiments of Scheme C, Step 4, about 0.75, 1.0, 1.25, 1.5 or 1.75 molar equivalents of the suitable activating agent (e.g., MsCl, TsCl) with respect to the quantity of Compound D are used. In some embodiments of Scheme C, Step 4, 3.0 molar equivalents of the suitable base (e.g., triethylamine) with respect to the quantity of Compound D are used. In some embodiments of Scheme C, Step 4, about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the suitable base (e.g., triethylamine) with respect to the quantity of Compound D are used. In some embodiments, the suitable base comprises about 3.0 molar equivalents of triethylamine and about 0.1 molar equivalents of 4-dimethylaminopyridine with respect to the quantity of Compound D. In some embodiments, the suitable base comprises about 2.0 molar equivalents of triethylamine and about 0.05 molar equivalents of 4-dimethylaminopyridine with respect to the quantity of Compound D. In some embodiments, Scheme C, Step 4 is carried out at about 20° Celsius. In some embodiments, Scheme C, Step 4 is carried out at 20±5° Celsius. In some embodiments, Scheme C, Step 4 is carried out at 0±5° Celsius. In some embodiments, Scheme C, Step 4 is carried out at0±5° Celsius, 5±5° Celsius, 15±5° Celsius, 20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5°Celsius, 40±5° Celsius, or 45±5° Celsius.

[0173] In some embodiments, the compound of Formula B is Compound 6-I. In some embodiments, the compound of Formula B is Compound 6-II. Synthesis of Compound E and a Compound of Formula H

[0174] Disclosed herein are methods for the synthesis of Compound E and a compound of Formula H as outlined in Scheme D.Scheme D

[0175] As disclosed herein, variables in Scheme D are defined as follows: PG1is a suitable protecting group; PG2is a suitable protecting group; Y is halogen; R1is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10- membered heterocycle. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In some embodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2-trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2-trifluoroethyl. In some embodiments, PG2is C1-10alkyl, C7-10ara-alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG2is C1-6alkyl or C7-10ara-alkyl. In some embodiments, PG2is C1-10alkyl. In some embodiments, PG2is C1-6alkyl. In some embodiments, PG2is C7-10ara-alkyl. In some embodiments, PG2is C7-8ara-alkyl. In some embodiments, PG2is methyl or benzyl. In some embodiments, PG2is methyl. In some embodiments, PG2is benzyl. In some embodiments, R1is identical to PG1. In some embodiments, R1is hydrogen, C1-10alkyl, or C1-10fluoroalkyl. In some embodiments, R1is R1A. In some embodiments, R1Ais C1-6alkyl. In some embodiments. R1Ais identical to PG1. In some embodiments, R1and PG1are each ethyl and PG2is benzyl. In some embodiments, R1and PG1are each ethyl and PG2is methyl. In some embodiments, R1is hydrogen; PG1is ethyl; and PG2is benzyl. In some embodiments, R1is hydrogen; PG1is ethyl; and PG2is methyl. In some embodiments, Y is fluoro, chloro, bromo, oriodo. In some embodiments, Y is chloro or bromo. In some embodiments, Y is chloro.Scheme D, Step 1: Synthesis of a Compound of Formula J

[0176] As disclosed herein, a compound of Formula J is prepared from a compound of Formula K. In some embodiments, a compound of Formula K is contacted to a suitable hydrogen source and a suitable metal catalyst in a suitable solvent to yield the compound of Formula J. In some embodiments, the suitable metal catalyst generated by combining a suitable ligated metal salt with a suitable chiral phosphine ligand.

[0177] In some embodiments, the suitable hydrogen source is dihydrogen (H2), hydrazine,dihydronaphthalene, dihydroanthracene, isopropanol, ammonium formate, or formic acid. Insome embodiments, the suitable hydrogen source is dihydrogen. In some embodiments, the suitable ligated metal salt comprises rhodium. In some embodiments, the suitable ligated metal salt comprises a rhodium-olefin complex. In some embodiments, the suitable ligated metal salt is [(norbornadiene)RhCl]2, [(norbornadiene)RhBr]2, [(norbornadiene)RhI]2, [(1,5- cyclooctadiene)RhCl]2, [(1,5-cyclooctadiene)RhBr]2, [(1,5-cyclooctadiene)RhI]2, [(1,5- cyclooctadiene)2Rh] tetrafluoroborate, [(1,5-cyclooctadiene)2Rh] tetraphenylborate, [(1,5- cyclooctadiene)2Rh] hexafluorophosphate, [(norbornadiene)2Rh] tetrafluoroborate, [(norbornadiene)2Rh] tetraphenylborate, [(norbornadiene)2Rh] hexafluorophosphate, or the like. In some embodiments, the suitable ligated metal salt is [(norbornadiene)RhCl]2, [(1,5- cyclooctadiene)RhCl]2, or [(1,5-cyclooctadiene)2Rh] tetrafluoroborate. In some embodiments, the suitable chiral phosphine ligand is axially chiral. In some embodiments, the suitable chiral phosphine ligand comprises at least one stereogenic center. In some embodiments, only a single enantiomer of the chiral phosphine ligand is used in Scheme D, Step 1. In some embodiments, the chiral phosphine ligand has at least 90% enantiomeric purity. In some embodiments, the chiral phosphine ligand has at least 95% enantiomeric purity. In some embodiments, the chiral phosphine ligand has at least 99% enantiomeric purity. In some embodiments, the suitable chiral phosphine ligand comprises a substituted ferrocene. In some embodiments, the suitable chiral phosphine ligand comprises a substituted 1,3-benzodioxole. In some embodiments, the suitable chiral phosphine ligand is (S)-(+)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′- bi-1,3-benzodioxole ((S)-DTBM-SEGPHOS®; CAS No.210169-40-7), I-(+)-1-[(Rp)-2’(2'- dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine (Walphos SL-W008-1; CAS No.821009-34-1), (R)-1-[(R)-1-[bis[3,5- bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene[(1S)-1-(diphenylphosphino)ethyl]ferrocene (JosiPhos SL-J502-2; CAS No.223121-01-5). In some embodiments, the suitable solvent in Scheme D, Step 1 is methanol, dichloromethane, or a combination thereof. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is dichloromethane.

[0178] As described herein, (S)-(+)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]- 4,4′-bi-1,3-benzodioxole ((S)-DTBM-SEGPHOS®; CAS No.210169-40-7) has the structure depicted below:

[0179] As described herein, I-(+)-1-[(Rp)-2’(2'- dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine (Walphos SL-W008-1; CAS No.821009-34-1) has the structure depicted below:

[0180] As described herein, (R)-1-[(R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]- 2-[2-(diphenylphosphino)phenyl]ferrocene (Walphos SL-W001-1; CAS No.565184-33-0) has the structure depicted below:

[0181] As described herein, (1S)-1-[bis(1,1-dimethylethyl)phosphino]-2-[(1S)-1- (diphenylphosphino)ethyl]ferrocene (JosiPhos SL-J502-2; CAS No.223121-01-5) has the structure depicted below:

[0182] In some embodiments, Scheme D, Step 1 provides the compound of Formula J in at least 90% enantiomeric purity. In some embodiments, Scheme D, Step 1 provides the compound of Formula J in at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% enantiomeric purity. In some embodiments, the amount of the suitable metal catalyst used in Scheme D, Step 1 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 molar equivalents with respect to the quantity of the compound of Formula K. In some embodiments, the amount of the suitable ligated metal salt used in Scheme D, Step 1 is about 0.005 molar equivalents with respect to the quantity of the compound of Formula K. In some embodiments, the amount of the suitable ligated metal salt used in Scheme D, Step 1 is about 0.0025 molar equivalents with respect to the quantity of the compound of Formula K. In some embodiments, the amount of the suitable ligated metal salt used in Scheme D, Step 1 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equivalents with respect to the quantity of the compound of Formula K. In some embodiments, the amount of the suitable chiral phosphine used in Scheme D, Step 1 is about 0.0115 molar equivalents with respect to the quantity of the compound of Formula K. In some embodiments, the amount of the suitable chiral phosphine used in Scheme D, Step 1 issome embodiments, the amount of the suitable chiral phosphine used in Scheme D, Step 1 isabout 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In someembodiments, the amount of the suitable metal catalyst used in Scheme D, Step 1 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments of Scheme D, Step 1, a molar excess of the suitable hydrogen source with respect to the quantity of the compound of Formula K is used. In some embodiments of Scheme D, Step 1, the suitable hydrogen source is dihydrogen at a pressure of about 0.5 MPa, 0.75 MPa, 1.0 MPa, 1.5 MPa, 2.0 MPa, 2.2 MPa, 2.5 MPa, 3.0 MPa, 3.5 MPa, 4.0 MPa, 4.5 MPa, or 5.0 MPa. In some embodiments of Scheme D, Step 1, the suitable hydrogen source is dihydrogen at a pressure of about 1.0 MPa. In some embodiments of Scheme D, Step 1, the suitable hydrogen source is dihydrogen at a pressure of about 1.3±0.5 MPa. In some embodiments, Scheme D, Step 1 is carried out at about 25° Celsius. In some embodiments, Scheme D, Step 1 is carried out at 25±5° Celsius. In some embodiments, Scheme D, Step 1 is carried out at 30±5° Celsius. In some embodiments, Scheme D, Step 1 is carried out at 5±5° Celsius, 10±5° Celsius, 15±5° Celsius,20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, 40±5° Celsius, or 45±5° Celsius.

[0183] In some embodiments, the compound of Formula K is a compound of Formula K-I:(Formula K-I).

[0184] In some embodiments, the compound of Formula K is a compound of Formula K-II:(Formula K-II).

[0185] In some embodiments, the compound of Formula J is a compound of Formula J-I:(Formula J-I).

[0186] In some embodiments the compound of Formula J is a compound of Formula J-II:(Formula J-II).

[0187] In some embodiments, the compound of Formula K is Compound 10: (Compound 10).

[0188] In some embodiments, the compound of Formula K is Compound 11:(Compound 11).

[0189] In some embodiments, the compound of Formula J is Compound 12:(Compound 12).

[0190] In some embodiments, the compound of Formula J is Compound 13:(Compound 13).

[0191] In some embodiments, the compound of Formula K is Compound 14:o pou ).

[0192] In some embodiments, the compound of Formula K is Compound 15:(Compound 15).

[0193] In some embodiments the compound of Formula J is Compound 16:(Compound 16).

[0194] In some embodiments, the compound of Formula J is Compound 17: (Compound 17).Scheme D, Step 2: Synthesis of a Compound of Formula I

[0195] As disclosed herein, a compound of Formula I is prepared from a compound of Formula J. In some embodiments, a compound of Formula J is contacted to a suitable halogenation reagent and a suitable organocatalyst in a suitable solvent to yield the compound of Formula I.

[0196] In some embodiments, the suitable halogenation reagent in Scheme D, Step 2 comprises a carbonyl halide. In some embodiments, the suitable halogenation reagent comprises an acid halide. In some embodiments, the suitable halogenation reagent is an acid chloride. In some embodiments, the suitable halogenation reagent is an acetyl halide, a benzoyl halide, an oxalyl halide, or the like. In some embodiments, the suitable halogenation reagent is acetyl chloride, benzoyl chloride, oxalyl chloride, or the like. In some embodiments, the suitable halogenation reagent is oxalyl chloride. In some embodiments, the suitable organocatalyst in Scheme D, Step 2 is a tertiary amide. In some embodiments, the suitable organocatalyst is N,N-dimethylformamide or N,N-dimethylacetamide. In some embodiments, the suitable organocatalyst is N,N- dimethylformamide. In some embodiments, the suitable solvent in Scheme D, Step 2 is dichloromethane or 1,2-dichloroethane. In some embodiments, the suitable solvent is dichloromethane.

[0197] In some embodiments, the amount of the suitable organocatalyst used in Scheme D,Step 2 is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1. 0.2, 0.3, 0.4, or 0.5 molarequivalents with respect to the compound of Formula J. In some embodiments, the amount of the suitable organocatalyst (e.g., N,N-dimethylformamide) used in Scheme D, Step 2 is about 0.05 molar equivalents with respect to the compound of Formula J. In some embodiments, the amount of the suitable organocatalyst (e.g., N,N-dimethylformamide) used in Scheme D, Step 2 is about 0.1 molar equivalents with respect to the compound of Formula J. In some embodiments, the amount of the suitable halogenation reagent used in Scheme D, Step 2 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula J. In some embodiments the amount of the suitable halogenation reagent (e g oxalyl chloride) usedin Scheme D, Step 2 is about 2.0 molar equivalents with respect to the compound of Formula J. In some embodiments, Scheme D, Step 2 is carried out at 30±5° Celsius. In some embodiments, Scheme D, Step 2 is carried out at 10±5° Celsius, 15±5° Celsius, 20±5° Celsius, 25±5° Celsius,30±5° Celsius, 35±5° Celsius, 40±5° Celsius, 45±5° Celsius, or 50±5° Celsius.

[0198] In some embodiments, the compound of Formula I is Compound 18:(Compound 18).

[0199] In some embodiments, the compound of Formula I is Compound 19:(Compound 19). Scheme D, Step 3: Synthesis of a Compound of Formula F

[0200] As disclosed herein, a compound of Formula F is prepared from a compound of Formula I. In some embodiments, a compound of Formula I is contacted to a suitable methylation reagent in a suitable solvent to yield the compound of Formula F.

[0201] In some embodiments, the suitable methylation reagent in Scheme D, Step 3 is methyllithium, a methylmagnesium halide, dimethylmagnesium, a methylcuprate salt, a methylzinc halide, dimethylzinc, or a solvate of any one thereof. In some embodiments, the suitable methylation reagent is a methylmagnesium halide or a solvate thereof. In some embodiments, the suitable methylation reagent is methylmagnesium chloride or a solvate thereof. In some embodiments, the suitable methylation reagent is methylmagnesium bromide or a solvate thereof. In some embodiments, the suitable solvent in Scheme D, Step 3 is tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, di(n-butyl) ether, methyl tert-butyl ether, 1,2-dimethoxyethane, or a combination thereof. In some embodiments, the suitable solvent is tetrahydrofuran. In some embodiments, the suitable methylation reagent is methylmagnesiumbromide or a solvate thereof and the suitable solvent is tetrahydrofuran.

[0202] In some embodiments, the amount of the suitable methylation reagent used in Scheme D, Step 3 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula I. In some embodiments, the amount of the suitable methylationreagent (e.g., methylmagnesium bromide) used in Scheme D, Step 2 is about 2.0 molar equivalents with respect to the compound of Formula I. In some embodiments, Scheme D, Step 3 is carried out at -25±10° Celsius. In some embodiments, Scheme D, Step 3 is carried out at - 45±5° Celsius, -40±5° Celsius, -35±5° Celsius, -30±5° Celsius, -35±5° Celsius, -20±5° Celsius, - 15±5° Celsius, -10±5° Celsius, or -5±5° Celsius.

[0203] In some embodiments, the compound of Formula F is Compound 20:(Compound 20).

[0204] In some embodiments, the compound of Formula F is Compound 21: Sc

[0205] As disclosed herein, Compound E is prepared from a compound of Formula F. In some embodiments, a compound of Formula F is contacted to a suitable to a suitable deprotection reagent in a suitable solvent to yield Compound E.

[0206] In some embodiments, the suitable deprotection reagent of Scheme D, Step 4 is a trimethylsilyl halide, hydrochloric acid, hydrobromic acid, hydroiodic acid, or a combination of a boron trihalide and an organosulfide. In some embodiments, the suitable deprotection reagent is trimethylsilyl iodide, hydrobromic acid, or a combination of a boron trihalide and an organosulfide. In some embodiments, the suitable deprotection reagent is a combination of a boron trihalide and an organosulfide. In some embodiments, the boron trihalide is boron trichloride, boron tribromide, or boron triiodide. In some embodiments, the organosulfide is a dialkylsulfide or a monoalkyl aryl sulfide. In some embodiments, the suitable deprotection reagent is a combination of boron trichloride and di(n-butyl)sulfide. In some embodiments, the suitable deprotection reagent is a combination of boron tribromide and di(n-butyl)sulfide. In some embodiments, the suitable deprotection reagent is a combination of boron trichloride and tetrahydrothiophene. In some embodiments, the suitable deprotection reagent is a combination ofboron tribromide and tetrahydrothiophene. In some embodiments, the suitable solvent in Scheme D, Step 4 is acetonitrile, benzonitrile, or the like. In some embodiments, the suitable solvent is acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent is acetonitrile. In some embodiments, the suitable solvent is toluene.

[0207] In some embodiments, the amount of the boron trihalide used in Scheme D, Step 4 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula F. In some embodiments, the amount of the boron trihalide (e.g., boron tribromide) used in Scheme D, Step 4 is about 1.5 molar equivalents with respect to the compound of Formula F. In some embodiments, the amount of the organosulfide used in Scheme D, Step 4 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula F. In some embodiments, the amount of the organosulfide (e.g., tetrahydrothiophene, di(n-butyl) sulfide) used in Scheme D, Step 4 is about 1.5 molar equivalents with respect to the compound of Formula F. In some embodiments, Scheme D, Step 4 is carried out at 60±5° Celsius. In some embodiments, Scheme D, Step 4 is carried out at 70±5° Celsius. In some embodiments, Scheme D, Step 4 is carried out at 40±5° Celsius, 45±5° Celsius, 50±5° Celsius, 55±5° Celsius, 60±5° Celsius, 65±5° Celsius, 70±5° Celsius, 75±5° Celsius, or 80±5° Celsius.

[0208] In some embodiments, the compound of Formula F is Compound 20. Sc

[0209] As disclosed herein, a compound of Formula H is prepared from a compound of Formula F. In some embodiments, a compound of Formula F is contacted to a suitable to a suitable hydrogen source and a suitable hydrogenation catalyst in a suitable solvent to yield a compound of Formula H.

[0210] In some embodiments, the suitable hydrogen source in Scheme D, Step 5 is dihydrogen (H2) or ammonium formate. In some embodiments, the suitable hydrogen source is dihydrogen. In some embodiments, the suitable hydrogenation catalyst in Scheme D, Step 5 is palladium on carbon (Pd / C) or platinum on carbon (Pt / C). In some embodiments, the suitable hydrogenation catalyst is palladium on carbon. In some embodiments, the suitable hydrogenation catalyst is platinum on carbon. In some embodiments, the weight percentage (i.e., % w / w) of palladium in the palladium on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, aboutembodiments, the weight percentage (i.e., % w / w) of platinum in the platinum on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the suitable solvent in Scheme D, Step 5 is methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable hydrogen source is dihydrogen; the suitable hydrogenation catalyst is palladium on carbon; and the suitable solvent is ethanol.

[0211] In some embodiments, the amount of the suitable hydrogenation catalyst used in Scheme D, Step 5 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments of Scheme D, Step 5, a molar excess of the suitable hydrogen source with respect to the quantity of the compound of Formula F is used. In some embodiments of Scheme D, Step 5, the suitable hydrogen source is dihydrogen at a pressure of about 0.5 MPa, 0.75 MPa, 1.0 MPa, 1.5 MPa, 2.0 MPa, 2.2 MPa, 2.5 MPa, 3.0 MPa, 3.5 MPa, 4.0 MPa, 4.5 MPa, or 5.0 MPa. In some embodiments, Scheme D, Step 5 is carried out at about 20° Celsius. In some embodiments, Scheme D, Step 5 is carried out at 20±5° Celsius. In some embodiments, Scheme D, Step 5 is carried out at 0±5° Celsius, 5±5° Celsius, 10±5° Celsius, 15±5° Celsius,20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, or 40±5° Celsius.

[0212] In some embodiments, the compound of Formula F is Compound 21.

[0213] In some embodiments, the compound of Formula H is Compound 7. Sc

[0214] As disclosed herein, Compound E is prepared from a compound of Formula H. In some embodiments, a compound of Formula H is contacted to a suitable to a suitable base in a suitable solvent to yield Compound E.

[0215] In some embodiments, the suitable base in Scheme D, Step 6 is a hydroxide base. In some embodiments, the hydroxide base is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide. In some embodiments, the suitable base is sodium hydroxide or potassium hydroxide. In some embodiments, the suitable solvent in Scheme D, Step 6 is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane,alcohol, water, methanol, ethanol, isopropanol, tert-butanol, n-butanol, or a combination thereof.In some embodiments, the suitable solvent is water, methanol, ethanol, or a combination thereof.

[0216] In some embodiments, the amount of the suitable base used in Scheme D, Step 6 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 molar equivalents with respect to the compound of Formula H. In some embodiments, the amount of the suitable base (e.g., sodium hydroxide, potassium hydroxide) used in Scheme D, Step 6 is more than 10.0 molar equivalents with respect to the compound of Formula H. In some embodiments, the amount of the suitable base (e.g., sodium hydroxide, potassium hydroxide) used in Scheme D, Step 6 is about 6.0 molar equivalents with respect to the compound of Formula H. In some embodiments, Scheme D, Step 6 is carried out at 20±5° Celsius. In some embodiments, Scheme D, Step 6 is carried out at 70±5° Celsius. In some embodiments, Scheme D, Step 6 is carried out at 80±5° Celsius. In some embodiments, Scheme D, Step 6 is carried out at 90±5° Celsius. In some embodiments, Scheme D, Step 6 is carried out at 40±5° Celsius, 45±5° Celsius, 50±5° Celsius, 50±5° Celsius, 60±5° Celsius, 65±5° Celsius, 70±5° Celsius, 75±5° Celsius, 80±5° Celsius, 85±5° Celsius, 90±5° Celsius, 95±5° Celsius, or 100±5° Celsius.

[0217] In some embodiments, the compound of Formula H is Compound 22:). Synthesis of a Compound of Formula K

[0218] Disclosed herein are methods for the synthesis of a compound of Formula K as outlined in Scheme E. In some embodiments, the compound of Formula K is as defined in Scheme D. In some embodiments, the compound of Formula K is a compound of Formula K-I. In some embodiments, the compound of Formula K is a compound of Formula K-II. Scheme E

[0219] As disclosed herein, variables in Scheme E are defined as follows: PG1is a suitable protecting group; PG2is a suitable protecting group; Z is a suitable leaving group; R1is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle; and M1is a suitable group comprising a metal ion. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In some embodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2-trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2-trifluoroethyl. In some embodiments, PG2is C1-10alkyl, C7-10ara-alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG2is C1-6alkyl or C7-10ara-alkyl. In some embodiments, PG2is C1-10alkyl. In some embodiments, PG2is C1-6alkyl. In some embodiments, PG2is C7-10ara-alkyl. In some embodiments, PG2is C7-8ara-alkyl. In some embodiments, PG2is methyl or benzyl. In some embodiments, PG2is methyl. In some embodiments, PG2is benzyl. In some embodiments, R1Ais identical to PG1. In some embodiments, R1Ais identical to each R2. In some embodiments, R1Ais C1-10alkyl or C1-10fluoroalkyl. In some embodiments, R1Ais C1-6alkyl. In some embodiments, R1Ais identical to PG1. In some embodiments, R1Aand PG1are each ethyl and PG2is benzyl. In some embodiments, R1Aand PG1are each ethyl and PG2is methyl. In some embodiments, R1Aand PG1are each 2,2,2-trifluoroethyl and PG2is benzyl. In some embodiments, R1Aand PG1are each 2,2,2-trifluoroethyl and PG2is methyl. In some embodiments, Z is halogen. In some embodiments, Z is fluoro, chloro, bromo, or iodo. In some embodiments, Z is chloro or bromo. In some embodiments, Z is chloro. In some embodiments, M1comprises magnesium or zinc. In some embodiments, M1comprises magnesium. In some embodiments, M1comprises zinc. In some embodiments, M1comprises magnesium and halogen. In some embodiments, M1comprises zinc and halogen. In some embodiments, M1is MgCl, MgBr, MgI, ZnCl, ZnBr, or ZnI. In some embodiments, M1is MgCl, MgBr, or MgI. In some embodiments, M1is ZnCl, ZnBr, or ZnI. In some embodiments, M1is MgBr.Scheme E, Step 1: Synthesis of a compound of Formula K-II

[0220] As disclosed herein, a compound of Formula L is prepared from a compound of Formula N and a compound of Formula O. In some embodiments, a compound of Formula N is contacted to compound of Formula O in a suitable solvent to yield a compound of Formula L.

[0221] In some embodiments, for the compound of Formula N in Scheme E, Step 1 M1is MgCl, MgBr, MgI, ZnCl, ZnBr, or ZnI; and for the compound of Formula O in Scheme E, Step 1 Z is halogen. In some embodiments, M1is MgCl, MgBr, or MgI; and Z is Cl or Br. In some embodiments, M1is MgBr and Z is Cl. In some embodiments, Scheme E, Step 1 further comprises contacting a suitable copper catalyst to the compound of Formula N and the compound of Formula O in a suitable solvent. In some embodiments, M1is ZnCl, ZnBr, or ZnI; and Scheme E, Step 1 further comprises contacting a suitable copper catalyst to the compound of Formula N and the compound of Formula O in a suitable solvent. In some embodiments, the suitable copper catalyst comprises copper cyanide. In some embodiments, the suitable copper catalyst comprises copper cyanide and a lithium halide. In some embodiments, the suitable copper catalyst is CuCN • 2(LiCl). In some embodiments, the suitable solvent of Scheme E, Step 1 is N-methyl-2- pyrrolidine, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dibutyl ether, diethyl ether, toluene, or a combination thereof. In some embodiments, the suitable solvent is N- methyl-2-pyrrolidine, toluene, or a combination thereof. In some embodiments, the suitable solvent is a combination of N-methyl-2-pyrrolidine and toluene.

[0222] In some embodiments of Scheme E, Step 1, the molar ratio of the amount of the compound of Formula N used to the amount of the compound of Formula O used is about 0.1:1,0.2:1, 0.3:1. 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 , 1:1, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4,1:0.3, 1:0.2, or 1:0.1. In some embodiments of Scheme E, Step 1, the molar ratio of the amount of the compound of Formula N (e.g., wherein M1is MgBr) used to the amount of the compound of Formula O (e.g., wherein Z is Cl) is about 1:0.5. In some embodiments of Scheme E, Step 1, the molar ratio of the amount of the compound of Formula N (e.g., wherein M1is MgBr) used to the amount of the compound of Formula O (e.g., wherein Z is Cl) is about 1:1.8. In some embodiments, Scheme D, Step 6 is carried out at 80±10° Celsius. In some embodiments, Scheme E Step 1 is carried out at 0±5° Celsius In some embodiments Scheme E Step 1 is carried out at-20±5° Celsius, -15±5° Celsius, -10±5° Celsius, -5±5° Celsius, 0±5° Celsius, 5±5° Celsius, 10±5° Celsius, 15±5° Celsius, or 20±5° Celsius.

[0223] In some embodiments, the compound of Formula N is Compound 23: (Compound 23).

[0224] In some embodiments, the compound of Formula N is Compound 24:(Compound 24).

[0225] In some embodiments, the compound of Formula O is Compound 25:(Compound 25).

[0226] In some embodiments, the compound of Formula L is Compound 26:(Compound 26).

[0227] In some embodiments, the compound of Formula L is Compound 27: Sc

[0228] As disclosed herein, a compound of Formula K-II is prepared from a compound of Formula L. In some embodiments, a compound of Formula L is contacted to a suitable olefination reagent in a suitable solvent to yield a compound of Formula K-II. In some embodiments, a compound of Formula L is subjected to a Horner-Wadsworth-Emmons reaction to yield a compound of Formula K-II.

[0229] In some embodiments, the suitable olefination reagent in Scheme E, Step 2 is generated by contacting a compound of Formula M to a suitable base in the suitable solvent: (Formula M).

[0230] In some embodiments of a compound of Formula M, each R2is independently selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R2is identical to PG1. In some embodiments, each R2is identical to R1A. In some embodiments, each R2is identical to PG1and R1A. In some embodiments, each R2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, each R2is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, each R2is C1-10alkyl. In some embodiments, each R2is C1-6alkyl. In some embodiments, each R2is C1-10fluoroalkyl. In some embodiments, each R2is C1-6fluoroalkyl. In some embodiments, each R2is ethyl or 2,2,2- trifluoroethyl. In some embodiments, each R2is ethyl. In some embodiments, each R2is 2,2,2- trifluoroethyl.

[0231] In some embodiments, the suitable olefination reagent of Scheme E, Step 2 is generated by contacting a compound of Formula M to a suitable base selected from an organolithium reagent and an amide base. In some embodiments, the suitable base is selected from an organolithium reagent, such as n-butyllithium or the like. In some embodiments, the suitable base is an amide base. In some embodiments, the amide base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In some embodiments, the amide base is lithium diisopropylamide.

[0232] In some embodiments, the suitable solvent of Scheme E, Step 2 is 1,4-dioxane, tetrahydrofuran, hexanes, or a combination thereof. In some embodiments, the suitable solvent is 1,4-dioxane. In some embodiments, the suitable solvent is a combination of 1,4-dioxane, toluene, tetrahydrofuran, and hexanes. In some embodiments, the suitable solvent is a combination of 1,4- dioxane, tetrahydrofuran, and hexanes.

[0233] In some embodiments, the amount of the suitable olefination reagent used in Scheme E, Step 2 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula L. In some embodiments, the amount of the suitable olefination reagent used in Scheme E, Step 2 is about 2.0 molar equivalents with respect to the compound of Formula L. In some embodiments, the amount of the compound of Formula M used in Scheme E, Step 2 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula L. In some embodiments, the amount of the compound of Formula M used in Scheme E Step 2 is about 20 molar equivalents with respect to the compound ofFormula L. In some embodiments, the amount of the suitable base used in Scheme E, Step 2 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, or 4.0 molar equivalents with respect to the compound of Formula L. In some embodiments, the amount of the suitable base (e.g., lithium diisopropylamide) used in Scheme E, Step 2 is about 2.0 molar equivalents with respect to the compound of Formula L. In some embodiments, Scheme E, Step 2 is carried out at 95±5° Celsius. In some embodiments, Scheme E, Step 2 is carried out at 75±5° Celsius, 80±5° Celsius, 85±5° Celsius, 90±5° Celsius, 95±5° Celsius, 100±5° Celsius, 105±5° Celsius, 110±5° Celsius, or 115±5° Celsius.

[0234] In some embodiments, the compound of Formula M is Compound 28:(Compound 28).

[0235] In some embodiments, the suitable olefination reagent of Scheme E, Step 2 is generated by contacting Compound 28 to lithium diisopropylamide in 1,4-dioxane, tetrahydrofuran, hexanes, or a combination thereof.

[0236] In some embodiments, the compound of Formula L is Compound 26. In some embodiments, the compound of Formula L is Compound 27. In some embodiments, the compound of Formula K-II is Compound 11. In some embodiments, the compound of Formula K-II is Compound 15. Scheme E, Step 3: Synthesis of a compound of Formula K-I

[0237] As disclosed herein, a compound of Formula K-I is prepared from a compound of Formula K-I. In some embodiments, a compound of Formula K-II is contacted to a suitable base in a suitable solvent to yield a compound of Formula K-I.

[0238] In some embodiments, the suitable base in Scheme E, Step 3 is a hydroxide base. Insome embodiments the hydroxide base is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide. In some embodiments, the suitable base is sodium hydroxide. In some embodiments, the suitable solvent of Scheme E, Step 3 is methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol, water, or a combination thereof. In some embodiments, the suitable solvent is methyl tert-butyl ether, 1,4-dioxane toluene tetrahydrofuran hexanes or a combination thereof

[0239] In some embodiments, the amount of the suitable base used in Scheme E, Step 3 is about 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 molar equivalents with respect to the compound of Formula K-II. In some embodiments, the amount of the suitable base (e.g., sodium hydroxide, potassium hydroxide) used in Scheme E, Step 3 is more than 10.0 molar equivalents with respect to the compound of Formula K-II. In some embodiments, the amount of the suitable base (e.g., sodium hydroxide, potassium hydroxide) used in Scheme E, Step 3 is about 6.0 molar equivalents with respect to the compound of Formula K-II. In some embodiments, Scheme D, Step 6 is carried out at 20±5° Celsius. In some embodiments, Scheme E, Step 3 is carried out at 70±5° Celsius. In some embodiments, Scheme E, Step 3 is carried out at 80±5° Celsius. In some embodiments, Scheme E, Step 3 is carried out at 90±5° Celsius. In some embodiments, Scheme E, Step 3 is carried out at 40±5° Celsius, 45±5° Celsius, 50±5° Celsius, 50±5° Celsius, 60±5° Celsius, 65±5° Celsius, 70±5° Celsius, 75±5° Celsius, 80±5° Celsius, 85±5° Celsius, 90±5° Celsius, 95±5° Celsius, or 100±5° Celsius.

[0240] In some embodiments, the compound of Formula K-II is Compound 11. In some embodiments, the compound of Formula K-II is Compound 15. In some embodiments, the compound of Formula K-I is Compound 10. In some embodiments, the compound of Formula K-I is Compound 14. First Alternative Synthesis of Compound D

[0241] Disclosed herein are methods for the synthesis of Compound D as outlined in Scheme F. Scheme FScheme F, Step 1: Synthesis of Compound T

[0242] As disclosed herein, Compound T is prepared from Compound U. In some embodiments, Compound U is contacted to a suitable aryl alkyl sulfone and a suitable base in a suitable solvent to yield Compound T.

[0243] In some embodiments, the suitable aryl alkyl sulfone in Scheme F, Step 1 comprises a 2-((3,3-dimethylbutyl)sulfonyl group bound to an aryl group. In some embodiments, the aryl group is benzo[d]thiazole. In some embodiments, the suitable aryl alkyl sulfone is 2-((3,3- dimethylbutyl)sulfonyl)benzo[d]thiazole. In some embodiments, the suitable base in Scheme F, Step 1 is an amide base. In some embodiments, the amide base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In some embodiments, the suitable base is lithium bis(trimethylsilyl)amide. In some embodiments, the suitable solvent in Scheme F, Step 1 is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, diethyl ether, di(n-butyl) ether, methyl tert-butyl ether, hexanes, or a combination thereof. In some embodiments, the suitable solvent is tetrahydrofuran.

[0244] In some embodiments, the amount of the suitable aryl alkyl sulfone used in Scheme F, Step 1 is about 0.9, 1.1, 1.2, 1.3, 1.4, or 1.5 molar equivalents with respect to the amount of Compound U. In some embodiments, the amount of the suitable aryl alkyl sulfone used in Scheme F, Step 1 is about 1.15 molar equivalents with respect to the amount of Compound U. In some embodiments, the amount of the suitable base used in Scheme F, Step 1 is about 0.9, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents with respect to the amount of Compound U. In some embodiments, the amount of the suitable base (e.g, LiHMDS) used in Scheme F, Step 1 is about 1.60 molar equivalents with respect to the amount of Compound U. In some embodiments, Scheme F, Step 1 is carried out between about -20 to about 45° Celsius. In some embodiments, Scheme F, Step 1 is carried out between about -40 to about 65° Celsius.Scheme F, Step 2: Synthesis of Compound S

[0245] As disclosed herein, Compound S is prepared from Compound T. In some embodiments, Compound T is contacted to a suitable hydrogen source and a suitable hydrogenation catalyst in a suitable solvent to yield Compound S.

[0246] In some embodiments, the suitable hydrogen source in Scheme F, Step 2 is dihydrogen (H2) or ammonium formate. In some embodiments, the suitable hydrogen source is dihydrogen. In some embodiments, the suitable hydrogenation catalyst in Scheme F, Step 2 is palladium on carbon (Pd / C) or platinum on carbon (Pt / C). In some embodiments, the suitable hydrogenation catalyst is palladium on carbon. In some embodiments, the suitable hydrogenation catalyst is platinum on carbon. In some embodiments, the weight percentage (i.e., % w / w) of palladium in the palladium on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the weight percentage (i.e., % w / w) of platinum in the platinum on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the suitable solvent in Scheme F, Step 2 is tetrahydrofuran, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tert- amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol, water, or a combination thereof. In some embodiments, the suitable solvent is tetrahydrofuran. In some embodiments, the suitable hydrogen source is dihydrogen; the suitablehydrogenation catalyst is palladium on carbon; and the suitable solvent is tetrahydrofuran.

[0247] In some embodiments, the amount of the suitable hydrogenation catalyst used in Scheme F, Step 2 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5 molar equivalents with respect to the amount of Compound T. In some embodiments of Scheme F, Step 2, a molar excess of the suitable hydrogen source with respect to the quantity of Compound T is used. In some embodiments of Scheme F, Step 2, the suitable hydrogen source is dihydrogen at a pressure of about 0.1 MPa, 0.2, MPa, 0.3, MPa, 0.4 MPa, 0.5 MPa, 0.75 MPa, 1.0 MPa, 1.5 MPa, 2.0 MPa, 2.2 MPa, 2.5 MPa, 3.0 MPa, 3.5 MPa, 4.0 MPa, 4.5 MPa, or 5.0 MPa. In some embodiments of Scheme F, Step 2, the suitable hydrogen source is dihout at about 40° Celsius. In some embodiments, Scheme F, Step 2 is carried out at 40±5° Celsius. In some embodiments, Scheme F, Step 2 is carried out at 20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, 40±5° Celsius, 45±5° Celsius, 50±5° Celsius, 55±5° Celsius, or 60±5° Celsius. Scheme F, Step 3: Synthesis of Compound D

[0248] As disclosed herein, Compound D is prepared from Compound S. In some embodiments, Compound S is contacted to a suitable borohydride reagent in a suitable solvent to yield Compound D.

[0249] In some embodiments, the suitable borohydride reagent in Scheme F, Step 3 comprises borohydride or an alkyl borohydride. In some embodiments, the suitable borohydride reagent is lithium borohydride, sodium borohydride, potassium borohydride, or lithium triethylborohydride. In some embodiments, the suitable borohydride reagent is lithium borohydride. In some embodiments, the suitable solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, di(n-butyl) ether, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent is tetrahydrofuran.

[0250] In some embodiments, the amount of the suitable borohydride reagent used in Scheme F, Step 3 is about 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents with respect to the amount of Compound S. In some embodiments, the amount of the suitable borohydride reagent used in Scheme F, Step 3 is about 1.2 molar equivalents with respect to the amount of Compound S. In some embodiments, Scheme F, Step 3 is carried out at about 35° Celsius. In some embodiments, Scheme F, Step 3 is carried out at 35±5° Celsius. In some embodiments, Scheme F, Step 3 is carried out at 20±5° Celsius, 25±5° Celsius, 30±5° Celsius,35±5° Celsius, 40±5° Celsius, 45±5° Celsius, 50±5° Celsius, 55±5° Celsius, or 60±5° Celsius.Second Alternative Synthesis of Compound D

[0251] Disclosed herein are methods for the synthesis of Compound D as outlined in Scheme G.Scheme G Sc

[0252] As disclosed herein, Compound X is prepared from Compound W. In some embodiments, Compound W is contacted to a suitable organometallic reagent in a suitable solvent to yield Compound X.

[0253] In some embodiments, the suitable organometallic reagent in Scheme G, Step 1 comprises a 3,3-dimethylbut-1-yn-1-yl anion bound to a metal center. In some embodiments, the metal center is lithium, magnesium, copper, or zinc. In some embodiments, the metal center is lithium or magnesium. In some embodiments, the metal center is magnesium. In some embodiments, the suitable organometallic reagent is a (3,3-dimethylbut-1-yn-1-yl)magnesium halide. In some embodiments, the suitable organometallic reagent is (3,3-dimethylbut-1-yn-1- yl)magnesium chloride. In some embodiments, the suitable organometallic reagent is provided by contacting 3,3-dimethylbut-1-yne to a suitable Grignard reagent. In some embodiments, the suitable Grignard reagent is an isopropylmagnesium halide In some embodiments the suitableGrignard reagent is isopropylmagnesium chloride. In some embodiments, the suitable solvent of Scheme G, Step 1 is tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, di(n-butyl) ether, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent is tetrahydrofuran. Scheme G, Step 2: Synthesis of Compound Y and Compound Y'

[0254] As disclosed herein, Compound Y and Compound Y' are prepared from Compound X. In some embodiments, Compound X is contacted to a suitable boron halide reagent and a suitable silane in a suitable solvent to yield Compound Y and Compound Y'.

[0255] In some embodiments, the suitable boron halide reagent in Scheme G, Step 2 is boron trifluoride, boron trichloride, boron tribromide, or an adduct thereof. In some embodiments, the suitable boron halide reagent is boron trifluoride or an adduct thereof. In some embodiments, the suitable boron halide reagent is boron trifluoride diethyl ether adduct (i.e., boron trifluoride diethyl etherate). In some embodiments, the suitable silane in Scheme G, Step 2 is a mono(alkyl) silane, a di(alkyl) silane, or a tri(alkyl) silane. In some embodiments, the suitable silane is a tri(alkyl) silane. In some embodiments, the suitable silane is triethyl silane. In some embodiments, the suitable boron halide reagent is boron trifluoride diethyl ether adduct and the suitable silane is triethyl silane. In some embodiments, the suitable solvent in Scheme G, Step 2 is dichloromethane or 1,2-dichloroethane. In some embodiments, the suitable solvent is dichloromethane.

[0256] In some embodiments, Scheme G, Step 2 yields a greater quantity of Compound Y than Compound Y'. In some embodiments, Compound Y and Compound Y' are isolated as a mixture. In some embodiments, Compound Y and Compound Y' are isolated as a mixture, wherein said mixture is used in a subsequent step (e.g., in Scheme G, Step 3). In some embodiments, Compound Y is separated from Compound Y', wherein Compound Y is used in a subsequent step (e.g., in Scheme G, Step 3). In some embodiments, Compound Y' is separated from Compound Y, wherein Compound Y' is used in a subsequent step (e.g., in Scheme G, Step 3).Scheme G, Step 3: Synthesis of Compound D

[0257] As disclosed herein, Compound D is prepared from Compound Y and Compound Y'. In some embodiments, Compound Y and Compound Y' are contacted to a suitable hydrogen source and a suitable hydrogenation catalyst in a suitable solvent to yield Compound Y and Compound Y'. In some embodiments, Compound Y is used in place of Compound Y and Compound Y'. In some embodiments, Compound Y' and / or a geometric isomer thereof is used in place of Compound Y and Compound Y'.

[0258] In some embodiments, the suitable hydrogen source in Scheme G, Step 3 is dihydrogen(H2) or ammonium formate. In some embodiments, the suitable hydrogen source is dihydrogen .In some embodiments, the suitable hydrogenation catalyst in Scheme G, Step 3 is palladium on carbon (Pd / C) or platinum on carbon (Pt / C). In some embodiments, the suitable hydrogenation catalyst is palladium on carbon. In some embodiments, the suitable hydrogenation catalyst is platinum on carbon. In some embodiments, the weight percentage (i.e., % w / w) of palladium in the palladium on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the weight percentage (i.e., % w / w) of platinum in the platinum on carbon is about 20%, about 10%, about 5%, about 1%, about 0.75%, about 0.5%, about 0.1% about 0.05%, about 0.01%, about 0.005%, or about 0.001%. In some embodiments, the suitable solvent in Scheme G, Step 3 is dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tert-amyl alcohol, water, or a combination thereof. In some embodiments, the suitable solvent is ethanol, water, or a combination thereof. In some embodiments, thesuitable solvent is dichloromethane, toluene, or a combination thereof. In some embodiments, thesuitable hydrogen source is dihydrogen; the suitable hydrogenation catalyst is palladium oncarbon; and the suitable solvent is dichloromethane, toluene, or a combination thereof.Alternative Synthesis of a Compound of Formula F

[0259] Disclosed herein are methods for the synthesis of a compound of Formula F as outlined in Scheme H.Scheme H

[0260] As disclosed herein, variables in Scheme H are defined as follows: PG1is a suitable protecting group; and PG2is a suitable protecting group. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10- membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In some embodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2-trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2-trifluoroethyl. In some embodiments, PG2is C1-10alkyl, C7-10ara-alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG2is C1-6alkyl or C7-10ara-alkyl. In some embodiments, PG2is C1-10alkyl. In some embodiments, PG2is C1-6alkyl. In some embodiments, PG2is C7-10ara-alkyl. In some embodiments, PG2is C7-8ara-alkyl. In some embodiments, PG2is methyl or benzyl. In some embodiments, PG2is methyl. In some embodiments, PG2is benzyl. Sc

[0261] As disclosed herein, a compound of Formula Z is prepared from a compound of Formula L. In some embodiments, a compound of Formula L is contacted to a suitable olefination reagent in a suitable solvent to yield a compound of Formula Z.

[0262] In some embodiments, the suitable olefination reagent in Scheme H, Step 1 is generated by contacting a compound of Formula M' to a suitable base in the suitable solvent: (Formula M')

[0263] In some embodiments of a compound of Formula M', each R2is independently selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle; and R3is methyl or -OR2. In some embodiments, R3is methyl. In some embodiments, R3is -OR2. In some embodiments, each R2is identical to PG1. In some embodiments, each R2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, each R2is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, each R2is C1-10alkyl. In some embodiments, each R2is C1-6alkyl. In some embodiments, each R2is C1-10fluoroalkyl. In some embodiments, each R2is C1-6fluoroalkyl. In some embodiments, each R2is ethyl or 2,2,2- trifluoroethyl. In some embodiments, each R2is ethyl. In some embodiments, each R2is 2,2,2- trifluoroethyl.

[0264] In some embodiments, the suitable olefination reagent of Scheme H, Step 1 is generated by contacting a compound of Formula M' to a suitable base selected from an organolithium reagent and an amide base. In some embodiments, the suitable base is selected from an organolithium reagent, such as n-butyllithium or the like. In some embodiments, the suitable base is an amide base. In some embodiments, the amide base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In some embodiments, the amide base is lithium diisopropylamide.

[0265] In some embodiments, the suitable solvent of Scheme H, Step 1 is 1,4-dioxane, tetrahydrofuran, hexanes, or a combination thereof. In some embodiments, the suitable solvent is1,4-dioxane. In some embodiments, the suitable solvent is a combination of 1,4 -dioxane,tetrahydrofuran, and hexanes.

[0266] In some embodiments, the compound of Formula M' is Compound 29:(Compound 29).

[0267] In some embodiments the compound of Formula M' is Compound 30:(Compound 30).

[0268] In some embodiments, the suitable olefination reagent of Scheme E, Step 2 is generated by contacting Compound 29 or Compound 30 to lithium diisopropylamide in 1,4-dioxane, tetrahydrofuran, hexanes, or a combination thereof.

[0269] In some embodiments, the compound of Formula L is Compound 26. In some embodiments, the compound of Formula L is Compound 27.

[0270] In some embodiments, the compound of Formula Z is Compound 31:(Compound 31).

[0271] In some embodiments, the compound of Formula Z is Compound 32: Sc

[0272] As disclosed herein, a compound of Formula F is prepared from a compound of Formula Z. In some embodiments, a compound of Formula Z is contacted to a suitable hydrogen source and a suitable metal catalyst in a suitable solvent to yield the compound of Formula F. In some embodiments, the suitable metal catalyst in Scheme H, Step 2 is generated by combining a suitable ligated metal salt with a suitable chiral phosphine ligand.

[0273] In some embodiments, the suitable hydrogen source in Scheme H, Step 2 is dihydrogen (H2), hydrazine, dihydronaphthalene, dihydroanthracene, isopropanol, ammonium formate, or formic acid. In some embodiments, the suitable hydrogen source is dihydrogen. In some embodiments, the suitable ligated metal salt comprises rhodium. In some embodiments, the suitable ligated metal salt comprises a rhodium-olefin complex. In some embodiments, the suitable ligated metal salt is [(norbornadiene)RhCl]2, [(norbornadiene)RhBr]2, [(norbornadiene)RhI]2, [(1,5-cyclooctadiene)RhCl]2, [(1,5-cyclooctadiene)RhBr]2, [(1,5- cyclooctadiene)RhI]2, [(1,5-cyclooctadiene)2Rh] tetrafluoroborate, [(1,5-cyclooctadiene)2Rh] tetraphenylborate, [(1,5-cyclooctadiene)2Rh] hexafluorophosphate, [(norbornadiene)2Rh] tetrafluoroborate, [(norbornadiene)2Rh] tetraphenylborate, [(norbornadiene)2Rh]hexafluorophosphate, or the like. In some embodiments, the suitable ligated metal salt is [(norbornadiene)RhCl]2, [(1,5-cyclooctadiene)RhCl]2, or [(1,5-cyclooctadiene)2Rh] tetrafluoroborate. In some embodiments, the suitable chiral phosphine ligand is axially chiral. In some embodiments, the suitable chiral phosphine ligand comprises at least one stereogenic center. In some embodiments, only a single enantiomer of the chiral phosphine ligand is used in Scheme H, Step 2. In some embodiments, the chiral phosphine ligand has at least 90% enantiomeric purity. In some embodiments, the chiral phosphine ligand has at least 95% enantiomeric purity. In some embodiments, the chiral phosphine ligand has at least 99% enantiomeric purity. In some embodiments, the suitable chiral phosphine ligand comprises a substituted ferrocene. In some embodiments, the suitable chiral phosphine ligand comprises a substituted 1,3-benzodioxole. In some embodiments, the suitable chiral phosphine ligand is (S)- (+)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole ((S)- DTBM-SEGPHOS®; CAS No.210169-40-7), I-(+)-1-[(Rp)-2’(2'- dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine (Walphos SL-W008-1; CAS No.821009-34-1), (R)-1-[(R)-1-[bis[3,5- bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (Walphos SL-W001-1; CAS No.565184-33-0), or (1S)-1-[bis(1,1-dimethylethyl)phosphino]-2- [(1S)-1-(diphenylphosphino)ethyl]ferrocene (JosiPhos SL-J502-2; CAS No.223121-01-5). In some embodiments, the suitable solvent in Scheme H, Step 2 is methanol, dichloromethane, or a combination thereof. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is dichloromethane.

[0274] In some embodiments, Scheme H, Step 2 provides the compound of Formula H in at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% enantiomeric purity. In some embodiments, the amount of the suitable metal catalyst used in Scheme H, Step 2 is about 0.001, 0.005, 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments, the amount of thesuitable ligated metal salt used in Scheme H, Step 2 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments, the amount of the suitable chiral phosphine used in Scheme H, Step 2 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv. In some embodiments, the amount of the suitable metal catalyst used in Scheme H, Step 2 is about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 equiv.

[0275] In some embodiments, the compound of Formula Z is Compound 31. In some embodiments, the compound of Formula Z is Compound 32. In some embodiments, the compound of Formula F is Compound 20. In some embodiments, the compound of Formula F is Compound 21Alternative Synthesis of a Compound of Formula G

[0276] Disclosed herein are methods for the synthesis of a compound of Formula G as outlined in Scheme I. Scheme I

[0277] As disclosed herein, variables in Scheme I are defined as follows: PG1is a suitable protecting group. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In some embodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2-trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2-trifluoroethyl.

[0278] As disclosed herein, a compound of Formula G is prepared from a compound of Formula H. In some embodiments, a compound of Formula H and Compound D to a suitable azoreagent and a suitable phosphine in a suitable solvent to yield the compound of Formula G. Insome embodiments, a compound of Formula H and Compound D are subjected to a Mitsunobu reaction to yield the compound of Formula G.

[0279] In some embodiments, the suitable azo reagent in Scheme I, Step 1 is a tetraalkylazodicarboxamide, a dialkylazodicarboxylate, a diarylazodicarboxylate, or the like. In some embodiments, the suitable azo reagent is dimethylazodicarboxylate,diethylazodicarboxylate, diisopropylazodicarboxylate, dibenzylazodicarboxylate, di(4 -chlorobenzyl)azodicarboxylate, di(tert-butyl)azodicarboxylate, diphenylazodicarboxylate, tetramethylazodicarboxamide, tetraethylazodicarboxamide, or 1,1′-(azodicarbonyl)dipiperidine. In some embodiments, the suitable azo reagent is tetramethylazodicarboxamide. In some embodiments, the suitable phosphine in Scheme I, Step 1 is a trialkylphosphine or a triarylphosphine. In some embodiments, the suitable phosphine is trimethylphosphine,triethylphosphine, tripropylphosphine, triisopropylphosphine, tri(n -butyl)phosphine, tri(tert-butyl)phosphine, or triphenylphosphine. In some embodiments, the suitable phosphine is tri(n -butyl)phosphine or triphenylphosphine. In some embodiments, the suitable phosphine is tri(n -butyl)phosphine. In some embodiments, the suitable solvent in Scheme I, Step 1 is ethyl acetate, diethyl ether, di(n-butyl) ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent is ethyl acetate.

[0280] In some embodiments, the compound of Formula H is Compound 7. In some embodiments, the compound of Formula G is Compound 9. Method for Increasing the Enantiomeric Purity of a Compound of Formula J-I

[0281] Disclosed herein is a method for increasing the enantiomeric purity of a compound of Formula J-I, the method comprising: a) contacting the compound of Formula J-I:); wherein PG1and PG2are each independently a suitable protecting group; with a suitable amine base in a suitable solvent to form a compound of Formula V:); wherein PG1and PG2are each independently a suitable protecting group, and H-B+is an ammonium cation generated by protonation of the suitable amine base by the compound of Formula J-I; b) isolating the compound of Formula V as a solid; and c) contacting the compound of Formula V with a suitable acid in a suitable solvent to provide the compound of Formula J-I with increased enantiomeric purity.

[0282] In some embodiments of a compound of Formula J-I and a compound of Formula V, PG1is a suitable protecting group and PG2is a suitable protecting group. In some embodiments, PG1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C1-10haloalkyl, C3-10carbocycle, or 3- to 10-membered heterocycle. In some embodiments, PG1is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG1is C1-6alkyl or C1-6fluoroalkyl. In some embodiments, PG1is C1-10alkyl. In some embodiments, PG1is C1-6alkyl. In some embodiments, PG1is C1-10fluoroalkyl. In some embodiments, PG1is C1-6fluoroalkyl. In some embodiments, PG1is ethyl or 2,2,2- trifluoroethyl. In some embodiments, PG1is ethyl. In some embodiments, PG1is 2,2,2- trifluoroethyl. In some embodiments, PG2is C1-10alkyl, C7-10ara-alkyl, C2-10alkenyl, C2-10alksome embodiments, PG2is C1-10alkyl or C1-10fluoroalkyl. In some embodiments, PG2is C1-6alkyl or C7-10ara-alkyl. In some embodiments, PG2is C1-10alkyl. In some embodiments, PG2is C1-6alkyl. In some embodiments, PG2is C7-10ara-alkyl. In some embodiments, PG2is C7-8ara- alkyl. In some embodiments, PG2is methyl or benzyl. In some embodiments, PG2is methyl. In some embodiments, PG2is benzyl.

[0283] In some embodiments, the suitable amine base In someembodiments, the suitable amine base is (1S,2R)-2-amino-1,2-diphenylethan-1-ol. In some embodiments, H+some embodiments, H-B is (1R,2S)-2-hydroxy- 1,2-diphenylethan-1-aminium. In some embodiments, the suitable solvent of a) is pentane, hexane, heptane, acetone, methanol, ethanol, water or a combination thereof. In some embodiments, the suitable solvent of a) is heptane, acetone, or a combination thereof. In some embodiments, the solid isolated in b) is a crystalline solid. In some embodiments, the solid isolated in b) is an amorphous solid. In some embodiments, the suitable acid of c) is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, nitric acid, trifluoroacetic acid, citric acid, or a combination thereof. In some embodiments, the suitable acid of c) is hydrochloric acid. In some embodiments, the suitable solvent of c) is dichloromethane or 1,2-dichloroethane. In some embodiments, the suitable solvent of c) is dichloromethane, water, or a combination thereof.

[0284] In some embodiments, the amount of the suitable amine base used in a) is about 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, 1.50, 2.0, 2.5, 3.0, 4.0, or 5.0 molar equivalents with respect to the amount of the compound of Formula J-I. In some embodiments, the amount of the suitable amine base used in a) is about 1.05 molar equivalents with respect to the amount of the compound of Formula J-I. In some embodiments, a) is carried out at about 25° Celsius. In some embodiments, a) is carried out at 25±5° Celsius. In some embodiments, a) is carried out at 5±5° Celsius, 10±5° Celsius, 15±5° Celsius, 20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, 40±5° Celsius, or 45±5° Celsius. In some embodiments, the amount of the suitable acid used in c) is about 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, 1.50, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 or 10.0 molar equivalents with respect to the amount of the compound of Formula V. In some embodiments, the amount of the suitable acid used in c) is about 5.0 molar equivalents with respect to the amount of the compound of Formula V of the compound of Formula J-I In someembodiments, a) is carried out at about 20° Celsius. In some embodiments, a) is carried out at 20±5° Celsius. In some embodiments, a) is carried out at 5±5° Celsius, 10±5° Celsius, 15±5° Celsius, 20±5° Celsius, 25±5° Celsius, 30±5° Celsius, 35±5° Celsius, 40±5° Celsius, or 45±5° Celsius.

[0285] In some embodiments, the compound of Formula J-I is Compound 12. In some embodiments, the compound of Formula J-I is Compound 16.

[0286] In some embodiments, the compound of Formula V is Compound 33:(Compound 33).

[0287] In some embodiments, the compound of Formula V is Compound 34:(Compound 34).

[0288] In some embodiments, the method for increasing the enantiomeric purity of a compound of Formula J-I increases the enantiomeric purity of the compound of Formula J-I by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 20%, at least 30%, or at least 40%. Synthesis of Compound 2 and Crystalline Forms Thereof

[0289] In one aspect, described herein is a process for the preparation of Compound 2, comprising treating Compound 1 or a salt thereof,(Compound 1); or the alkyl ester of Compound 1:wherein R1isC1-C6alkyl; with a sodium hydroxide solution in the presence of a suitable solvent to provide Compound 2.

[0290] In some embodiments, R1is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R1is ethyl. In some embodiments, the suitable solvent is water, methanol, ethanol, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or a combination thereof. In some embodiments, the suitable solvent is water. In some embodiments, the suitable solvent is a combination of water and 2-methyl tetrahydrofuran. In some embodiments, the sodium hydroxide solution is an aqueous sodium hydroxide solution.

[0291] In some embodiments, the preparation of Compound 2 comprises treating Compound 1 with a sodium hydroxide solution in the presence of a suitable solvent, wherein the suitable solvent is water, methanol, ethanol, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate,acetone, acetonitrile, or a combination thereof . In some embodiments, the preparation ofCompound 2 comprises treating Compound 1 with a sodium hydroxide solution in the presenceof a suitable solvent, wherein the suitable solvent is water or a combination of water and 2 -methyl tetrahydrofuran. In some embodiments, the preparation of Compound 2 comprises treating the ethyl ester of Compound 1 with a sodium hydroxide solution in the presence of asuitable solvent, wherein the suitable solvent is water, methanol, ethanol, tetrahydrofuran, 2 -methyl tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or a combination thereof . In someembodiments, Compound 2 is crystalline. In some embodiments, crystalline Compound 2 is Crystalline Form 1 of Compound 2. In some embodiments, crystalline Compound 2 comprises Crystalline Form 1 of Compound 2.

[0292] In some embodiments, the process further comprises a process for the preparation of Compound 1, comprising contacting Compound 4:(Compound 4);with a suitable acid in a suitable solvent to provide Compound 1.

[0293] In some embodiments, the suitable acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, nitric acid, trifluoroacetic acid, citric acid, or a combination thereof. In some embodiments, the suitable acid is trifluoroacetic acid or citric acid. In some embodiments, the suitable acid is trifluoroacetic acid. In some embodiments, the suitable acid is citric acid. In some embodiments, the suitable solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert- butanol, isoamyl alcohol, or a combination thereof. In some embodiments, the suitable solvent is2-methyl tetrahydrofuran, water, or a combination thereof . In some embodiments, the suitableacid is trifluoroacetic acid and the suitable solvent is 2-methyl tetrahydrofuran, water, or a combination thereof. In some embodiments, the suitable acid is citric acid and the suitablesolvent is 2-methyl tetrahydrofuran, water, or a combination thereof .

[0294] In one aspect, described herein is a process for the preparation of Crystalline Form 1 of Compound 2, comprising dissolving Compound 2 or a crystalline form thereof in a first suitable solvent to form a solution; and adding a second suitable solvent to the solution to provide Crystalline Form 1 of Compound 2. In some embodiments, the first suitable solvent is water,methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tetrahydrofuran, 2 -methyltetrahydrofuran, or a combination thereof; and the second suitable solvent is heptane, hexane, pentane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, diethyl ether, dibutylether, methyl tert-butyl ether, acetonitrile, water, or a combination thereof . In someembodiments, the first suitable solvent is a combination of water and ethanol; and the second suitable solvent is a combination of heptane and methyl tert-butyl ether. In some embodiments, the first suitable solvent is water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol,tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof . In some embodiments, thesecond suitable solvent is heptane, hexane, pentane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, diethyl ether, dibutyl ether, methyl tert-butyl ether, acetonitrile, water, or a combination thereof. In some embodiments, the first suitable solvent is a combination of water and ethanol. In some embodiments, the second suitable solvent is a combination of heptane and methyl tert-butyl ether. In some embodiments, the process further comprises concentrating thesolution before the second suitable solvent is added thereto .

[0295] In one aspect, described herein is a process for the preparation of Crystalline Form 1 of Compound 2, comprising dissolving Compound 2 or a crystalline form thereof in a solvent to form a solution; and evaporating the solution to provide the Crystalline Form 1 of Compound 2. In some embodiments, the suitable solvent is water, methanol, ethanol, isopropanol, isobutanol,acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropylacetate, methyl tert-butyl ether, toluene, acetonitrile, or a combination thereof .Certain Compounds of the Disclosure

[0296] In one aspect, disclosed herein is a compound selected from: a pharmaceuticallyacceptable solvate thereof; and.

[0297] In another aspect, disclosed herein is a compound selected from: , nd. Further Considerations

[0298] Due to the fact that some of the synthetic methods described above utilize a transition meplatinum in the product(s). Purification steps to reduce the amount of palladium in a product are conducted so that active pharmaceutical ingredients meet palladium and platinum specification guidelines. (“Guideline on the Specification Limits for Residues of Metal Catalysts” European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use, London, January 2007, Doc. Ref. CPMP / SWP / QWP / 4446 / 00 corr.). In some embodiments, purification steps to reduce the amount of palladium and / or platinum in a product includes, but is not limited to, treatment with solid trimercaptotriazine (TMT), polystyrene-bound TMT, mercapto-porous polystyrene-bound TMT, polystyrene-bound ethylenediamine, activated carbon, glass bead sponges, SmopexTM, silica bound scavengers, thiol-derivatized silica gel, N-acetylcysteine, n- Bu3P, crystallization, extraction, L-cysteine, n-Bu3P / lactic acid (Garrett et al., Adv. Synth. Catal. 2004, 346, 889-900). In some embodiments, activated carbon includes but is not limited to DARCO®KB-G, DARCO®KB-WJ. In one aspect silica bound scavengers include but are not li, , ; ica gel. In some embodiments, the purification steps to reduce the amount of palladium include the use of activated carbon, derivatized silica gel (e.g., thiol derivatized silica gel), or combinations thereof.

[0299] In some embodiments, Compound 1, or salt thereof, is further treated with a metal scavenger to remove residual palladium and / or platinum. In some embodiments, the metal scavenger comprises SiO2, charcoal, aqueous solution of L-cysteine, a Silicycle metal scavenger, Si-thiol, SiliaBond DMT, SiliaBond Cysteine, or 3-mercaptopropyl ethyl sulfide silica. In some embodiments, the scavenger loading (w / w) is about 1:3, about 1:2, or about 1:1. In some embodiments, the metal scavenger is 3-mercaptopropyl ethyl sulfide silica. In some embodiments, the metal scavenger is L-cysteine.

[0300] In some of these embodiments, palladium levels are reduced to about 100 ppm or less.In some of these embodiments, palladium levels are reduced to about 10 ppm. In some of theseembodiments, palladium levels are reduced sufficiently to be undetectable .

[0301] In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by utilizing methods known in the art. In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by the use of inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by the use of techniques described in U.S. Pharmacopeia General Chapter <231> Heavy Metals.

[0302] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0303] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use ,Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selectivedissolution in one or another part of the digestive tract is possible and this cap ability can bemanipulated as one aspect of delayed and sustained release behaviors. Also, because the salt -forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0304] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, the compound disclosed herein(i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganicacids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuricacid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0305] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with a base. In some embodiments, the compound disclosed herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound disclosed herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0306] In some embodiments, a GPR40 agonist (e.g., Compound 1) made according to the methods disclosed herein are further processed to provide pharmaceutically-acceptable salts of said GPR40 agonist. As used herein, “pharmaceutically acceptable salt” includes pharmaceutically acceptable co-crystalline materials comprising a compound of the present disclosure (e.g., Compound 1, Compound 2).

[0307] In some embodiments, a compound disclosed herein (e.g., Compound 1) is prepared as the sodium salt. In some embodiments, a compound disclosed herein (e.g., Compound 1) is prepared as the sodium salt hemiheptahydrate. In some embodiments, a compound disclosed herein is prepared as the potassium salt.

[0308] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water ethanol and the like Hydrates are formedwhen 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.

[0309] Therapeutic agents that are administrable to mammals, such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities andconsistent with industrial safety concerns. Categories of solvents are defined in, for example, theInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0310] Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

[0311] Class 1 solvents, which are to be avoided, include: benzene; carbon tetrachloride; 1,2 -dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0312] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N- dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.

[0313] Class 3 solvents, which possess low toxicity, include: acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2- methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0314] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs mayenhance the yield, or determine characteristics such as crystal form, purity, and solubility.Therefore, the solvent is a critical parameter in the synthetic process.

[0315] In some embodiments, compositions comprising Compound 1, Compound 2, or Compound 3 comprise an organic solvent(s). In some embodiments, compositions comprising Compound 1, Compound 2, or Compound 3 include a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2- propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butylmethylether, heptane, isopropanol, and ethanol.

[0316] In some embodiments, the compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof include a detectable amount of an organic solvent. In some embodiments, the compositions comprising Compound 1, Compound 2, or Compound 3 include a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0317] In other embodiments are compositions comprising Compound 1, Compound 2, or Compound 3 wherein the composition comprises a detectable amount of solvent that is less than about 1%, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In a further embodiment are compositions comprising Compound 1, Compound 2, or Compound 3 wherein the composition comprises a detectable amount of solvent which is less than about 5000 ppm. In yet a further embodiment are compositions comprising Compound 1, Compound 2, or Compound 3, wherein the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0318] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0319] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can beincorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl,123I,124I,125I,131I,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C areincorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect,substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or altered metabolic pathways to reduce undesirable metabolites or reduced dosage requirements.

[0320] In some embodiments, one or more hydrogen atoms on Compound 1, Compound 2, or Compound 3 are replaced with deuterium. In some embodiments, substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0321] In some embodiments, the pharmaceutically acceptable salt of the compound is a sodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound is a potassium salt.

[0322] The compounds presented herein include all diastereomeric, individual enantiomers,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. Pharmaceutical Compositions

[0323] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitateprocessing of the active compounds into preparations that are used pharmaceutically. Properformulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0324] In one aspect, described herein is a pharmaceutical composition comprising crystalline Compound 2 and at least one pharmaceutically acceptable excipient. In some embodiments, crystalline Compound 2 is Crystalline Form 1 of Compound 2. In some embodiments, crystalline Compound 2 is Crystalline Form 2 of Compound 2 In some embodiments crystallineCompound 2 is Crystalline Form 3 of Compound 2. In some embodiments, crystalline Compound 2 is Crystalline Form 4 of Compound 2. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal byoral administration in the form of a tablet, a pill, a capsule, a suspension, or a solution . In someembodiments, the pharmaceutical composition is in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

[0325] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. Methods of Treatment

[0326] In one embodiment, the compounds disclosed herein, or the crystalline forms thereof disclosed herein, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of GPR40 activity. Methods fortreating any of the diseases or conditions described herein in a mammal in need of suchtreatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0327] In certain embodiments, the compositions (e.g., pharmaceutical compositions) containing the compounds disclosed herein, or the crystalline forms thereof disclosed herein, are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0328] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated, and the subject or host being treated. EXAMPLES

[0329] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0330] List of Abbreviations: 2-Me-THF or 2-MeTHF = 2-methyltetrahydrofuran; ACN or MeCN = acetonitrile; DAD = diode-array detection; DCM = dichloromethane; DMAc = N,N-dimethylacetamide; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; DMSO = dimethylsulfoxide; DI = deionized; DSC = differential scanning calorimetry; Et = ethyl; EtOAc or EA = ethyl acetate; EtOH = ethanol; equiv or eq. = equivalent(s); FTIR or FT-IR = Fourier transform infrared; g = gram(s); GC-MS or GCMS or GC / MS = gas chromatography-mass spectrometry; GVS = gravimetric vapor sorption; h or hr = hour; hrs = hours; HPLC = high-performance liquid chromatography; IBA = Isobutanol; IC = ion chromatography; IPA = isopropyl alcohol; IPAC = isopropyl acetate; KF = Karl Fisher titration; kg or KG or Kg = kilogram(s); L = lit L L y; L M M M M M M M M Me); mg = milligram(s); mins or min = minutes;mol. = mole; mL or ml = milliliter; µL = microliter; MTBE or TBME = tert-butyl methyl ether; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; PPAR-delta or PPARδ = peroxisome proliferator-activated receptor delta; ppm = parts per million; rbf or RBF = round bottom flask; RH = relative humidity; rpm = revolutions per minute; rt or RT = room temperature; Rt = retention time; TEA = triethylamine; TFA = trifluoroacetic acid; TGA = thermogravimetric analysis; THF = tetrahydrofuran; TMAD = tetramethylazodicarboxamide; Tol or tol = toluene; Ts = 4-methylbenzenesulfonyl (tosyl); vol or vols = volume(s); w / w = weight ratio; XRPD = X-ray powder diffraction.

[0331] 1H NMR spectra were collected on a Bruker 400 MHz instrument with the following parameters: scan times = 4; temperature = 295 K, relaxation delay = 1 s. Unless specified, samples were dissolved in DMSO-d6solvent and measured. The data were analyzed using MestReNova.

[0332] Polarized light microscopy (PLM) analysis was performed using a Polarizing MicroscopeEclipse LV100POL. A small amount of the sample was placed on a glass slide with a drop ofimmersion oil and covered with a glass slip. The sample was observed by the microscope.

[0333] HPLC analysis was performed with an Agilent HPLC 1260 series instrument. HPLC method for solubility and stability testing are described in the following table: mGradient 0.0 52 48Instrument Agilent 1260 SeriesI. Chemical Synthesis

[0334] Unless otherwise noted, solvents were used as received from commercial suppliers.

[0335] In the following Examples, “V” denotes “Volumes” of the specified reagent or solvent. Unless specified otherwise, 1 Volume is defined as about 1 mL of the specified reagent, solution, or solvent per gram of the starting material that defines the scale of the reaction. By way of Example, in Example 2, Step 1 the reaction was conducted using 100 g of Compound 24, thus 2 V of NMP (N-methyl pyrrolidinone) at such a scale was about 200 mL. Example 1. Preparation of (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 1)

[0336] The preparation of Compound 1 has been previously described (see, PCT / US2021 / 019975, US 17 / 745126, PCT / US2023 / 068729, and US 18 / 387170, each of which is incorporated by reference in its entirety).

[0337] Additionally, the preparation of Compound 1 can be achieved using the procedures in the following examples.Example 2. Synthesis of Compound E

[0338] Step 1: Synthesis of cyclopropyl(3-methoxyphenyl)methanone (Compound 27): Solvent volume and chemical stoichiometry are calculated based on assay of Compound 24. N- methylpyrrolidinone (NMP; 2 V, 200 mL) was charged into an appropriately sized jacketed reactor. Karl-Fischer titration demonstrated the water content of the NMP in the reactor was ≤ 0.1%. Cyclopropane carbonyl chloride (Compound 25; 1.8 molar equivalents, 89.0 g) was addedto the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minute s,and then cooled to 0±5 °C. (3-Methoxyphenyl)magnesium bromide (Compound 24; 1.0 molar equivalents, 1 M solution in THF, 473.2 mL, 454.3g, contain Compound 24 is 100 g) was addedto the reactor at 0±5 °C. The resulting mixture was stirred at 0±5 °C for a t least 1 hour. Thereaction was quenched by addition of 5% w / v aqueous sodium sulfate solution (3 V, 300 mL) at 0±5 °C, and then toluene (2 V, 200 mL) was added to the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minutes. The organic and aqueous phases of the mixture in the reactor were separated, and the organic phase was washed with 10% w / v aqueous NH4Cl solution (1 x 3 V, 1 x 300 mL) and 10% w / v aqueous sodium carbonate solution (1 x 3 V, 1 x 300 mL) at 20±5 °C. The organic phase was concentrated to 1 ± 0.5 V with the jacket of the reactor maintained at ≤ 50 °C. Karl-Fischer titration demonstrated the water content of the concentrated organic phase was 0.05%.111.2 g of crude Compound 27 was obtained. Assay of the crude Compound 27 was 75% mass purity by HPLC curve. Yield of Compound 27 was100%. The crude Compound 27 was used directly in the next step. Compound 27: LCMS (m / z) = 177.1 (M-H+).

[0339] The HPLC assay used to determine the yield of Example 2, Step 1 was as follows: 38.8 mg of crude Compound 27 was collected; the collected sample was diluted to a volume of 50 mL by adding methanol to the sample in a 50 mL volumetric flask; the UV absorbance peak area (absorbance signal at 225 nm with a 4 nm bandwidth) of the diluted solution of Compound 27 by HPLC was found to be 1859.8; using an HPLC calibration curve for Compound 27 of y = 3046.3x + 87.2, wherein y is UV absorbance peak area and x is concentration, it was determined that x = 0.58 mg / mL for the diluted solution of Compound 27; by extension, the mass percentage of Compound 27 in the crude Compound 27 was calculated to be 75%; as the total mass of the crude Compound 27 was 111.2 g and the theoretical yield of Compound 27 was 83.4 g, the yield of Example 2, Step 1 was determined to be 100%. In the foregoing procedures, yields determined using an HPLC assay were determined in a substantially similar manner as detailed above.

[0340] Steps 2 and 3: Synthesis of ethyl hydrogen (E)-(2-cyclopropyl-2-(3- methoxyphenyl)vinyl)phosphonate (Compound 14): Solvent volume and chemical stoichiometry are calculated based on assay of Compound 27.1,4-Dioxane (3 V, 249 mL) was charged into an appropriately sized jacketed reactor. Karl-Fischer titration demonstrated the water content of the 1,4-dioxane in the reactor was ≤ 0.1%. Tetraethyl methylenebis(phosphonate) (Compound 28; 2.0 molar equivalents, 272 g) was charged into the reactor. Lithium diisopropylamide solution (2.0 molar equivalents, 2 M in THF / n-Hexane, 472 mL) was charged into the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for 1 hour. The crude Compound 27 in Toluene (1.0 molar equivalents, 83 g of Compound 27 as determined by assay) yielded from Example 2, Step 1 was then charged into the reactor at 20±5 °C. The resulting mixture was heated to 95±5 °C and stirred while being maintained at that temperature for at least 16 hours. The mass signal of Compound 15 was detected by LCMS (liquid chromatography-mass spectrometry). The resulting mixture was concentrated to 3±1 V (249-332 mL) with the jacket of the reactor maintained at ≤ 50 °C and quenched by addition of NaOH (4.0 molar equivalents, 75.4 g in 664 mL H2O). The reaction mixture was heated to 70±5°C and stirred for at least 3 hours. After the reaction was completed, it was cooled to 20±5 °C. Methyl tert-butyl ether (MTBE; 3 V, 249 mL) was charged with stirring for at least 30 min at 20±5 °C and settled for at least 30 min at 20±5 °C. Aqueous phase was collected after separation. MTBE (3 V, 249 mL) was charged with stirring for at least 30 min at 20±5 °C and settled for at least 30 min at 20±5 °C. Aqueous phase was collected after separation. MTBE (5 V, 415 mL) was added to the mixture. The pH of solution was adjusted to 1-2 with HCl (6N aqueous solution). The mixture was stirred for at least 30 min at 20±5 °C and settled for at least 30 min Organic phase was collected after separation Aqueous NaOH (105molar equivalents, 19.8 g in 415 mL H2O) was added and stirred for at least 30 min at 20±5 °C. Aqueous phase was collected after separation. DCM (3V, 249 mL) was added and stirred for at least 30 min at 20±5 °C. Aqueous phase was collected after separation. DCM (3V, 249 mL) was added and stirred for at least 30 min at 20±5 °C. Aqueous phase was collected after separation. MTBE (5V, 415 mL) was added and stirred for at least 30 min at 20±5 °C. The pH of solution was adjusted to 1-2 with HCl (6 N). The mixture was stirred for at least 30 min at 20±5 °C and settled for at least 30 min. Organic phase was collected after separation and washed with water (3 V, 249 mL). The resulting mixture was concentrate to 1.5±0.5 V (124.5-166 mL) with the jacket of the reactor maintained at ≤ 50 °C. Toluene (2 V, 166 mL) was added and concentrate to 1.5±0.5 V (124.5-166 mL) with the jacket of the reactor maintained at ≤ 50 °C. Karl-Fischer titration demonstrated the water content of the concentrated organic phase was 0.02%.125 g of crude Compound 14 was obtained. Assay of crude Compound 14 determined its mass purity was 91%. Yield of Compound 14 was 85%. The crude Compound 14 was used directly in the next step. Compound 14: LCMS (m / z) = 283.1 (M-H+).

[0341] Step 4: Synthesis of ethyl hydrogen ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)phosphonate (Compound 16): Solvent volume and chemical stoichiometry are calculated based on assay of Compound 14. Methanol (9 V, 945 mL) and crude Compound 14 (1.0 molar equivalents, equivalent to 105.2 g of Compound 14) were charged into an appropriately sized jacketed reactor. Bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer (0.0025 molar equivalents, alternatively termed [(norbornadiene)RhCl]2, 122 mg) was charged into the reactor under a dinitrogen atmosphere at 20±5 °C. (S)-1-[(R)-2-(di-tert- butylphosphino)ferrocenyl]ethyldiphenylphosphine (0.00575 molar equivalents, 1.15 g; CAS No. 223121-01-5) was charged into the reactor under a dinitrogen atmosphere at 20 ± 5 °C. Additional methanol (1 V, 105 mL) was used to wash the charging funnel and reactor wall. The atmosphere within the reactor was evacuated and replaced with dihydrogen 5 times. The reactorwas then pressurized under a dihydrogen atmosphere to 1.3±0.5 MPa. The resu lting mixture wasstirred for 16 hours at 30±5 °C. Following depressurization, sodium hydroxide (1.05 molar equivalents, 15.7 g) in water (5 V, 526 mL) was added to the reactor, and the resulting mixture was concentrated (to 4.5 ± 0.5 V) under vacuum with the jacket of the reactor maintained at ≤ 50 °C. The aqueous phase within the reactor was extracted with methyl tert-butyl ether (3 V x 2, 316 mL x 2). The pH of aqueous phase was adjusted to 1-2 by addition of 6 N aqueous hydrochloric acid solution at 20±5 °C. The aqueous layer was extracted with methyl tert-butyl ether (4 V, 526 mL). The methyl tert-butyl ether extracts were concentrated to 1 ± 0.5 V with the jacket of the reactor maintained at ≤ 40 °C. Toluene (2 V, 211 mL) was added to the reactor and concentrated (1±05 V) to remove water until Karl Fisher titration demonstrated the water content of thesolution was ≤ 0.1%, then DCM (1 V, 105 mL) was added to provide a solution of Compound 16 in dichloromethane. Assay (e.g., HPLC assay) of the solution of Compound 16 in dichloromethane demonstrated the yield was 91.7%. The solution of Compound 16 in dichloromethane was used directly in the next step.

[0342] Step 5: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)phosphonochloridate (Compound 18): Solvent volume and chemical stoichiometry are calculated based on assay of Compound 16. Dichloromethane (4 V, 382 mL) was charged into an appropriately sized jacketed reactor. After the dichloromethane was stirred for at least 5 minutes, Karl-Fischer titration demonstrated the water content of the dichloromethane in the reactor was ≤ 0.1%. N,N-dimethylformamide (DMF; 0.1 molar equivalents, 2.46 g) was charged into the reactor at 20±5 °C. Oxalyl chloride (2.0 molar equivalents, 85.3 g) was charged dropwise into the reactor at 20±5 °C. The resulting mixture was stirred for at least 30 minutes at 20±5 °C. The solution of Compound 16 in dichloromethane (ca. 2.5 V) was added to the reactor in a dropwise manner at 20±5 °C. The resulting mixture was heated to 30±5 °C and stirred while being maintained at that temperature for at least 16 hours. The mixture was concentrated to 1±0.5 V with the jacket of the reactor maintained at ≤ 35 °C. Then, the following was conducted 3 times, iteratively, in sequence: 1) dichloromethane (5 V) was added to the reactor, and 2) the mixture was concentrated to 1.5±0.5 V with the jacket of the reactor maintained at ≤ 35 °C. Then dichloromethane (0.5 V, 53 mL) was added to the reactor a final time to provide a solution of Compound 18 in dichloromethane that was used directly in the next step.

[0343] Step 6: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)(methyl)phosphinate (Compound 20): Solvent volume and chemical stoichiometry are calculated based on the assay of Compound 16. Tetrahydrofuran (THF; 4 V, 382 mL) was charged into an appropriately sized jacketed reactor. After the tetrahydrofuran was stirred for at least 5 minutes, Karl-Fischer titration demonstrated the water content of the tetrahydrofuran in the reactor was ≤ 0.1%. Methylmagnesium bromide solution (2.0 molar equivalents, 1 M in THF, ca.4.5 V, 223 mL) was charged into the reactor at 20±5 °C. The resulting solution was cooled to -25±10 °C. The solution of Compound 18 in dichloromethane yielded from Step 5 (2 V, 210 mL) was then charged into the reactor dropwise at -25±10 °C, and the resulting mixture was stirred for at least 1 hour at -25±10 °C. The resulting mixture was quenched by adding it to a 20% w / v aqueous citric acid solution (3 V, 286.5 mL) at 5±5 °C. Organic phase was collected after separation. Aqueous phase was extracted with ethyl acetate (2 V, 191 mL) and the resulting mixture was stirred for at least 30 minutes before being allowed to stand for at least 30 minutes. The aqueous and organic phases of the mixture were separated. Thecombined organic phases were washed with 5% w / v aqueous sodium carbonate solution (1 x 5 V, 477.5 mL) at 20±5 °C. The organic phase was concentrated to 1.5±0.5 V with the jacket of the reactor maintained at ≤ 50 °C. Toluene (2 V, 191 mL) was added and evaporated away under vacuum with the jacket of the reactor maintained at ≤ 50 °C. The remaining solvent was provided a solution of Compound 20 in toluene that was used directly in the next step. Karl-Fischer titration demonstrated the water content of the solution of Compound 20 in toluene was ≤ 0.1%. HPLC assays determined the overall yield over Example 2, Step 5 and Step 6 was 90.3%.

[0344] Step 7: Synthesis of ((S)-2-cyclopropyl-2-(3-hydroxyphenyl)ethyl)(methyl)phosphinic acid (Compound E): Solvent volume and chemical stoichiometry are calculated based on the assay of the solution of Compound 20 in toluene yielded from Example 2, Step 6. Boron trichloride (3.5 molar equivalents, 12.4 V, 1.05 L, 1 M in toluene) was charged into the reactor at 20±5 °C. Di(n-butyl)sulfide (3.5 molar equivalents, 153.3 g) was charged into the reactor at 20±5 °C. Compound 20 (1.0 molar equivalents, equivalent to 85 g of Compound 20 as measured using quantitative NMR) was charged into an appropriately sized jacketed reactor. The resulting mixture was heated to 70±5 °C and stirred while being maintained at that temperature for at least 16 hours. The bottom phase was collected after separation and quenched into sodium hydroxide (17 molar equivalents, 204 g) dissolved in water (15 V, 1.43 L) were added to the reactor. The resulting mixture was heated to 70±5°C and stirred while being maintained at that temperature for at least 1 hour. The reaction mixture was cooled to 20±5 °C and extracted with isopropylacetate (3 V, 286.5 mL). The aqueous phase was collected and its pH was adjusted to 1 -2 byaddition of aqueous phosphoric acid solution (85% wt) at 5±5 °C. The resulting suspension was separated by filtration, and the resulting cake of isolated white solids was washed with water (2 V, 191 mL). Compound E wet cake was isolated as an off-white solid following removal of residual solvent and water. The yield of Example 2, Step 7 was 80%. The purity of Compound E isolated was 98% as determined by using quantitative NMR. Compound E: LCMS (m / z) = 241.1 (M-H+).Example 2a. Alternative Synthesis of Compound E

[0345] Step 1: Synthesis of cyclopropyl(3-methoxyphenyl)methanone (Compound 27): Volumes and stoichiometry are based upon an assay of Compound 24. N-methylpyrrolidinone (NMP; 2 V, 200 mL) was charged into an appropriately sized jacketed reactor. Karl-Fischer titration demonstrated the water content of the NMP in the reactor was ≤ 0.1%. Cyclopropane carbonyl chloride (Compound 25; 2.0 molar equivalents, 89.0 g) was added to the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minutes, and then cooled to 0±5 °C. (3-Methoxyphenyl)magnesium bromide (Compound 24; 1.0 molar equivalents, 1 M solution in THF, 473.2 mL, 454.3g, Compound 24 is 100 g) was added to the reactor at 0±5 °C. The resulting mixture was stirred at 0±5 °C for at least 1 hour. The reaction was quenched by addition of 5% w / v aqueous sodium sulfate solution (3 V, 300 mL) at 0±5 °C, and then toluene (2 V, 200 mL) was added to the reactor. The resulting mixture was stirred at 0±5 °C for at least 30 minutes before being warmed to 20±5 °C. The organic and aqueous phases of the mixture in the reactor were separated, and the organic phase was washed with 5% w / v aqueous sodium carbonate solution (1 x 3 V) at 20±5 °C. The organic phase was concentrated to 2 V with the jacket of the reactor maintained at ≤ 50 °C. Karl-Fischer titration demonstrated the water content of the concentrated organic phase was ≤ 0.1%. The solvent phase in the concentrated organic phase was evaporated away and 1,4-dioxane (5 V) was added to the reactor to provide a solution of Compound 27 in 1,4-dioxane. Assay of the solution of Compound 27 in 1,4-dioxanedemonstrated the yield was 80%. The solution of Compound 27 in 1,4-dioxane was used directly in the next step.

[0346] The HPLC assay used to determine the yield of Example 2a, Step 1 was as follows: 52.2 mg of crude Compound 27 was collected; the collected sample was diluted to a volume of 5 mL by adding methanol to the sample in a 5 mL volumetric flask; the UV absorbance peak area (absorbance signal at 225 nm with a 4 nm bandwidth) of the diluted solution of Compound 27 by HPLC was found to be 2986.7; using an HPLC calibration curve for Compound 27 of y = 3046.3x + 87.2, wherein y is UV absorbance peak area and x is concentration, it was determined that x = 0.95 mg / mL for the diluted solution of Compound 27; by extension, the mass percentage of Compound 27 in the crude Compound 27 was calculated to be 9.1%; as the total mass of the crude Compound 27 was 730 g and the theoretical yield of Compound 27 was 83.4 g, the yield of Example 2a, Step 1 was determined to be 80%.

[0347] Example 2a, Step 1 was adapted to synthesize Compound 26 by using Compound 23 in place of Compound 24. Compound 26: LCMS (m / z) = 253.1 (M-H+).

[0348] Step 2: Synthesis of diethyl (E)-(2-cyclopropyl-2-(3-methoxyphenyl)vinyl)phosphonate (Compound 15): Volumes and stoichiometry are based upon an assay of Compound 27.1,4- Dioxane (5 V) was charged into an appropriately sized jacketed reactor. Karl-Fischer titration demonstrated the water content of the 1,4-dioxane in the reactor was ≤ 0.1%. Tetraethyl methylenebis(phosphonate) (Compound 28; 2.0 molar equivalents) was charged into the reactor. Lithium diisopropylamide (2.0 molar equivalents, 2M in THF / n-hexane) was charged into the reactor at 25±5 °C. The resulting mixture was stirred at 25±5 °C for 1 hour. The solution of Compound 27 in 1,4-dioxane yielded from Example 2a, Step 1 was then charged into the reactor at 25±5 °C. The resulting mixture was heated to 95±5 °C and stirred while being maintained at that temperature for at least 16 hours. The resulting mixture was then cooled to 25±5 °C andquenched by addition of aqueous hydrochloric acid solution until the pH of the mixture was 4 -6at 25±5 °C. The organic and aqueous phases of the mixture in the reactor were separated, and the aqueous layer was extracted with ethyl acetate (2 x 5 V). The ethyl acetate extracts were combined and concentrated to 2 V with the jacket of the reactor maintained at ≤ 50 °C. The remaining ethyl acetate was evaporated away and ethanol (4 V) was added to the reactor to provide a solution of Compound 15 in ethanol. Assay of the solution of Compound 15 in ethanol demonstrated the yield was 85%. The solution of Compound 15 in ethanol was used directly in the next step.

[0349] Example 2a, Step 2 was adapted to synthesize Compound 11 by using Compound 26 in place of Compound 27.Example 2a, Step 2 was adapted to synthesize Compound 31 by using Compound 29 or Compound 30 in place of Compound 28. It was determined that the yield and purity of Compound 31 provided by this adapted step made it less preferable as an alternative to the sequence of Steps 1-7 in Example 2a as detailed herein; however, the production of Compound 31 by such means remains a practicable alternative. Step 3: Synthesis of ethyl hydrogen (E)-(2-cyclopropyl-2-(3-methoxyphenyl)vinyl)phosphonate (Compound 14): Volumes and stoichiometry are based upon an assay of Compound 15. The solution of Compound 15 in ethanol provided by Example 2a, Step 2 was charged into an appropriately sized jacketed reactor. A solution of sodium hydroxide (6.0 molar equivalents) in water (2 V) was charged into the reactor at 25±5 °C. The resulting mixture was heated to 90±5 °C and stirred while being maintained at that temperature for at least 1 hour. The resulting mixture was then cooled to 25±5 °C and diluted by addition of water (3 V). The resulting mixture was concentrated (to 4.5±0.5 V) with the jacket of the reactor maintained at ≤ 50 °C. Dichloromethane (5 V) was charged into the reactor at 25±5 °C and subsequently separated from the aqueous phase in the reactor. This step was repeated, with dichloromethane (5 V) again charged into the reactor at 25±5 °C and again subsequently separated from the aqueous phase in the reactor. The aqueous phase was adjusted to a pH of 1-2 by addition of 6 N aqueous hydrochloric acid solution at 25±5 °C. The aqueous layer was extracted with methyl tert-butyl ether (2 x 5 V). The separated organic phases of dichloromethane and methyl tert-butyl ether) were combined and washed with saturated aqueous sodium sulfate solution (2 x 5 V). The organic phases were concentrated to 3 V with the jacket of the reactor maintained at ≤ 50 °C. The remaining solvents in the organic phases were evaporated away and methanol (9 V) was added to the reactor to provide a solution of Compound 14 in methanol. Assay of the solution of Compound 14 in methanol demonstrated the yield was 95%. The solution of Compound 14 in methanol was used directly in the next step.

[0350] Example 2a, Step 3 was adapted to synthesize Compound 21 by using Compound 31 in place of Compound 15. It was determined that the yield and purity of Compound 21 provided by this adapted step made it less preferable as an alternative to the sequence of Steps 1-7 in Example 2 or Example 2a as detailed herein; however, the production of Compound 21 by such means remains a practicable alternative.

[0351] Step 4: Synthesis of ethyl hydrogen ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)phosphonate (Compound 16): Volumes and stoichiometry are based upon an assay of Compound 14. The solution of Compound 14 in methanol provided by Example 2a, Step 3 was charged into an appropriately sized jacketed reactor. Bicyclo[2.2.1]hepta-2,5-diene- rhodium(I) chloride dimer (0005 molar equivalents; alternatively termed[(norbornadiene)RhCl]2) was charged into the reactor under a dinitrogen atmosphere at 20±5 °C. I-(+)-1-[(Rp)-2’(2'-dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5- trifluoromethylphenyl)phosphine (0.0115 molar equivalents; Walphos SL-W008-1; CAS No. 821009-34-1) was charged into the reactor under a dinitrogen atmosphere at 20±5 °C. Additional methanol (1 V) was charged into the reactor at 20±5 °C. The atmosphere within the reactor was evacuated and replaced with dihydrogen 5 times. The reactor was then pressurized under a dihydrogen atmosphere to 1 MPa. The resulting mixture was stirred for 16 hours at 25±5 °C.Following depressurization, sodium hydroxide (1.05 molar equivalents) in water (5 V) was addedto the reactor, and the resulting mixture was concentrated (to 4.5±0.5 V) under vacuum with the jacket of the reactor maintained at ≤ 45 °C. The aqueous phase within the reactor was extracted with methyl tert-butyl ether (5 V). The aqueous phase was cooled to 5±5 °C and its pH was adjusted to 1-2 by addition of 6 N aqueous hydrochloric acid solution at 5±5 °C. The aqueous layer was again extracted with methyl tert-butyl ether (5 V). Th combined methyl tert-butyl ether extracts were concentrated to 1-2 V with the jacket of the reactor maintained at ≤ 40 °C. The remaining methyl tert-butyl ether was evaporated away and dichloromethane (6 V) was added to the reactor to provide a solution of Compound 16 in dichloromethane. Assay of the solution of Compound 16 in dichloromethane demonstrated the yield was 95%. The solution of Compound 16 in dichloromethane was used directly in the next step.

[0352] Step 5: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)phosphonochloridate (Compound 18): Volumes and stoichiometry are based upon an assay of the solution of Compound 16. Dichloromethane (4 V) was charged into an appropriately sized jacketed reactor. After the dichloromethane was stirred for at least 5 minutes, Karl-Fischer titration demonstrated the water content of the dichloromethane in the reactor was ≤ 0.1%. N,N-dimethylformamide (DMF; 0.05 molar equivalents) was charged into the reactor at 20±5 °C. Oxalyl chloride (2.0 molar equivalents) was charged into the reactor at 20±5 °C. The resulting mixture was stirred for at least 30 minutes at 20±5 °C. The solution of Compound 16 in dichloromethane (ca.2.5 V) was added to the reactor in a dropwise manner at20±5 °C. The resulting mixture was heated to 30±5 °C and stirred while being mainta ined at thattemperature for at least 12 hours. The mixture was concentrated to 2.5±0.5 V with the jacket of the reactor maintained at ≤ 35 °C. Then, the following was conducted 3 times, iteratively, in sequence: 1) dichloromethane (8 V) was added to the reactor, and 2) the mixture was concentrated to 2.5±0.5 V with the jacket of the reactor maintained at ≤ 35 °C. Then dichloromethane (0.5 V) was added to the reactor a final time to provide a solution of Compound 18 in dichloromethane that was used directly in the next step.

[0353] Step 6: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3- methoxyphenyl)ethyl)(methyl)phosphinate (Compound 20): Volumes and stoichiometry are based upon an assay of the solution of Compound 16. Tetrahydrofuran (THF; 4 V) was charged into an appropriately sized jacketed reactor. After the tetrahydrofuran was stirred for at least 5 minutes, Karl-Fischer titration demonstrated the water content of the tetrahydrofuran in the reactor was ≤ 0.1%. Methylmagnesium bromide solution (2.0 molar equivalents, 1 M in THF, ca. 4.5 V) was charged into the reactor at 20±5 °C. The resulting solution was cooled to -25±10 °C. The solution of Compound 18 in dichloromethane yielded from Example 2a, Step 5 (3 V) was then charged into the reactor at -25±10 °C, and the resulting mixture was stirred for at least 1 hour at -25±10 °C. The resulting mixture was quenched by adding it to a 20% w / v aqueous citric acid solution (8 V) at 5±5 °C. Ethyl acetate (4 V) was added and the resulting mixture was stirred for at least 30 minutes before being allowed to stand for at least 30 minutes. The aqueous and organic phases of the mixture were separated. The organic phase was washed with 5% w / v aqueous sodium carbonate solution (2 x 5 V) at 20±5 °C, and subsequently organic phase was washed with 9% w / v aqueous sodium sulfate solution (2 x 5 V) at 20±5 °C. The pH of the final aliquot of 9% w / v aqueous sodium sulfate solution used in washing the organic phase was ca.7. The organic phase was concentrated to ca.2.5 V with the jacket of the reactor maintained at ≤ 50 °C. The remaining solvent in the organic phase was evaporated away and acetonitrile (10 V) was added to provide a solution of Compound 20 in acetonitrile that was used directly in the next step. Karl-Fischer titration demonstrated the water content of the solution of Compound 20 in acetonitrile was ≤ 0.1%. Assays determined the overall yield over Example 2a, Step 5 and Example 2a, Step 6 was 95%.

[0354] Step 7: Synthesis of ((S)-2-cyclopropyl-2-(3-hydroxyphenyl)ethyl)(methyl)phosphinic acid (Compound E): Volumes and stoichiometry are based upon an assay of the solution of Compound 20. The solution of Compound 20 in acetonitrile yielded from Example 2a, Step 6was charged into an appropriately sized jacketed reactor. Tetrahydrothiophene (1.5 molarequivalents) was charged into the reactor at 20±5 °C. Boron tribromide (1.5 molar equivalents) was charged into the reactor at 20±5 °C. The resulting mixture was heated to 60±5 °C and stirred while being maintained at that temperature for at least 3 hours. The resulting mixture was quenched by addition of methanol (5 V). Sodium hydroxide (2.2 molar equivalents) dissolved in water (10 V) was added to the reactor. The resulting mixture was concentrated to 9±1 V with the jacket of the reactor maintained at ≤ 50 °C. The concentrated mixture was cooled to 5±5 °C, and its pH was adjusted to 1-2 by addition of 6N aqueous hydrochloric acid solution at 5±5 °C. The resulting suspension was separated by filtration, and the resulting cake of isolated white solids was washed with water (2 x 1 V) Compound E was isolated as a white solid following removalof residual solvent. The yield of Example 2a, Step 7 was 80%. Compound E: LCMS (m / z) = 241.1 (M-H+).

[0355] Compound E was also prepared according to Example 2a, Step 7, using Compound 21 in place of Compound 20. Example 3. Synthesis of Compound 6-I

[0356] Step 1: Synthesis of 1-(2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxyphenyl)ethan-1- one (Compound Q): Solvent volume and chemical stoichiometry are calculated based on weight of Compound R. N,N-Dimethylacetamide (DMAc; 1 V, 200 mL) was charged into an appropriately sized jacketed reactor. Karl-Fischer titration demonstrated the water content of the DMAc in the reactor was ≤ 0.1%. Piperidin-4-ylmethanol (1.2 molar equivalents, 164.4 g) and KHCO3(0.6 molar equivalents, 71.4 g) was added to the reactor at 20±5 °C. The charging funnel and reactor wall were washed with DMAc (0.3 V, 60 mL). The resulting mixture was heated to 105 ± 5oC. A solution of 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (Compound R; 1.0 molar equivalents, 200.0 g) in DMAc (0.7 V, 140 mL) was charged into the mixture in a dropwise manner at 105±5°C. The resulting mixture was stirred at 105±5 °C for at least 16 hours, and then cooled to 20±5 °C. The reaction was quenched by addition of H2O (5 V, 1000 mL) at 20±5 °C, and then ethyl acetate (5 V, 1000 mL) was added to the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minutes. The organic and aqueous phases of the mixture in the reactor were separated. The organic phase was concentrated to 1 ± 0.5 V (100-300 mL) with the jacket of the reactor maintained at ≤ 50 °C. Karl-Fischer titration demonstrated the water content of the concentrated organic phase was 0.46%. Gas chromatography demonstrated the ethyl acetate content of the concentrated organic phase was 4.51%. 2-Methyl tetrahydrofuran (2 V, 400 mL) was added to mixture. Crude Compound Q was obtained. The crude Compound Q was used directly in the next step directly. Compound Q: LCMS (m / z) = 264.2 (M-H+).

[0357] Step 2: Synthesis of (E)-1-(2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxyphenyl)- 4,4-dimethylpent-2-en-1-one (Compound P): Solvent volume and chemical stoichiometry are calculated based on weight of Compound R. Compound Q solution (1.0 molar equivalents in 2 V 2-methyl tetrahydrofuran, ca.3 V, 300 mL) was charged into an appropriately sized jacketed reactor. Pivalaldehyde (1.2 molar equivalents, 61.5 g) was added to the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minutes, and then cooled to 0±5 °C. KOH (1.05 molar equivalents, 35.0 g) was added to the reactor in portions at 0±5 °C. The resultingmixture was stirred at 25±5 °C for at least 2 hours. Add MTBE (5 V, 500 mL) into mixture at20±5oC. The reaction was quenched by addition of acetic acid (0.7 V, 70 mL) at 0-30 °C.5% w / w aqueous NaHCO3solution (5 V, 500 mL) was added to the mixture at 20±5oC. The resulting mixture was stirred at 20±5 °C for at least 30 minutes. The organic and aqueous phases of the mixture in the reactor were separated. The organic phase was concentrated to 3 V with the jacketof the reactor maintained at ≤ 50 °C. The mixture was stirred for 1 hour at 0±5oC, over whichtime solid precipitated out. n-Heptane (10 V, 1000 mL) was added to the mixture at 0±5oC, and the mixture was stirred for 2 hours at 0±5oC. The mixture was filtered and the collected solids were rinsed with n-heptane (2 V, 200 mL). The cake of solids was dried at 40±5oC for at least 8 hours.165.3 g of Compound P was obtained as a yellow solid. The purity of the Compound P was 95% as measured by quantitative NMR. The yield of Compound P was 83.9% over Example 3, Steps 1 and 2. Compound P: LCMS (m / z) = 332.2 (M-H+).

[0358] Step 3: Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methanol (Compound D): Solvent volume and chemical stoichiometry are calculated based on weight of Compound P. Ethanol (4 V, 320 mL), Compound P (1.0 molar equivalents, 80.0 g) and H2O (0.8 V, 64 mL) was charged into an appropriately sized jacketed reactor. Methanesulfonic acid (0.4 V, 32 mL) was added dropwise to the reactor at 20 ± 10 °C. Platinum on carbon (4.0 g; 5 wt% of wet platinum of carbon with respect to Compound P, wherein wet platinum on carbon consists of about 50% water, 45% carbon, and 5% platinum by weight) was added to the reactor at 20 ± 5 °C. The atmosphere of the reactor was evacuated and replaced three times with H2. H2(2.2 In some embodiments of Scheme C, Step 3, the suitable hydrogen source is dihydrogen at a pressure of about 2.2 MPa.0.2 MPa) was passed over the reaction mixture, which was stirred at 95±5 °C for at least 16 hours, and then cooled to 20 ± 5 °C. The reaction mixture was filtered and the filter was rinsed through with ethanol (2 V, 160 mL). H2O (3 V, 240 mL) was added to the mixture. The pH of the mixture was adjusted to pH = 8-9 with 2M aqueous NaOH (~ 3 V, 240 mL) at 0±5oC. The mixture was concentrated to 5-6 V (400-480 mL) with the jacket of the reactor maintained at ≤ 50 °C. The mixture was extracted with MTBE (5 V, 400 mL). The organic phase was washed with 10%w / w aqueous Na SO solution (5 V 400 mL) The organicphase was concentrated to 1-2 V (80-160 mL) with the jacket of the reactor maintained at ≤ 50 °C. Add MTBE (5 V, 400 mL) to mixture. Add 2M HCl solution (in MTBE, 1.1 molar equivalents, 132.7 mL) dropwise to mixture at 0oC. The mixture was stirred at 0±5 °C for at least 2 hours. Add MeOH (0.5 V, 40 mL) to mixture at 0oC. The mixture was stirred at 0±5 °C for at least 2 hours. Filter and rinse with MTBE (2 V, 160 mL). Add wet cake and MTBE (5 V, 400 mL) to a reactor. Add 2M aqueous NaOH solution (5 V, 400 mL) at 20oC. The mixture was stirred for 1h at 20oC. The organic and aqueous phases of the mixture in the reactor were separated. The aqueous phases were extracted with MTBE (5 V, 400 mL). The combined organic phase was concentrated to 2-3 V (160-240 mL) with the jacket of the reactor maintained at ≤ 50 °C. EtOH (3 V, 24 mL) was added to mixture. The organic phase was concentrated to 2-3 V (160-240 mL) with the jacket of the reactor maintained at ≤ 50 °C. EtOH (3 V, 24 mL) was added to mixture. The mixture was added dropwise to H2O (10 V, 800 mL) at 20±5oC. The mixture was stirred for 2 hours at 0±5oC, and then filtered and washed with H2O (2 V, 160 mL). The collected cake of solids was dried at 50±5oC for at least 18 hours. Karl-Fischer titration demonstrated the water content of the dried solids was 0.09%.55.9 g of Compound D was obtained as an off-white solid. Purity assay of the Compound D was 98% by quantitative NMR. The yield of Compound D was 72.5%. Compound D: LCMS (m / z) = 320.2 (M-H+).

[0359] Step 4: Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methyl 4-methylbenzenesulfonate (Compound 6-I): Solvent volume and chemical stoichiometry are calculated based on weight of Compound D. Compound D (1.0 molar equivalents, 50 g) and dichloromethane (3 V, 150 mL) were charged into an appropriately sized jacketed reactor. The contents of the reactor were cooled to 0±5 °C. Triethylamine (2.0 molarequivalents, 31.6 g) was charged into the reactor at 0±5 °C. A solution of 4 -methylbenzenesulfonyl chloride (1.3 molar equivalents, 38.8 g) in dichloromethane (2 V, 100 mL) was added at 0±5 °C. A solution of 4-dimethylaminopyridine (DMAP; 0.02 molar equivalents, 0.38 g) in dichloromethane (0.1 V, 5 mL) was added at 0±5 °C. The reaction mixture was stirred at 0±5 °C for 2 hours. Water (5 V, 250 mL) was added to the reaction mixture, and the resulting mixture was stirred for at least 15 minutes. The aqueous and organic phases in thereactor were separated, and the aqueous phase was extracted with dichloromethane (1 x 5 V, 1 x250 mL). The organic phase and the dichloromethane extract were combined, washed with 5% w / v aqueous sodium bicarbonate solution (2 x 2.5 V, 2 x 125 mL), and washed with water (2 x 2.5 V, 2 x 125 mL). The washed dichloromethane phase was concentrated to 3 V (150 mL), and then n-heptane (3 V, 150 mL) was added. The mixture was concentrated to 3 V (150 mL), and then n-heptane (3 V, 150 mL) was added. The mixture was stirred at 0±5 °C for 1 hour. The solids in the slurry were isolated by centrifugation and washing with n heptane (2 V 100 mL)The filter cake was concentrated to dry to give Compound 6-I (mass = 69.1 g, yield = 93.2%) as a yellow solid. Compound 6-I: LCMS (m / z) = 474.4 (M-H+). Example 3a. Alternative Synthesis of Compound 6-I

[0360] Step 1: Synthesis of 1-(2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxyphenyl)ethan-1- one (Compound Q): Solvent volume and chemical stoichiometry are calculated based on weight of Compound R.1-(2-Fluoro-4-methoxyphenyl)ethan-1-one (1.0 molar equivalents; Compound R), piperidin-4-ylmethanol (1.2 molar equivalents), potassium bicarbonate (1.5 molar equivalents) and N,N-dimethylacetamide (4 V) were charged into an appropriately sized jacketed reactor. The resulting mixture was heated to 100 °C and stirred while being maintained at that temperature for 16 hours. The reaction mixture was cooled to 25±5 °C and diluted with water (5 V). The resulting mixture was extracted with ethyl acetate (10 V). The ethyl acetate extract was washed with saturated aqueous sodium chloride solution (3 x 5 V) and concentrated a volume of 1 V. Then, the following was conducted 2 times, iteratively, in sequence: 1) 2-methyl tetrahydrofuran (3 V) was added to the reactor, and 2) the mixture was concentrated to ca.1 V. Then 2-methyl tetrahydrofuran (3 V) was added to the reactor a final time to provide a solution of Compound Q in 2-methyl tetrahydrofuran that was used directly in the next step. Compound Q: LCMS (m / z) = 264.2 (M-H+).

[0361] Step 2: Synthesis of (E)-1-(2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxyphenyl)- 4,4-dimethylpent-2-en-1-one (Compound P): Solvent volume and chemical stoichiometry are calculated based on assay of the solution of Compound Q. The solution of Compound Q in 2- methyl tetrahydrofuran yielded from Example 3a, Step 1 (4 V) was charged into an appropriately sized jacketed reactor. Potassium hydroxide (3.0 molar equivalents) and pivalaldehyde (1.2 molar equivalents) were chared into the reactor. The resulting mixture was stirred for 4 hours. The reaction mixture was cooled to 0 °C and its pH was adjusted to 7-9 by addition of 2N aqueous hydrochloric acid solution The resulting mixture was extracted with ethyl acetate (10 V) Theethyl acetate extract was washed with saturated aqueous sodium chloride solution (5 V) and concentrated to a volume of 3 V. n-Heptane was added to the concentrated ethyl acetate extract, leading to precipitation of a yellow solid that was isolated by filtration to give Compound P. The combined yield of Example 3, Step 1 and Example 3a, Step 2 was 80%. Compound P: LCMS (m / z) = 332.2 (M-H+).

[0362] Example 3a, Step 2 was adapted using Compound R in place of Compound Q, thereby providing Compound P’. Compound P’: LCMS (m / z) = 237.1 (M-H+). It was determined that Compound P’ is obtained in lower yield and lower purity than is Compound Q.

[0363] To determine the usefulness of Compound P’ as an intermediate Example 3a, Step 1 was conducted using Compound P’ in place of Compound R to successfully provide Compound P.

[0364] Step 3: Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methanol (Compound D): Solvent volume and chemical stoichiometry are calculated based on weight of Compound P. Compound P (1.0 molar equivalent), ethanol (10 V), water (2 V), methanesulfonic acid (1 V), and platinum on carbon (5 wt% of wet platinum on carbon with respect to Compound P, wherein wet platinum on carbon consists of about 50% water, 45% carbon, and 5% platinum by weight) were charged into an appropriately sized jacketed reactor. The atmosphere within the reactor was evacuated and replaced with dihydrogen 3 times. The reactor was then pressurized under a dihydrogen atmosphere to 2.2 MPa. The resulting mixture was stirred for 16 hours at 90 °C. The reaction mixture was filtered, and the filter cake was rinsedwith ethanol (5 V). The pH of the combined f iltrate was adjusted to 8-9 by addition of 2Maqueous sodium hydroxide solution at 0 °C. The resulting mixture was concentrated to a volume of 10 V and then extracted with methyl tert-butyl ether (2 x 10 V). The combined methyl tert- butyl ether extracts were washed with saturated aqueous sodium chloride solution (10 V) and then concentrated to a volume of 3 V. Then, the following was conducted 3 times, iteratively, in sequence: 1) methyl tert-butyl ether (5 V) was added, and 2) the mixture was concentrated to ca. 3 V. Then, methyl tert-butyl ether (7 V) was again added, followed by addition of 2M aqueous hydrochloric acid solution (1.1 molar equivalents) at 0 °C. The resulting mixture was stirred for 2 hours at 0 °C Methanol (1 V) was then added the mixture was stirred for 2 hours at 0 °C andthe resulting suspension was filtered. The solids obtained by filtration and methyl tert-butyl ether (10 V) were charged into an appropriately sized reactor.20% w / v aqueous sodium carbonate solution (20 V) was charged into the reactor at 0 °C, and the resulting mixture was stirred at 0 °C for 1 hour. The aqueous and organic phases in the reactor were separated, and the separated aqueous phase was extracted with methyl tert-butyl ether (10 V). The organic phase and the methyl tert-butyl ether extract were combined and washed with saturated aqueous sodium chloride solution (10 V). The methyl tert-butyl ether and other solvents were removed by evaporation, and then ethanol (105 V) was added. The resulting ethanol solution was combined with water (10 V) and filtered. Compound D was obtained in 75% yield following concentration of the filtrate to dryness. Compound D: LCMS (m / z) = 320.2 (M-H+).

[0365] Step 4: Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methyl 4-methylbenzenesulfonate (Compound 6-I): Solvent volume and chemical stoichiometry are calculated based on weight of Compound D. Compound D (1.0 molar equivalents) and dichloromethane (3 V) were charged into an appropriately sized jacketed reactor. The contents of the reactor were cooled to 0±5 °C. Triethylamine (3.0 molar equivalents) was charged into the reactor at 0±5 °C. A solution of 4-methylbenzenesulfonyl chloride (1.5molar equivalents) in dichloromethane (2 V) was added at 0±5 °C. A solution o f 4-dimethylaminopyridine (DMAP; 0.1 molar equivalents) in dichloromethane (0.1 V) was added at 0±5 °C. The reaction mixture was warmed to 20±5 °C and stirred at that temperature for 2 hours. Water (5 V) was added to the reaction mixture, and the resulting mixture was stirred for at least 15 minutes. The aqueous and organic phases in the reactor were separated, and the aqueous phase was extracted with dichloromethane (1 x 5 V). The organic phase and the dichloromethane extract were combined, washed with 5% w / v aqueous sodium bicarbonate solution (2 x 5 V), and washed with saturated aqueous sodium chloride solution (5 V). The washed dichloromethane phase was concentrated to 3 V, and then n-heptane (10 V) was added. Concentration of the resulting mixture to dryness gave Compound 6-I in 95% yield as a yellow solid. Compound 6-I: LCMS (m / z) = 474.4 (M-H+).

[0366] Compound 6-II is obtained from Compound D according to Example 3a, Step 4 using methanesulfonyl chloride in place of 4-methylbenzenesulfonyl chloride. Compound 6-II: LCMS (m / z) = 398.3 (M-H+). Example 4. Synthesis of Potassium (S)-(2-Cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 4)and ((S)-2-Cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic Acid (Compound 1)

[0367] Step 1: Synthesis of potassium (S)-(2-cyclopropyl-2-(3- oxidophenyl)ethyl)(methyl)phosphinate (Compound 5): Solvent volume and chemical stoichiometry are calculated based on weight of Compound 6-I used in Example 4, Step 2. Dimethyl sulfoxide (5 V, 75 mL) was charged into an appropriately sized reactor under protection of a dinitrogen atmosphere. Compound E (1.0 molar equivalent, 7.61 g) was then charged into the reactor at 20±10 °C. The resulting mixture was stirred for at least 30 minutes at 20±10 °C until Compound E was dissolved. Potassium tert-butoxide (t-BuOK; 2.05 molar equivalents, 7.28 g) was charged into the reactor at 20±10 °C. The resulting mixture was stirred for at least 30 minutes at 20±10 °C until the potassium tert-butoxide was dissolved. Nitrogen was bubbled through the solution in the reactor for at least 10 minutes. The resulting solution, called “Mixture A”, was discharged from the reactor and stored for later use.

[0368] Step 2: Synthesis of Potassium (S)-(2-Cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 4): Solvent volume and chemical stoichiometry are calculated based on weight of Compound 6-I. Tetrahydrofuran (0.5 V, 7.5 mL) was charged into an appropriately sized reactor under protection of a dinitrogen atmosphere. Compound 6-I (1.0 molar equivalent, 15.0 g) was then charged into the reactor at 20±5 °C. The resulting mixture was stirred for at least 30 minutes at 20±5 °C until Compound 6-I was dissolved. Nitrogen was bubbled through the solution in the reactor for at least 10 minutes. The resulting solution, called “Mixture B”, was discharged from the reactor and stored for later use. The synthesis of Compound 4 was then completed as follows at a desiredtime following providing solutions of “Mixture A” and “Mixture B” as detailed above. A mixed solvent of acetonitrile / water (1 / 1, 15 V, 225 mL) was charged into an appropriately sized reactor. Nitrogen was bubbled through the mixed solvent for at least 10 minutes to remove dissolved dioxygen, and the temperature of the mixed solvent was adjusted to and maintained at 20±5 °C. Separately, two continuously stirred tank reactors (CSTRs) were preheated to and maintained at 65±5 °C and purged with nitrogen for at least 5 minutes. The two CSTRs were configured in series, with the outlet of the second CSTR configured to enter the reactor containing water described above. The “Mixture A” and the “Mixture B” were independently configured to flow into the first CSTR, such that the two solutions combined in the first CSTR. The flow rate of the “Mixture A” into the first CSTR was 0.455 mL / min and the flow rate of the “Mixture B” into the first CSTR was 0.100 mL / min (each based on a liquid holdup of 50 mL). The contents of the first CSTR were flowed into the second CSTR in a continuous manner, such that the residencetime of the first CSTR was ca.1.5 hours. The contents of the second CSTR were flowed into thereactor containing acetonitrile / water in a continuous manner, such that the residence time of the second CSTR was ca.1.5 hours. The reaction mixture was quenched upon addition to the mixed solvent (acetonitrile / water =1 / 1, 15 V, 225 mL) inside the reactor, leading to the formation of a slurry. The solids in the slurry were isolated by centrifugation and washing with acetonitrile / water (1 / 1, 2 V, 30 mL) to give “Cake A”, which comprises primarily Compound 4.. Compound 4: LCMS (m / z): 542.5 (Observed as M-H+ of Compound 1).

[0369] Example 4, Step 2 was also conducted in bulk solution (e.g., in a batch reactor) without CSTRs under similar thermal conditions. Compound 4 was reliably generated in bulk solution however in diminished yield. Example 4, Step 2 was also successfully carried out under similar thermal conditions using a coil reactor in place of CSTRs. As such, synthesis of Compound 4 without use of CSTRs is a practicable alternative to Example 4, Step 2 as described above.

[0370] Evaluation of various alternative bases for Example 4, Step 2 was conducted, and it was determined that potassium tert-butoxide provided Compound 4 in greater yield and purity than alternative bases. Alternative bases evaluated included: sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert- butoxide, sodium 2-methylbutan-2-olate, sodium trimethylsilanolate, sodium hydroxide, potassium hydroxide, potassium phosphate, triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, DABCO, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. Similarly, sodium bases such as sodium tert-butoxide were evaluated in place of potassium tert-butoxide according to Example 4, Step 2 (which would generate the sodium salt of Compound 1) and these alternatives were also found to promote the desiredsubstitution reaction while providing the product in diminished yield and purity. Alternative solvents evaluated in Example 4, Step 2 that were also found suitable for generating a detectable and / or isolable quantity of the desired product included: acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl- 2-imidazolidinone, tert-amyl alcohol, water, methanol, ethanol, isopropanol, tert-butanol, and n- butanol.

[0371] Step 3: Synthesis of ((S)-2-Cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic Acid (Compound 1): 2-Methyl tetrahydrofuran (4 V, 60 mL) was charged into a reactor, and nitrogen was bubbled through the 2-methyl tetrahydrofuran for at least 10 minutes. The “Cake A” obtained from Example 4, Step 2 was then added to the reactor, and additional 2-methyl tetrahydrofuran (1 V, 15 mL) was used to rinse the walls of the reactor to ensure all of the solids were suspended in solution. Nitrogen was bubbled through the resulting suspension for at least 10 minutes, and then an aqueous solution of citric acid (0.4 M, 5 V, 75 mL) was charged into the reactor. Nitrogen was bubbled through the resulting mixture for at least 10 minutes, and the mixture was stirred for at least 30 minutes at 20±10 °C. The organic and aqueous phases were separated. The organic phase was a solution comprising Compound 1. Evaporation of the organic phase can provide Compound 1. Compound 1: LCMS (m / z): 542.5 (M-H+).

[0372] Example 4, Step 3 was also adapted to utilize an aqueous solution of trifluoracetic acid (e.g., 0.1 M; e.g., 5 V) in place of the aqueous solution of citric acid to provide a solution of Compound 1.

[0373] The synthetic procedures detailed in Example 4 were successfully adapted to provide Compound 9 by employing Compound 7 in place of Compound E and using about half of the molar quantity of potassium tert-butoxide. Use of CSTRs was not required to provide Compound 9, such that Compound 6-I and Compound 5 (generated by contacting Compound 7 with potassium tert-butoxide) were combined in a single reactor to generate Compound 9.Example 5. Synthesis of Ethyl ((S)-2-Cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 9)Step 1: Synthesis of diethyl (S)-(2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)phosphonate (Compound 13): Diethyl (E)-(2-(3-(benzyloxy)phenyl)-2-cyclopropylvinyl)phosphonate (Compound 11; 130 kg, 328 mol, 97.4% purity) and dichloromethane (1300 L) were charged into a 3000 L reactor at 25-30 °C. (S)-(+)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]- 4,4′-bi-1,3-benzodioxole (2.78 kg, 2.35 mol, 0.007 molar equivalents) and [(1,5- cyclooctadiene)2Rh] tetrafluoroborate (409 g, 1.01 mol, 0.003 molar equivalents) were charged into the reactor sequentially at 25-30 °C. The reactor was pressurized to 2.0 MPa under a dihydrogen atmosphere and stirred at 25-30 °C for 12 hours. The reaction mixture was combined with additional two reaction mixtures prepared in a substantially identical manner, and one additional reaction mixture prepared using 30 kg of Compound 11 in a substantially identical manner. The combined reaction mixtures (derived from 420 kg, 1.06 kmol of Compound 11 in total) were filtered and concentrated in vacuo to provide Compound 13 as a yellow oil (374 kg, 962 mol, 95.4% yield). The enantiomeric purity of the Compound 13 obtained was 96%. Compound 13:1H NMR, 400 MHz, CDCl3δ 7.44-7.21 (m, 5H), 6.87-6.82 (m, 3H), 5.05 (s, 2H), 3.97-3.70 (m, 4H), 2.29-2.20 (m, 4H), 5.05 (s, 2H), 1.34-1.22 (m, 1H), 1.20-1.10 (m, 6H), 0.40- 0.13 (m, 4H). Compound 13: LCMS (m / z) = 389.1 (M-H+).

[0374] Step 2: Synthesis of ethyl hydrogen (S)-(2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)phosphonate (Compound 12): Water (360 L) and sodium hydroxide (111 kg2.78 kmol, 6.0 molar equivalents) were charged into a 3000 L reactor at 20-30 °C. Compound 13 (180 kg, 463 mol, 1.0 molar equivalents) and ethanol were charged into the reactor at 20-30 °C. The resulting mixture was stirred at 80-100 °C for 22 hours. The reaction mixture was combined with one additional reaction mixture prepared in a substantially identical manner, and one additional reaction mixture prepared using a smaller quantity of Compound 13 in a substantially identical manner. The combined reaction mixtures were derived from 374 kg of Compound 13 in total. The combined reaction mixtures were concentrated at 40-50 °C, and then 10 M aqueous hydrochloric acid solution (374 M) and water (748 L) were added. The resulting mixture was stirred at 20-30 °C, and the organic and aqueous phases where then separated. The organic phase was concentrated at 40-50 °C to provide Compound 12 as a brown oil (281 kg, 761 mol, 91.3% yield, 97.7% purity). Compound 12: LCMS (m / z) = 361.2 (M-H+).

[0375] Step 3: Synthesis of (1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium ethyl (S)-(2-(3- (benzyloxy)phenyl)-2-cyclopropylethyl)phosphonate (Compound 33): Compound 12 (90 kg, 249mol, 1.0 molar equivalent) and acetone (1800 L) were charged into a 6300 L reactor at 20 -25 °C.(1R,2S)-2-Hydroxy-1,2-diphenylethan-1-amine (55.9 kg, 262 mol, 1.05 molar equivalents) was charged into the reactor at 20-25 °C. The resulting mixture was stirred at 20-25 °C for 2 hours and then filtered. The solids obtained by filtration are combined with solids obtained by repeating the aforementioned sequence twice in an identical manner, in addition to a smaller batch of solids obtained according to the same sequence, such that the total combined solids are derived from 280 kg of Compound 12. The combined solids were purified by recrystallization: the combined solids were dissolved in a mixture of tetrahydrofuran (1400 L) and n-heptane (2800 L) between 20-55 °C. Following cooling of the resulting mixture to 20-25 °C, the mixture was filtered and dried in a vacuum oven at 50-55 °C to provide Compound 33 as a white solid (351 kg, 606 mol, 80.9% yield, 99.1% purity). Compound 33: 1H NMR, 400 MHz, MeOD δ 7.42-7.30 (m, 4H), 7.28-7.25 (m, 4H), 7.25-7.20 (m, 6H), 7.19-7.18 (m, 2H), 7.17-6.79 (m, 3H), 5.21-5.20 (d, J = 4.0 Hz, 1H), 5.07 (s, 2H), 4.45-4.44 (d, J = 3.6 Hz, 1H), 3.62-3.44 (m, 2H), 2.29-2.27 (m, 1H), 2.06-2.04 (m, 2H), 1.08-0.94 (m, 4H), 0.52-0.05 (m, 4H). The enantiomeric purity of the Compound 33 obtained was over 99.8%.

[0376] Step 4: Synthesis of ethyl hydrogen (S)-(2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)phosphonate (Compound 12): Water (10 V) was charged into an appropriately sized reactor. Concentrated aqueous hydrochloric acid solution (2.0 molar equivalents) was added to the reactor at 20±5 °C. Compound 33 (94 kg) was added to the reactor at 20±5 °C, and the resulting mixture was stirred at 20±5 °C for 30 minutes. Dichloromethane (5 V) was added to the reactor at 20±5 °C and the resulting mixture was stirred at 20±5 °C for at least 1 hour. The organic and aqueous phases in the reactor were separated and the organic phase was washedwith 1N aqueous hydrochloric acid solution (3 V) at 20±5 °C. The washing step with 1N aqueous hydrochloric acid solution (3 V) can be optionally repeated to remove additional (1R,2S)-2- hydroxy-1,2-diphenylethan-1-amine from the organic phase. The organic phase was then washed with 20% w / v aqueous sodium chloride solution (3 V). The volume of the organic phase was concentrated to 1.5 V by evaporation, with the jacket of the reactor not exceeding 40 °C. Toluene (1 V) was added, and the resulting mixture was concentrated to 1.5 V by evaporation, with the jacket of the reactor not exceeding 60 °C. Karl-Fisher titration demonstrated the water content of the resulting solution, a solution of Compound 12 in toluene was ≤ 0.1%. HPLC assay of the solution of Compound 12 in toluene demonstrated the yield was 94% (equivalent to 55.4 kg of Compound 12). The enantiomeric purity of the Compound 12 obtained was over 99.8%. Compound 12: LCMS (m / z) = 361.2 (M-H+).

[0377] Step 5: Synthesis of ethyl ((S)-2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)phosphonochloridate (Compound 19): Dichloromethane (6 V) was charged into a reactor at 20±5 °C. Karl-Fisher titration demonstrated the water content of the dichloromethane in the reactor was ≤ 0.1%. N,N-dimethylformamide (0.05 molar equivalents) was added to the reactor in a dropwise manner at 20±5 °C. Oxalyl chloride (2.0 molar equivalents) was added to the reactor at 20±5 °C. The resulting mixture was stirred at 20±5 °C for at least 30 minutes. The toluene solution of Compound 12 obtained from Example 5, Step 4 (equivalent to 55.4 kg of Compound 12; 1.0 molar equivalent, ca.2.5 V) was added to the reactor in a dropwise manner at 20±5 °C. The resulting mixture was heated to 30±5 °C and stirred at that temperature for at least 12 hours. The volume of the reaction mixture was concentrated to 2.5 V by evaporation, with the jacket of the reactor not exceeding 35 °C. Then, the following was conducted 3 times, iteratively, in sequence: 1) dichloromethane (8 V) was added to the reactor, and 2) the mixture was concentrated to 2.5±0.5 V with the jacket of the reactor maintained at ≤ 35 °C. Then dichloromethane (0.5 V) was added to the reactor a final time to provide a solution of Compound 19 in dichloromethane and toluene that was used directly in the next step without additional purification.

[0378] Step 6: Synthesis of ethyl ((S)-2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)(methyl)phosphinate (Compound 21): Tetrahydrofuran (THF; 4 V) was charged into an appropriately sized jacketed reactor. After the tetrahydrofuran was stirred for at least 5 minutes, Karl-Fischer titration demonstrated the water content of the tetrahydrofuran in the reactor was ≤ 0.1%. Methylmagnesium bromide solution (2.0 molar equivalents, 3 M in 2-methyl THF, ca.1.8 V) was charged into the reactor at 20±5 °C. The resulting solution was cooled to - 25±10 °C. The solution of Compound 19 in dichloromethane and toluene yielded from Example 5, Step 5 (ca 3 V) was then charged into the reactor at 25±10 °C and the resulting mixture wasstirred for at least 1 hour at -25±10 °C. The resulting mixture was quenched by adding it in a dropwise manner to a 20% w / v aqueous citric acid solution (8 V) at 5±5 °C. The resultingmixture was stirred for at least 30 minutes before being allowed to stand f or at least 30 minutes.The aqueous and organic phases of the mixture were separated. The aqueous phase was extracted with ethyl acetate (5 V) at 20±5 °C and the ethyl acetate extract was combined with the organic phase. The combined organic solutions were washed with 5% w / v aqueous sodium carbonate solution (2 x 5 V) at 20±5 °C, and subsequently washed with 9% w / v aqueous sodium sulfate solution (2 x 5 V) at 20±5 °C. The washed solution was concentrated to a volume of 2.5 V by evaporation with the jacket of the reactor maintained at ≤ 25 °C. Ethyl acetate (8 V) was then added to yield a solution of Compound 21 in toluene and ethyl acetate. HPLC assays determined the yield of Compound 21 was 95% over two steps (equivalent to 52.3 kg of Compound 21). Compound 21: LCMS (m / z) = 359.2 (M-H+).

[0379] Step 7: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3- hydroxyphenyl)ethyl)(methyl)phosphinate (Compound 7): The solution of Compound 21 in toluene and ethyl acetate provided by Example 5, Step 6 (equivalent to 52.3 kg of Compound 21; 2.5 V) was charged into an autoclave reactor. Ethyl acetate (0.5 V) was used to rinse the sides of the reactor and ensure all of Compound 21 was in solution in the reactor.10 wt% palladium on carbon (5.5% w / w basis with respect to Compound 21) was charged into the reactor, which was again rinsed with ethyl acetate (1 V) to ensure all of the added palladium on carbon was in suspension. The resulting mixture was stirred and the reactor was pressurized to contain a dihydrogen atmosphere at 0.1-0.4 MPa. Stirring at 20±5 °C was continued for at least 12 hours. To workup the reaction mixture, microcrystalline cellulose (15% w / w basis with respect to Compound 21) was loaded into a pressure filter, wetted with ethyl acetate, and compacted with a flow of nitrogen through the filter. The reaction mixture was filtered through the compactedmicrocrystalline cellulose, which was then washed with ethyl acetate (2 x 4 V). The combinedfiltrate was charged into a reactor, where in was concentrated to 2-3 V by evaporation with the jacket of the reactor maintained at ≤ 50 °C. Then, the following was conducted 2 times, iteratively, in sequence: 1) ethyl acetate (5 V) was added to the reactor, and 2) the mixture was concentrated to 2-3 V with the jacket of the reactor maintained at ≤ 50 °C. Karl-Fischer titration demonstrated the water content of the resulting solution in the reactor, a solution of Compound 7 in toluene and ethyl acetate, was ≤ 0.1%. HPLC assay of the solution of Compound 7 in toluene and ethyl acetate indicated the yield was 97% (equivalent to 38.0 kg of Compound 7). Compound 7: LCMS (m / z) = 269.1 (M-H+).

[0380] Step 8: Synthesis of ethyl ((S)-2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin 4 yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 9): Ethylacetate (19 V) was charged into a reactor under a nitrogen atmosphere. Nitrogen was bubbled through the ethyl acetate in the reactor for at least 30 minutes. Karl-Fischer titration demonstrated the water content of the ethyl acetate in the reactor was ≤ 0.1%. Tetramethylazodicarboxamide (TMAD; 2.30 molar equivalents) was charged into the reactor at 20±5 °C, with ethyl acetate (2 V) used to rinse any residual reagent into the reactor. The headspace of the reactor was purged with nitrogen for 5 minutes. The mixture in the reactor was cooled to 0±5 °C. Tri(n-butyl)phosphine (2.50 molar equivalents) was charged into the reactor at 0±5 °C and the headspace of the reactor was purged with nitrogen for 5 minutes. The resulting mixture was stirred at 0±5 °C for 20-60 minutes. Separately, a solution of Compound 7 in toluene and ethyl acetate obtained from Example 5, Step 7 (1.0 molar equivalent, 3 V; equivalent to 35.0 kg of Compound 7) was charged into a reactor. Compound B (1.0 molar equivalent) was then added to the reactor at 20±5 °C, with ethyl acetate (1 V) used to rinse any residual reagent into the reactor. Nitrogen was bubbled through the resulting mixture for at least 30 minutes. The aforementioned mixture of TMAD and tri(n-butyl)phosphine was then charged into the reactor in a portionwise manner at 20±5 °C, and the resulting mixture was stirred for at least 5 hours at 20±5 °C. The reaction mixture was quenched by addition of 10% w / v aqueous sodium chloride solution (20 V) at 15±5 °C. The resulting mixture was stirred for at least 30 minutes and then allowed to stand for at least 30 minutes before the organic and aqueous phases were separated. The organic phase was washed with 20% w / v aqueous sodium chloride solution (3 x 10 V) at 20±5 °C, with every washing being stirred for at least 30 minutes and then allowed to stand for at least 30 minutes before the organic and aqueous phases were separated. The washed organic phase was concentrated to 4-6 V by evaporation with the jacket of the reactor maintained at ≤ 60 °C. Then, the following was conducted 3 times, iteratively, in sequence: 1) methanol (6 V) was added, and 2) the mixture was concentrated to 4-6 V with the jacket of the reactor maintained at ≤ 60 °C. This procedure yielded a solution of Compound 9 in methanol with residual toluene and ethyl acetate. Compound 9: LCMS (m / z) = 570.4 (M-H+). Example 6. Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methanol (Compound D)

[0381] Step 1: Synthesis of methyl (E)-1-(2-(4,4-dimethylpent-1-en-1-yl)-5- methoxyphenyl)piperidine-4-carboxylate (Compound T): Tetrahydrofuran (600 L, 5 V) was charged into a 5000 L reactor with a solution of Compound U (200 kg, 432 mol, 1.0 molar equivalents) in tetrahydrofuran (1 V) at 15-20 °C.2-((3,3- dimethylbutyl)sulfonyl)benzo[d]thiazole (791 kg, 497 mol, 1.15 molar equivalents) in tetrahydrofuran was then added to the reactor at 15-20 °C. Under a nitrogen atmosphere, the resulting mixture was cooled to a range of -10 to -20 °C. Lithium bis(trimethylsilyl)amide (1.0 molar equivalent, 384 kg, 1 M solution in THF) was added to the reactor slowly at -20 to 0 °C, and the resulting mixture was stirred at -20 to 0 °C for 30 minutes. Lithium bis(trimethylsilyl)amide (0.6 molar equivalents, 228 kg, 1 M solution in THF) was added to the reactor slowly at -20 to 0 °C, and the resulting mixture was stirred at -20 to 0 °C for 30 minutes. The reaction mixture was maintained at a temperature of 35 to 45 °C for 4 hours, and then cooledto 15 to 25 °C. The reaction mixture was then quenched by addition of water (360 L, 3 V) at 20 -30 °C before the aqueous and organic phases were separated. The aqueous phase was extracted with methyl tert-butyl ether (2 x 360 L). The organic phase and methyl tert-butyl ether extracts were combined and concentrated to 3-4 V at 40-50 °C. Then, the following was conducted 2 times, iteratively, in sequence: 1) methanol (3 V) was added, and 2) the mixture was concentrated to 2-3 V at 40-50 °C. Water (60 L, 0.5 V) was then added, and the resulting mixture was stirred with heating at 60-70 °C for 1 hour. After the resulting mixture was cooled to 15-25 °C it was filtered, and the solids were washed with methanol (120 L, 1 V). The washed solids andmethanol (360 L, 3 V) were charged into a reactor and stirred for 4 hours at 15 -25 °C. Theresulting mixture was filtered and the solids were dried in an oven at 50-55 °C for 24 hours to yield Compound T as a white solid (105 kg, 67.2% yield). Compound T: LCMS (m / z) = 346.4 (M-H+).1H NMR (400 MHz, chloroform-d) δ 0.82-1.02 (m, 9H), 1.84-2.05 (m, 4H), 2.07-2.26 (m, 2H), 2.37-2.50 (m, 1H), 2.57-2.72 (m, 2H), 3.21-3.37 (m, 2H), 3.69-3.77 (m, 3H), 3.78-3.84 (m, 3H), 5.64-6.14 (m, 1H), 6.41-6.62 (m, 3H), 7.36 (d, J=8.38 Hz, 1H).

[0382] Step 2: Synthesis of methyl 1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidine-4- carboxylate (Compound S): Tetrahydrofuran (1050 L, 10 V) and Compound T (105 kg, 305 mol, 1.0 molar equivalents) was charged into a 2000 L reactor at 15-20 °C. The headspace in the reactor was evacuated and replaced with argon three times. Palladium on carbon (21 kg, 20% w / w with respect to Compound T) was added to the reactor at 15-20 °C. The headspace in the reactor was evacuated and replaced with argon three times. The headspace in the reactor wasevacuated and replaced with hydrogen three times. The resulting mixture was stirred unde r ahydrogen atmosphere at a pressure of 0.4 MPa for 12 hours at 25-30 °C. The reaction mixture was cooled to 15-20 °C and the headspace in the reactor was evacuated and replaced with argon three times. The reaction mixture was filtered and the solids were washed with tetrahydrofuran (315 L, 3 V). The combined filtrate was concentrated at 40-45 °C to obtain Compound S as a tetrahydrofuran solution (equivalent to 322 kg Compound S, 90% yield). Compound S:1H NMR (400 MHz, chloroform-d) δ 0.89 (s, 9H), 1.20-1.30 (m, 2H), 1.52-1.62 (m, 2H), 1.84-1.96 (m, 2H), 1.97-2.05 (m, 2H), 2.44 (tt, J=11.23, 4.16 Hz, 1H), 2.49-2.59 (m, 2H), 2.67 (td, J=11.44, 2.50 Hz, 2H), 3.09 (dt, J=11.94, 2.91 Hz, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 6.60 (dd, J=8.38, 2.63 Hz, 1H), 6.63 (d, J=2.50 Hz, 1H), 7.12 (d, J=8.25 Hz, 1H).

[0383] Step 3: Synthesis of (1-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methanol (Compound D): Tetrahydrofuran (90 L, 1 V) and the solution of Compound S in tetrahydrofuran obtained from Example 6, Step 2 (equivalent to 322 kg Compound S, 260 mol, 1.0 molar equivalents, 1 V) were charged into a 1000 L reactor at 15-25 °C. The headspace in the reactor was purged with nitrogen for 20 minutes. Lithium borohydride (139 kg, 312 mol, 1.2 molar equivalents, 2M in THF) was added to the reactor in a dropwise manner at 25-40 °C. The reaction mixture was then stirred for 12 hours at 30-40 °C. The reaction mixture was slowly added to a 10% w / v aqueous ammonium chloride solution (270 L, 3 V) at 20-30 °C. Methyl tert- butyl ether (270 L, 3 V) was added and the organic and aqueous phases were separated. The aqueous phase was extracted with an additional aliquot of methyl tert-butyl ether (270 L, 3 V). The organic phase and methyl tert-butyl ether extract were combined and concentrated in vacuo until no further distillate was observed. n-Heptane (89.6 L, 1 V) was added to the resulting residue, and the resulting mixture was concentrated in vacuo until no further distillate was observed. A slurry was formed by adding n-heptane (180 L, 2 V) to the resulting residue and stirring the resulting mixture for 2 hours at 5-20 °C. The slurry was filtered and the solids were collected and dried in vacuo at 20-30 °C to provide Compound D (72 kg, 224 mol, 86% yield) as a white solid. Compound D: LCMS (m / z) = 320.20 (M-H+).Example 7. Alternative Syntheses of Cyclopropyl(3-methoxyphenyl)methanone (Compound 27)

[0384] Alternative Synthesis 1: Under N2protection, to a mixture of cyclopropanecarbonyl chloride (Compound 25, 119 mg, 1.14 mmol, 1.2 eq) and THF (1 V, 1 mL) was added CuCN·2LiCl (1.14 mL, 1.2 eq, 1 M in THF) at 20 ± 5 °C. The resulting mixture was cooled to 0 ± 5 °C, and then ZnCl2(1.36 mL, 1.0 eq, 0.7 M in THF) and (3-methoxyphenyl) magnesium bromide (Compound 24, 0.95 mL, 0.95 mmol, 1.0 eq, 1 M in THF, 200 mg) were added in a dropwise manner, followed by stirring for at least 16 h at 20±5°C. Water (2 V, 2 mL) was added to the reaction mixture, and the aqueous and organic phases of resulting mixture were separated. The aqueous phases was extracted with ethyl acetate (2 V, 2 mL) and the ethyl acetate extracts were combined with the organic phase. The combined organic phases were concentrated under vacuum to provide Cyclopropyl(3-methoxyphenyl)methanone (300 mg).

[0385] Alternative Synthesis 2: Under N2protection, to a mixture of cyclopropanecarbonyl chloride (Compound 25, 119 mg, 1.14 mmol, 1.2 eq) and THF (5V, 5 mL) was added CuCN·2LiCl (0.1 mL, 0.1 eq, 0.095 mmol, 1 moL in THF) at 20±5°C. The resulting mixture was cooled to 0±5°C, and then (3-methoxyphenyl)magnesium bromide (Compound 24, 0.95 mL, 1.0 eq, 1 M in THF, 200 mg) was added in a dropwise manner, followed by stirring for at least 16 h at 20±5°C. Water (5 V, 5 mL) was added to the reaction mixture, and the aqueous and organic phases of resulting mixture were separated. The aqueous phases was extracted with ethyl acetate (5 V, 5 mL) and the ethyl acetate extracts were combined with the organic phase. The combined organic phases were concentrated under vacuum to provide Cyclopropyl(3- methoxyphenyl)methanone (220 mg). Example 8. Compound 1 Salt Screen

[0386] Appropriate amounts of 8 bases were dissolved in MeOH or MeOH / H2O (4 / 1) to prepare a solution with concentration of 0.1 M.

[0387] About 315 mg of Compound 1 was dissolved in 10.5 mL of MeOH at RT to prepare a solution of Compound 1 of 30 mg / mL.

[0388] The solution of Compound 1 (30mg / mL) was distributed into a 96-well plate. Each well contained 200 µL of the solution of Compound 1.1.1 eq. of each base solution (0.1M) as described above was added, according to the following tables: MeOH EtOH IPA IBA MEK THF T-S TCR = Crystalline; WCR = Weak crystalline; Hemi-S = Hemi-solid; - indicates the samples were sticky or glassy state.* represents the samples were analyzed by XRPD. Other samples were only observed by PLM.

[0389] After evaporated to dryness, 200 µL of the selected solvent was added into each well.Wells were covered with a film with pinhole, and evaporated under ambient conditions. Somesolids with sufficient quantity were analyzed by XRPD and1H-NMR. Compound 1 formed salts with all selected bases.

[0390] CaCl2and MgCl2were utilized to transform the potassium salt of Compound 1 into the calcium salt and magnesium salt after metathetical reactions. About 21 mg of Compound 1 was added into 1 mL of EtOH at RT and 1.1 eq. of KOH (10 M in water) was added to form K salt firstly. Then, either 0.55 eq. of CaCl2solution (1 M in water) or either 0.55 eq. of MgCl2solution (1 M in water) was added to prepare Ca salt and Mg salt respectively.

[0391] From the salt screens, two hydrate form of the sodium salt were identified. One sodium form had high crystallinity, was slightly hygroscopic and easy to prepare. The other form was hygroscopic and had poor repeatability for the preparation. Thus, one of the sodium salts showed acceptable solid-state properties.

[0392] Two hydrate form of the potassium salt (Compound 4) were identified. Multiple thermal events were observed by DSC for K salts. Therefore, K salts were not further evaluated.

[0393] One hydrate form of the calcium salt was identified. TGA showed 2.9% weight loss at 26 - 108 °C, may be due to loss of water. DSC exhibited one broad endothermic peak near 83 °C due to dehydration and melting, which were observed by the hot-stage microscope. It showed relatively weak crystallinity, low dehydrated temperature and seems had quite low solubility inorganic solvents and water. Hence, it was not suitable for development.

[0394] One hydrate form of the magnesium salt was identified. It was hygroscopic with 14.2% of water uptake at 90% RH and would convert to a hydrate above 50% RH. The crystal form remained unchanged after DVS testing. Hence, it was not suitable for development due to the strong hygroscopicity.

[0395] Four potential ammonium salt forms were identified. The DSC thermograms for all samples exhibited broad endothermic peaks beginning at RT, might be due to dehydration / desolvation, suggesting all of them were likely unstable hydrates / solvates. Therefore, no more analysis was performed.

[0396] One form of the Meglumine salt was identified. DSC showed broad endothermic peaks at 52 °C due to dehydration closely followed by a sharp endothermic peak at 82 °C due to melting.

[0397] One form of the Tromethamine salt was identified. DSC showed one broad endothermic peak at 66 °C due to dehydration closely followed by a sharp endothermic peak at 97 °C due to melting DVS result showed the form was physically stable at 10 - 90% RH with reversible sorption and desorption, and the water content was about 3.2-3.7%. The form remained unchanged after DVS testing.

[0398] One form of the Arginine salt was identified. It was irregular shaped crystals. Almost no weight loss and one endothermic peak at 132°C due to melting were observed by TGA and DSC. DVS result indicated Form I was hygroscopic with 7.2% and 8.3% water uptake at 80 and 90% RH, and likely converted toa hydrate above 50% RH. The crystal form remained unchanged after DVS testing.

[0399] One form of the Lysine salt was identified. It was irregular shaped crystals. Almost no weight loss was observed by TGA. DSC exhibited one endothermic peak at 194 °C due to melting. DVS result showed the form was very hygroscopic with 22.3% and 33.9% of water uptake at 80 and 90% RH. The critical point was 60% RH.

[0400] No crystalline forms of the Choline salt could be obtained. Example 9. Stability Testing

[0401] About 10 mg of Compound 2, Crystalline Form 1 of Compound 2 (sodium salt), the potassium salt form and tromethamine salt form were placed at 60 °C and 40 °C / 75%RH up to 10days in the open. At 0, 4, and 10 days the sample was dissolved with the diluent to prepare a solution for purity analysis by HPLC. Solid samples were analyzed by XRPD to check the crystal form.

[0402] Compound 2 remained unchanged after 10 days upon two conditions. The crystallinity of Crystalline Form 1 of Compound 2 (sodium salt) decreased at 60 °C for 4 days and 10 days due to loss of water, but increased after exposed at ambient conditions. The potassium salt form may convert to another form under two conditions. Tromethamine salt converted to a mixture of forms and an unknown pattern at 60 °C for 4 days, suggesting water was partially lost, whileremained unchanged at 10 days, might be due to the higher lab humidity, indicating thedehydrated form re-adsorbed water easily.

[0403] Overall, four samples were physically and chemically stable at 40 °C / 75%RH for 10 days. But, the purity of Compound 2, Crystalline Form 1 of Compound 2 (sodium salt) and the potassium salt decreased at 60 °C due to an increasing impurity. Among them, Crystalline Form 1 of Compound 2 (sodium salt) showed the least purity decrease.

[0404] Results of the stability testing are found in the following table: ge C d ity T alExample 10. Preparation Crystalline Form 1 of sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4- dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 2)

[0405] To open head round bottom flask containing 37 mL of acetone and 1.95 mL of water was added Compound 1 (1.7 g, 3.14 mmol) to obtain a slightly turbid suspension. Then, 315 µL of NaOH (10 M in water) was added. Precipitation occurred immediately. The suspension was stirred at RT for 5 hours. Solids were collected by filtration, vacuum dried at 50 °C overnight and characterized. Crystalline Form 1 of Compound 2 was obtained as a white solid with 87% yield and purity of 99.98%

[0406] The sample was short rod-like crystals with few flakes. Obvious chemical shifts and noresidual solvent were detected by1H-NMR. TGA exhibited 7.4% of weight loss after removal of the sample from the drying oven, while the weight loss increased to 8.6% and 9.9% after exposed at ambient conditions for 8 h and 4 days, respectively. DSC showed two overlapped broad endothermic peaks at RT-130 °C, followed by a small endothermic peak at 266 °C. Hence, Crystalline Form 1 was a hemiheptahydrate (3.5 hydrate). The theoretical water content is 10%. Example 11. Preparation Crystalline Form 2 of sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4- dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 2)

[0407] To a vial containing 1 mL of EtOH was added Compound 1 (22 mg, 0.04 mmol) to obtain a solution. Then, 400 µL of NaOH (0.1 M in EtOH) was added. With stirring, 3.8 mL of n-heptane was then added and the solvent was concentrated to ~ 3 mL by N2 flow. After stirring for 2 days, solids were collected by filtration. Crystalline Form 2 of Compound 2 was obtained as a white solid.

[0408] The sample was thin needle shaped crystals with moderate crystallinity. TGA exhibited 2.1% of weight loss at 48 - 208 °C attributed to water. A broad endothermic peak at 121 °C was observed by DSC, followed by a small endothermic peak at 265 °C, suggesting Crystalline Form 2 was a hydrate. The theoretical water content for monohydrate is 3.1%. DVS result showed Crystalline Form 2 was hygroscopic with 14.6% of water uptake at 90% RH and the crystal form likely converted to Crystalline Form 1 above 50% RH. Overall, Crystalline Form 2 was a monohydrate containing about 2% of water. Example 12. Preparation Crystalline Form 3 of Compound 2 from Crystalline Form 1 of Compound 2

[0409] A sample of Crystalline Form 1 of Compound 2 was slurred in dry acetone, the solid collected by filtration, and heated to 150 °C by DSC to afford Crystalline Form 3 of Compound 2.

[0410] The sample was irregular shaped crystals with weak crystallinity. Almost no weight loss and a sharp endothermic peak at 167 °C due to melting, followed by a small endothermic peak at 268 °C were observed by TGA and DSC, suggesting Crystalline Form 3 was an anhydrate. DVS results showed that Crystalline Form 3 adsorbed moisture quickly at > 30%RH, and the water uptake increased to 14% at 60% RH.Example 13. Preparation Crystalline Form 4 of Compound 2 from Crystalline Form 1 of Compound 2

[0411] A sample of Crystalline Form 1 of Compound 2 was heated to 230 °C at 10 °C / min by DSC.

[0412] The sample was glass-like material with weak birefringence. DSC exhibited two very shallow peaks at 55 °C and 105 °C and a small and sharp endothermic peak at 268 °C with the enthalpy of 3.6 J / g. It was very hygroscopic with 18% water uptake at 90% RH, and the critical point was 30% RH. The crystal form was similar as Na salt Form 1 with very weak crystallinity after DVS testing, indicating Crystalline Form 4 would convert to Crystalline Form 1 above 30% RH.

[0413] Summary of the Crystalline Forms of Compound 2 are found in the following table: H H H H H H. . H Example 14. Preparation Crystalline Form 4 of Compound 2 from Crystalline Form 1 of Compound 2

[0414] Inter-conversion and water activity study for Crystalline Forms 1, 2, 3 and 4 were performed in acetone / water systems (containing 0, 0.5%, 1%, 20% and 100% of water, respectively) at RT and 50 °C. The mixtures converted to Crystalline Form 3 in dry acetone at 50 °C after 4 days, and tended to convert to Form 3 in dry acetone at RT and acetone / 0.5% water at 50 °C, suggesting Crystalline Form 3 was the most stable form in non-aqueous systems and inaqueous systems at aw ≤ 0.1 at 50 °C. In other systems, all mixtures converted to Crystalline Form1, indicating Form 1 was the most stable form in aqueous systems with aw ≥ 0.1 at RT and aw ≥ 0.25 at 50 °C.

[0415] Results of the inter-conversion and water activity study results are found in the following table:Sample Solvent AwTemp. Time Result F 2 F FExample 15. Physical Stability upon High Humidity

[0416] Physical stability of Crystalline Form 1 was evaluated at RT / 92.5%RH for 13 days. No change was observed. Hence, Crystalline Form 1 was physically stable upon high humidity condition for 13 days. Example 16. Micronization of Crystalline Form 1 of Compound 2

[0417] Crystalline Form 1 of Compound 2 was micronized by jet milling with the following parameters to evaluate the milling feasibility: feed pressure: 0.45 Mpa feed manually; (2) milling pressure 1: 0.5 Mpa; and (3) milling pressure 2: 0.5 Mpa.

[0418] After milling, about 110 mg of the material was obtained with the yield of 58%, andanalyzed by XRPD, PLM, DSC and TGA immediately. The particle size decreased from 20 - 100 µm to less than 10 µm, and the crystal form remained unchanged. However, the TGA showed about 11% of weight loss in two steps, and the DSC curve exhibited one more endothermic peakat 126 °C. In addition, the purity did not decrease confirmed by HPLC. Furthermore, the milledmaterial still had about 11% weight loss in two steps by TGA after being exposed at ambient condition for 3 days and RT / 92.5% RH for 5 days.

[0419] To investigate the 2-step weight loss at 150 - 270 °C was due to loss of water or decomposition, the initial material and the milled material (exposed at RT for 3 days and storedin closed vial at RT for 10 days) was heated to 250 °C by TGA and then checked the purity byHPLC, respectively. Both samples slightly decomposed after being heated to 250 °C by TGA,while the decreased purity of the milled material was ~2.4 folds higher than that of the initialmaterial, and the color of the heated sample turned to light yellow for the milled material,suggesting the second step weight loss for the milled material might be due to decomposition. Overall, micronization may reduce the decomposition temperature of Crystalline Form 1.

[0420] Results of micronization on weight loss by TGA are found in the following table: Weight loss by TGA C EExample 17. Solubility Screening of Crystalline Form 1 of Compound 2

[0421] The solubility of Crystalline Form 1 of Compound 2 was estimated in 14 organic solvents. About 2 mg of Crystalline Form 1 was weighed into a sample vial and the solvent wasadded gradually with vortex until the drug solution was clear by observation or up to 1000 V.The estimated solubility (mg / mL) was calculated.

[0422] Results of solubility screening are found in the following table:EA <1 Water 0.1 Example 18. Polymorphic Screening – Slurry Study

[0423] Based on the estimated solubility of Crystalline Form 1 of Compound 2, an appropriate amount Crystalline Form 1 was weighed into a sample vial and the solvent was added to make a suspension at the concentration of 15 - 100 mg / mL. All suspensions were stirred at RT for 3 days and 50 °C for 1 day. Then, the solid was filtered and the filter cake was analyzed by XRPD.

[0424] At RT, Crystalline Form 1 converted to a mixture of Crystalline Form 1 and Crystalline Form 2 with extra peaks in EA, IPAC, acetone and MEK and remained unchanged in other solvents, decreased crystallinity was observed in ACN and MTBE.

[0425] While at 50 °C, Crystalline Form 1 converted to a mixture of Crystalline Form 1 and Crystalline Form 2 in EA, IPAC, ACN, MEK and MTBE and remained unchanged in heptane, water, and toluene. A mixture of Crystalline Form 1 and Crystalline Form 3 was obtained from acetone.

[0426] Results of the slurry study are summarized in the following table: )Example 19. Polymorphic Screening – Anti-solvent Addition Study

[0427] An amount Crystalline Form 1 was dissolved in MeOH at 150 mg / mL and in EtOH at136 mg / mL, respectively. The drug solutions were filtered and the filtrates were equallydistributed into sample vials. Each vial contained 0.1 mL or 0.12 mL of drug solution.Subsequently, the anti-solvent was added gradually, 0.1 - 0.5 mL per time, until solids precipitated. If precipitation occurred, products were characterized accordingly. Crystalline Form 1 was obtained from most of the solvents, except in MeOH / MTBE.

[0428] Resul f h i l d i d i h f ll i bl :Acetone 1:40 Form 1Example 20. X-Ray Powder Diffraction (XRPD)

[0429] XRPD diffractograms were collected on an X-ray diffractometer. The sample wasprepared on a zero-background silicon wafer by gently pressing onto the flat surface.

[0430] The Parameters of XRPD diffractions are summarized in the following table:p g p p g p pan

[0431] XRPD peaks characteristic of Crystalline Form 1 of Compound 2 (see FIG.1) are provided in the following table:. . .. . . 15169 583615 02% 20268 437798 08%Angle d-Value Relative Angle d-Value Relative

[0432] XRPD peaks characteristic of Crystalline Form 2 of Compound 2 (see FIG.3) are provided in the following table:19.003 4.66652 15.2% 37.468 2.39837 1.1%

[0433] XRPD peaks characteristic of Crystalline Form 3 of Compound 2 (see FIG.5) are provid4.015 21.98922 69.8% 6.883 12.83192 9.3%Angle d-Value Relative Angle d-Value Relative

[0434] XRPD peaks characteristic of Crystalline Form 4 of Compound 2 (see FIG.7) are provided in the following table:17.288 5.12525 2.3% Example 21. Thermogravimetric Analysis (TGA)

[0435] TGA data were collected on a TA Instrument and analyzed using TRIOS. About 1-5 mg of a sample was loaded onto a pre-tared aluminum TGA pan and heated with the parameters in the following table:Heating rate 10 °C / minInstrument TA, Discovery TGA 55

[0436] The TGA patterns for Crystalline Form 1 (Figure 2), Crystalline Form 2 (Figure 4), and Crystalline Form 3 (Figure 6) were acquired with the above parameters.

[0437] Crystalline Form 1 of Compound 2 demonstrated a TGA pattern with an about 9.9% w / w mass loss from about 26 °C to about 123 °C.

[0438] Crystalline Form 2 of Compound 2 demonstrated a TGA pattern with an about 2.1% mass loss from about 48 °C to about 208 °C.

[0439] Crystalline Form 3 of Compound 2 demonstrated a TGA pattern with no substantial mass loss from about 50 °C to about 200 °C. Example 22. Differential Scanning Calorimetry (DSC)

[0440] DSC data were collected on a TA Instrument and analyzed using TRIOS. About 1-3 mg of a sample was placed into a pin-holed aluminum pan and heated with the parameters in the following table:

[0441] The combined DSC and TGA plots for Crystalline Form 1 (Figure 2), Crystalline Form 2 (Figure 4), Crystalline Form 3 (Figure 6), and Crystalline Form 4 (Figure 8) were acquired with the above parameters.

[0442] Crystalline Form 1 of Compound 2 demonstrated a DSC thermogram with two endothermic events having: an onset at about 88.3 °C and peak at about 111.7 °C; and an onset at about 265.6 °C and peak at about 267.0 °C.

[0443] Crystalline Form 2 of Compound 2 demonstrated a DSC thermogram with two endothermic events having: an onset at about 120.9 °C and peak at about 130.4 °C; and an onset at about 264.5 °C and peak at about 266.0 °C.

[0444] Crystalline Form 3 of Compound 2 demonstrated a DSC thermogram with two endothermic events having: an onset at about 167.1 °C and peak at about 169.4 °C; and an onset at about 268.3 °C and peak at about 269.5 °C.

[0445] Crystalline Form 4 of Compound 2 demonstrated a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C. Example 23. Dynamic Vapor Sorption (DVS)

[0446] Moisture sorption / desorption data were collected on a DVS Intrinsic.7-20 mg of asample was placed into a tared sample chamber and automatically weighed.

[0447] DVS data was collected with the following parameters: Anh drate Samples H drated Samples D P , 0, ,, , , ,

[0448] Representative DVS Mass Plots for Crystalline Form 1 (Figure 9), Crystalline Form 2 (Figure 10), Crystalline Form 3 (Figure 11), and Crystalline Form 4 (Figure 12) were acquired with the above parameters.

[0449] Crystalline Form 1 of Compound 2 demonstrated reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; and reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C. Crystalline Form 1 of Compound 2 has an unchanged XRPD after DVS analysis up to 90% RH and 25 °C. Crystalline Form 1 of Compound 2 has an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days. Example 24. Single Crystal X-Ray Diffraction (SCXRD) Preparation of Single Crystal

[0450] A crystal of Compound 2 (Crystalline Form 1) was suspended in perfluoroether oil and a suitable colourless block-shaped crystal with dimensions 0.26 x 0.14 x 0.05 mm3was selected. This was mounted to a MITIGEN holder. Collection and Characterization

[0451] Data were collected on a Rigaku 007HF equipped with Varimax confocal mirrors and an AFC11 goniometer and HyPix 6000 detector equipped with an Oxford Cryosystems low- temperature device. The crystal was kept at a steady T= 100(2) K during data collection. The structure was solved with the ShelXT 2014 / 5 (Sheldrick, 2014) solution program using dual methods and by using Olex21.3 (Dolomanov et al., 2009) as the graphical interface. The model was refined with ShelXL 2014 / 7 (Sheldrick, 2015) using full matrix least squares minimization on F2.

[0452] Data were measured using profile data from co-scans of 0.4 ° per frame for 0.5 / 2.0 susing Cu Kα radiation (Rotating anode, 40.0 kV, 30.0 mA). The total number of runs and imageswas based on the strategy calculation from the program CrysAlisPro 1.171.41.93a (Rigaku OD, 2020). The maximum resolution achieved was ^ = 67.028°.

[0453] Cell parameters were retrieved using the CrysAlisPro 1.171.41.93a (Rigaku OD, 2020) software and refined using CrysAlisPro 1.171.41.93a (Rigaku OD, 2020) on 35459 reflections, 71 % of the observed reflections. Data reduction was performed using the CrysAlisPro1.171.41.93a (Rigaku OD, 2020) software which corrects for Lorentz po larisation. The finalcompleteness is 99.40 % (IUCr) out to 67.028° in ^^

[0454] A multi-scan absorption correction was performed using CrysAlisPro 1.171.41.93a (Rigaku Oxford Diffraction, 2020) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ of this material is 1.034 mm-1at this wavelength (λ = 1.54184Å) and the minimum and maximum transmissions are 0.620 and 1.000.

[0455] The structure was solved in the space group C2 (# ...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. Crystalline sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 2).

2. The crystalline Compound 2 of claim 1, wherein the crystalline Compound 2 is a hydrate.

3. The crystalline Compound 2 of claim 1, wherein the crystalline Compound 2 is a hemiheptahydrate.

4. The crystalline Compound 2 of any one of claims 1-3 that is Crystalline Form 1 of Compound 2, which is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 1; (b) an XRPD pattern with peaks at about 4.4 º 2-Theta, about 6.6 º 2-Theta, about 13.2 º 2-Theta, about 17.7 º 2-Theta, about 21.0 º 2-Theta, about 22.8 º 2-Theta, and about 24.7 º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 2; (d) a DSC thermogram with two endothermic events having: i. an onset at about 88.3 °C and peak at about 111.7 °C; and ii. an onset at about 265.6 °C and peak at about 267.0 °C; (e) a TGA pattern substantially the same as shown in Figure 2; (f) a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C; (g) unit cell parameters substantially equal to the following at 100 K:F(000) 1176 ; (h) reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; (i) reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C; (j) h d XRPD f DVS l i 90% RH d 25 °C(k) an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days; or (l) a combination thereof.

5. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having: an XRPD pattern substantially the same as shown in Figure 1; or an XRPD pattern with peaks at about 4.4 º 2-Theta, about 6.6 º 2-Theta, about 13.2 º 2-Theta, about 17.7 º 2-Theta, about 21.0 º 2-Theta, about 22.8 º 2-Theta, and about 24.7 º 2-Theta as measured using Cu Kα radiation.

6. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having: a DSC thermogram substantially the same as shown in Figure 2; or a DSC thermogram with two endothermic events having: i. an onset at about 88.3 °C and peak at about 111.7 °C; and ii. an onset at about 265.6 °C and peak at about 267.0 °C.

7. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having: a TGA pattern substantially the same as shown in Figure 2; or a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C.

8. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having: unit cell parameters substantially equal to the following at 100 K:F(000) 1176 .

9. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having:reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C; or an unchanged XRPD after DVS analysis up to 90% RH and 25 °C.

10. The crystalline Compound 2 of claim 4, wherein the Crystalline Form 1 of Compound 2 is characterized as having: an unchanged XRPD after storage at 92.5% RH over 1 day or over 13 days.

11. The crystalline Compound 2 of claim 1 or 2 that is Crystalline Form 2 of Compound 2, which is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 3; (b) an XRPD pattern with peaks at about 3.89º 2-Theta, about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta, and about 20.81º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 4; (d) a DSC thermogram with two endothermic events having: i. an onset at about 120.9 °C and peak at about 130.4 °C; and ii. an onset at about 264.5 °C and peak at about 266.0 °C; (e) a TGA pattern substantially the same as shown in Figure 4; (f) a TGA pattern with an about 2.1% w / w loss from about 48 °C to about 208 °C; or (g) a combination thereof.

12. The crystalline Compound 2 of claim 11, wherein the Crystalline Form 2 of Compound 2 is characterized as having: an XRPD pattern substantially the same as shown in Figure 3; or an XRPD pattern with peaks at about 3.89º 2-Theta, about 6.96º 2-Theta, about 7.82º 2-Theta, about 10.57º 2-Theta, about 14.17º 2-Theta, about 19.00º 2-Theta as measured using Cu Kα radiation.

13. The crystalline Compound 2 of claim 11, wherein the Crystalline Form 2 of Compound 2 is characterized as having: a DSC thermogram substantially the same as shown in Figure 4; or a DSC thermogram with two endothermic events having: i. an onset at about 120.9 °C and peak at about 130.4 °C; and ii. an onset at about 264.5 °C and peak at about 266.0 °C.

14. The crystalline Compound 2 of claim 11, wherein the Crystalline Form 2 of Compound 2 is characterized as having: a TGA pattern substantially the same as shown in Figure 4; or a TGA pattern with an about 2.1% w / w loss from about 48 °C to about 208 °C.

15. The crystalline Compound 2 of claim 1, wherein the crystalline Compound 2 is unsolvated.

16. The crystalline Compound 2 of claim 1 or 15 that is Crystalline Form 3 of Compound 2, which is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 5; (b) an XRPD pattern with peaks at about 3.64º 2-Theta, about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 6; (d) a DSC thermogram with two endothermic events having: i. an onset at about 167.1 °C and peak at about 169.4 °C; and ii. an onset at about 268.3 °C and peak at about 269.5 °C; (e) a TGA pattern substantially the same as shown in Figure 6; (f) a TGA pattern with substantially no loss in weight from about 50 °C to about 200 °C; or (g) a combination thereof.

17. The crystalline Compound 2 of claim 16, wherein the Crystalline Form 3 of Compound 2 is characterized as having: an XRPD pattern substantially the same as shown in Figure 5; or an XRPD pattern with peaks at about 3.64º 2-Theta, about 4.02º 2-Theta, about 5.52º 2-Theta, about 8.12º 2-Theta, about 9.03º 2-Theta, about 13.41º 2-Theta, and about 16.83º 2-Theta as measured using Cu Kα radiation.

18. The crystalline Compound 2 of claim 16, wherein the Crystalline Form 3 of Compound 2 is characterized as having: a DSC thermogram substantially the same as shown in Figure 6; or a DSC thermogram with two endothermic events having: i. an onset at about 167.1 °C and peak at about 169.4 °C; and ii. an onset at about 268.3 °C and peak at about 269.5 °C.

19. The crystalline Compound 2 of claim 16, wherein the Crystalline Form 3 of Compound 2 is characterized as having: a TGA pattern substantially the same as shown in Figure 6; or a TGA pattern with substantially no loss in weight from about 50 °C to about 200 °C.

20. The crystalline Compound 2 of claim 1 or 15 that is Crystalline Form 4 of Compound 2, which is characterized as having: (a) an XRPD pattern substantially the same as shown in Figure 7; (b) an XRPD pattern with peaks at about 3.87º 2-Theta, about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation; (c) a DSC thermogram substantially the same as shown in Figure 8; (d) a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C; or a combination thereof.

21. The crystalline Compound 2 of claim 20, wherein the Crystalline Form 4 of Compound 2 is characterized as having: an XRPD pattern substantially the same as shown in Figure 7; or an XRPD pattern with peaks at about 3.87º 2-Theta, about 6.75º 2-Theta, about 7.82º 2-Theta, and about 10.38º 2-Theta as measured using Cu Kα radiation.

22. The crystalline Compound 2 of claim 20, wherein the Crystalline Form 4 of Compound 2 is characterized as having: a DSC thermogram substantially the same as shown in Figure 8; or a DSC thermogram with an endothermic event having an onset at about 268.3 °C and peak at about 269.1 °C.

23. Crystalline sodium (S)-(2-cyclopropyl-2-(3-((1-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinate (Compound 2) hemiheptahydrate characterized as having an XRPD pattern with a peak at 4.35 ± 0.2 º 2- Theta as measured using Cu Kα radiation.

24. The crystalline Compound 2 hemiheptahydrate of claim 23, further characterized by at least one XRPD pattern reflection selected from: 6.56 ± 0.2 º 2-Theta, 13.22 ± 0.2 º 2-Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2-Theta, and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation.

25. The crystalline Compound 2 hemiheptahydrate of claim 23, further characterized by at least three XRPD pattern reflection selected from: 6.56 ± 0.2 º 2-Theta, 13.22 ± 0.2 º 2-Theta, 17.67 ± 0.2 º 2-Theta, 21.01 ± 0.2 º 2-Theta, 22.80 ± 0.2 º 2-Theta, and 24.66 ± 0.2 º 2-Theta as measured using Cu Kα radiation.

26. The crystalline Compound 2 hemiheptahydrate of any one of claims 23-25, further characterized as having: (a) a DSC thermogram with two endothermic events having:i. an onset at about 88.3 °C and peak at about 111.7 °C; and ii. an onset at about 265.6 °C and peak at about 267.0 °C; (b) a TGA pattern with an about 9.9% w / w loss from about 26 °C to about 123 °C; (c) unit cell parameters substantially equal to the following at 100 K: Crystal System Monoclinic ;(d) reversible water uptake (about 10.5% w / w) between 0 and 10% Relative Humidity (RH) at about 25 °C; (e) reversible water uptake (about 3.3% w / w) between 10 and 90% Relative Humidity (RH) at about 25 °C; (f) an unchanged XRPD after DVS analysis up to 90% RH and 25 °C; (g) an unchanged XRPD after storage at 92.5% RH over 1 day or 13 days; or (h) a combinations thereof.

27. The crystalline Compound 2 hemiheptahydrate of any one of claims 23-25, further characterized as having unit cell parameters substantially equal to the following at 100 K:F(000) 1176 .

28. The crystalline Compound 2 of any one of claims 1-27, wherein crystalline Compound 2 is substantially free of impurities.

29. The crystalline Compound 2 of any one of claims 1-28, wherein crystalline Compound 2 is at least about 95%, about 96%, about 97%, about 98%, or about 99% pure.

30. A pharmaceutical composition comprising the crystalline Compound 2 of any one of claims 1-29 and at least one pharmaceutically acceptable excipient.

31. A process for the preparation of Compound 2: );comprising treating: Compound 1:(Compound 1); or a salt thereof, or the alkyl ester of Compound 1:wherein R1is C1-C6alkyl; with a sodium hydroxide solution in the presence of a suitable solvent to provide Compound 2.

32. The process of claim 31, wherein: the suitable solvent is water, methanol, ethanol, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or a combination thereof .

33. The process of claim 31, wherein the preparation of Compound 2 comprises treating Compound 1 with a sodium hydroxide solution in the presence of a suitable solvent, whereinthe suitable solvent is water, methanol, ethanol, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or a combination thereof .

34. The process of claim 31, wherein the preparation of Compound 2 comprises treating Compound 1 with a sodium hydroxide solution in the presence of a suitable solvent, wherein the suitable solvent is water or a combination of water and 2-methyl tetrahydrofuran.

35. The process of any one of claims 31-34, wherein Compound 2 is crystalline.

36. The process of any one of claims 31-35, wherein Compound 2 is the Crystalline Form 1 of any one of claims 4-10.

37. A process for the preparation of Formula A:(Formula A); wherein M+is an alkali metal cation or an alkylammonium cation; comprising: (1) contacting a compound of Formula B:); wherein X is a suitable leaving group; with a compound of Formula C-I:(Formula C-I); wherein M+is an alkali metal cation or an alkylammonium cation; in a suitable solvent to provide a compound of Formula A.

38. The process of claim 37, wherein in step (1): X is a suitable leaving group selected from halogen, -OTs, and -OMs; each M+is a lithium cation, a sodium cation, a potassium cation, a cesium cation, a triethylammonium cation, a diisopropylethylammonium cation, a 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.2.2]octan-1- ium; and the suitable solvent is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof .

39. The process of claim 37, wherein in step (1): X is a suitable leaving group selected from -OTs; each M+is a potassium cation; and the suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof .

40. A process for the preparation of Formula G:(Formula G); wherein PG1is a suitable protecting group; comprising: (2) contacting a compound of Formula B:( ormu a ); wherein X is a suitable leaving group; with a compound of Formula C-II:(Formula C-II); wherein M+is an alkali metal cation or an alkylammonium cation, and wherein PG1is a suitable protecting group; in a suitable solvent to provide a compound of Formula G.

41. The process of claim 40, wherein in step (2): X is a suitable leaving group selected from halogen OTs and OMs;each M+is a lithium cation, a sodium cation, a potassium cation, a cesium cation, a triethylammonium cation, a diisopropylethylammonium cation, a 2,3,4,6,7,8,9,10- octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.2.2]octan-1- ium; and the suitable solvent is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea, tert-amyl alcohol, water, or a combination thereof.

42. The process of claim 40, wherein in step (2): X is a suitable leaving group selected from -OTs; each M+is a potassium cation; and the suitable solvent is dimethyl sulfoxide, tetrahydrofuran, or a combination thereof.

43. A process for the preparation of Formula G:(Formula G); wherein PG1is a suitable protecting group; comprising: (3) contacting Compound D:(Compound D); and a compound of Formula H:(Formula H); wherein PG1is a suitable protecting group; to a suitable azo reagent and a suitable phosphine in a suitable solvent to provide a compound of Formula G.

44. The process of claim 43 wherein in step (3):the suitable azo reagent is tetramethylazodicarboxamide; the suitable phosphine is tri(n-butyl)phosphine; and the suitable solvent is ethyl acetate.

45. A process for the preparation of Compound 1:(Compound 1); comprising: (4) contacting a compound of Formula A:(Formula A); wherein M+is an alkali metal cation or an alkylammonium cation; with a suitable acid in a suitable solvent to provide Compound 1.

46. The process of claim 45, wherein in step (4): M+is a lithium cation, a sodium cation, a potassium cation, a cesium cation, a triethylammonium cation, a diisopropylethylammonium cation, a 2,3,4,6,7,8,9,10- octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.2.2]octan-1- ium; the suitable acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, nitric acid, trifluoroacetic acid, citric acid, or a combination thereof; and the suitable solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, or a combination thereof.

47. The process of claim 45, wherein in step (4): M+is a potassium cation; the suitable acid is trifluoroacetic acid or citric acid; and the suitable solvent is 2-methyl tetrahydrofuran, water, or a combination thereof.

48. A process for the preparation of Formula A:); where n s an a a meta caton or an a y ammon um caton; comprising: a) providing a first solution comprising a compound of Formula B and a first suitable solvent:); wherein X is a suitable leaving group; b) providing a second solution comprising a compound of Formula C-I and a second suitable solvent:(Formula C-I); wherein M+is an alkali metal cation or an alkylammonium cation; c) combining the first solution and the second solution for form a reaction mixture, thereby contacting the compound of Formula B with the compound of Formula C- I to provide the compound of Formula A.

49. The process of claim 48, wherein: X is a suitable leaving group selected from halogen, -OTs, and -OMs; each M+is a lithium cation, a sodium cation, a potassium cation, a cesium cation, a triethylammonium cation, a diisopropylethylammonium cation, a 2,3,4,6,7,8,9,10- octahydropyrimido[1,2-a]azepin-1-ium cation, or 1,4-diazabicyclo[2.22]octan-1- ium; and the suitable solvent is dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, sulfolane, N-methyl-2-pyrrolidine, 1,3-dimethyl-2-imidazolidinone, N,N′- dimethylpropyleneurea tert amyl alcohol water or a combination thereof50. The process of claim 49, wherein: X is a suitable leaving group selected from -OTs; each M+is a potassium cation; the first suitable solvent is tetrahydrofuran; and the second suitable solvent is dimethyl sulfoxide.

51. The process of any one of claims 48-50, wherein: the compound of Formula A is Compound 4:(Compound 4); the compound of Formula B is Compound 6-I:(Compound 6-I); and the compound of Formula C-I is Compound 5:o pou ).

52. The process of claim 51, wherein step b) comprises contacting Compound E:(Compound E); with potassium tert-butoxide in dimethyl sulfoxide to provide the second solution.

53. A compound, selected from:,.

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