WO2023077049A1

WO2023077049A1 - Methods of preparing 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds

Info

Publication number: WO2023077049A1
Application number: PCT/US2022/078850
Authority: WO
Inventors: Paul GAUVREAU; Xiaowei Yang; Shufeng Fan
Original assignee: Trevena, Inc.
Priority date: 2021-10-29
Filing date: 2022-10-28
Publication date: 2023-05-04
Also published as: WO2023070605A1

Abstract

The present embodiments are directed, in part, to processes and compositions that can, for example, be used in the preparation compounds of Formula (XIV), or pharmaceutically acceptable salts thereof. In some embodiments, a method of treating or preventing pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD and related disorders and conditions comprising administering to a patient in need thereof, a compound of Formula (XVI) is provided.

Description

Methods of Preparing 6-Membered Aza-Heterocyclic Containing Delta-Opioid Receptor Modulating Compounds

Cross Reference to Related Applications

The present application claims priority to PCT/CN2021/127727, filed October 29, 2021, which which is hereby incorporated by reference in its entirety.

The present application is also related to U.S. Patent No 10,246,436, which is hereby incorporated by reference in its entirety.

Field

The present disclosure is directed to compounds and methods of preparing compounds, or pharmaceutically acceptable salts thereof, that can, for example, be used for modulating Delta- Opioid Receptor activity.

Background

Compounds described herein required synthesis. The present disclosure fulfills these needs and others.

Summary of Embodiments

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are provided. In some embodiments, the processes comprise contacting a racemic compound having formulae of Formula (Il-a)

Formula (Il-b) with an activation agent in the presence of an esterase enzyme and, optionally in a solvent, under suitable conditions to produce a compound having the formula of

Formula (I) in a substantially enantiopure form, wherein R₁, R₂, R₃, R₄, and R₁o are as provided for herein and, for example, can be selected from the respective groups of chemical moi eties described herein. In some embodiments, the compound of Formula (I) has a formula of

Formula (III). In some embodiments, the compound of Formula (I) has a formula of Formula (IV). In some embodiments, the compound of

Formula (I) has a formula of Formula (V). In some embodiments, the

compound of Formula (I) has a formula of

Formula (VI). In some embodiments, the compound of Formula (I) has a formula of

Formula (VII). In some embodiments, the compound of Formula

(I) has a formula of Formula (VIII). In some embodiments, the

compound of Formula (I) has a formula of

Formula (IX).

In some embodiments, processes of isolating compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided. In some embodiments, the process comprises isolating the compound of Formula (I) from a suspension formed from the process of preparing compounds of Formula (I) as described herein. In some embodiments, the process comprises isolating the compound of Formula (I) from a filtrate produced by filtering the suspension as described herein. In some embodiments, the filtrate is a mixture comprising the compound of Formula (I). In some embodiments, the isolating the compound of Formula (I) from the filtrate comprises contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture, wherein the cyclic anhydride together with the compound of

Formula (Il-b) forms an acid having a formula of

Formula (XVI-c), wherein R₁, R₂, R₃, R₁₀, R₁₂, R₁₃, R₁₄, R₁₅, R₁₀, R₁₂’, R₁₃’, R₁₄’, and R₁₅’ are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. In some embodiments, processes of preparing compounds of

Formula

(Il-a), or a pharmaceutically acceptable salt thereof, are provided. In some embodiments, the process comprises hydrolyzing the compound of Formula (I) to form the compound of Formula (Il-a) in a substantially enantiopure form,, wherein R₁, R₂, R₃, and R₁₀

are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. In some embodiments, the compound of Formula (Il-a) in a substantially enantiopure form has a formula of

Formula (II-c). In some embodiments, the compound of Formula (Il-a) in a substantially enantiopure form has a formula

Formula (X-a).

In some embodiments, processes of preparing compounds of Formula (XI), or a pharmaceutically acceptable salt thereof, are provided. In some embodiments, the process comprise contacting the compound of Formula (Il-a) with a suitable substance to form a compound having a formula of

Formula (XI), wherein R₁, R₂, R₃, R₁₀, and R11 are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. In some embodiments, the compound of Formula (XI) has a formula of

Formula (Xl-b). In some embodiments, the process further comprises contacting the compound of Formula (XI) with 6-hydroxy-2,3-dihydro-lH-isoindol-l- one to form a compound having a formula of

Formula (XII). In some embodiments, the compound of Formula (XII) has a formula of

Formula (Xll-a). In some embodiments, the process as described and provided herein further comprises contacting the compound of Formula (Xll-a) with a deprotection agent to form a compound having a formula of

Formula (XIII). In some embodiments, the process as described and provided herein further comprises contacting the compound of Formula (XIII) with l-(2-bromomethyl)-lH-pyrrole under a suitable condition to form a compound having a formula of

Formula (XIV), or a pharmaceutically acceptable salt. In some embodiments, the compound of Formula (XIV) has a

Formula (XlV-a). In some embodiments, the compound of Formula (XIV) has a formula of

Formula (XlV-b). In some embodiments, the compound of Formula (XIV) has a formula of

Formula (XIV-c). In some embodiments, the compound of

Formula (XIV) has a formula of Formula (XlV-d).

In some embodiments, processes of preparing the compound of Formula (XlV-d), or pharmaceutically acceptable salts thereof, are provided. In some embodiments, the process comprise: a) contacting a racemic compound having formulae of Formula (X-a)

and

Formula (X-b) with an activation agent in the presence of an esterase enzyme in a solvent under suitable conditions to produce a suspension comprising a compound having the formula of

Formula (IX) and

b) isolating the compound of Formula (IX) from the suspension of step a); c) hydrolyzing the compound of Formula (IX) isolated from step b) with a first base under a suitable condition to form the compound of

Formula (X-a) in a substantially enantiopure form; d) contacting the compound of Formula (X-a) of step c) with methanesulfonyl chloride and a second base under a suitable condition to form a compound of

Formula (Xl-a); e) contacting the compound of Formula (Xl-a) of step d) with 6-hydroxy-2,3-dihydro-lH- isoindol-l-one and a third base under a suitable condition to produce a compound of

Formula (Xll-b); f) contacting the compound of Formula (Xll-b) with an acid under a suitable condition to produce a compound of

Formula (Xlll-a); and g) contacting the compound of Formula (Xlll-a) with 1 -(2 -bromomethyl)- IH-pyrrole and a fourth base to form a compound having a formula of

Formula

(XlV-d), wherein the activation agent, esterase enzyme, solvent, acid, and base are as described and provided herein.

In some embodiments, compounds having a formula of the formula of

Formula (I) are provided, wherein R₁, R₂, R₃, R₄, and R₁₀ are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. In some embodiments, the compound of Formula (I) has a formula of

Formula (III). In some embodiments, the compound of Formula (I)

Formula (IV). In some embodiments, the compound of Formula (I) has a formula of

Formula (V). In some embodiments, the compound of Formula (I) has a formula of Formula (VI). In some embodiments, the compound of

Formula (I) has a formula of

Formula (VII). In some embodiments, the compound of Formula (I) has a formula of

Formula (VIII). In some embodiments, the compound of Formula (I) has a formula of

Formula (IX).

In some embodiments, a pharmaceutical composition comprising a compound of Formula (XVI) is provided.

In some embodiments, the pharmaceutical composition comprises a compound of Formula (XVI) further comprising an additional drug for the treatment of pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD and related disorders and conditions in or any combination thereof.

In some embodiments, a method of treating or preventing pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD and related disorders and conditions in or any combination thereof comprising administering to a patient in need thereof, a compound of Formula (XVI) is provided.

In some embodiments, a pharmaceutical composition comprising a compound of Formula (XVI-d) is provided.

In some embodiments, the pharmaceutical composition comprises a compound of Formula (XVI-d) further comprising an additional drug for the treatment of pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD and related disorders and conditions in or any combination thereof.

In some embodiments, a method of treating or preventing pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, and related disorders and conditions in or any combination thereof comprising administering to a patient in need thereof, a compound of Formula (XVI-d) is provided.

The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages of the present teachings will be apparent from the description of examples and also from the appending claims.

Brief Description of Drawings

FIG. 1 : High performance liquid chromatography (HPLC) chromatogram of the suspension mixture in the first kinetic resolution comprising the compound of Formula (IX) and the compound of Formula (X-b). FIG. 2: High performance liquid chromatography (HPLC) chromatogram of the heated mixture after additions of succinic anhydride and DMAP in the first kinetic resolution comprising the compound of Formula (IX) and the compound of Formula (XVII-a).

FIG. 3 : High performance liquid chromatography (HPLC) chromatogram of the reaction mixture after the hydrolysis of the compound of Formula (IX).

FIG. 4: High performance liquid chromatography (HPLC) chromatogram of the suspension mixture in the second kinetic resolution comprising the compound of Formula (IX).

FIG. 5: High performance liquid chromatography (HPLC) chromatogram of the heated mixture after additions of succinic anhydride and DMAP in the second kinetic resolution comprising the compound of Formula (IX).

FIG. 6: High performance liquid chromatography (HPLC) chromatogram of the mixture of compounds of Formula (X-a), (X-b), (IX-a), and (IX).

FIG. 7: Analytical High performance liquid chromatography (HPLC) chromatogram of the compound of Formula (X-a) prepared according to Example 1-1.

FIG. 8: Chiral High performance liquid chromatography (HPLC) chromatogram of the compound of Formula (X-a) prepared according to Example 1-1.

FIG. 9: Analytical High performance liquid chromatography (HPLC) chromatogram of compound of Formula (IX) prepared according to Example 1-1 after the second resolution.

FIG. 10: Analytical High performance liquid chromatography (HPLC) chromatogram of the sample prepared according to Example 4, Step (A), #11.

FIG. 11 : Analytical High performance liquid chromatography (HPLC) chromatogram of the compound of Formula (XLa) prepared according to Example 4, Step (A).

FIG. 12: Analytical High performance liquid chromatography (HPLC) chromatogram of the sample prepared according to Example 4, Step (B), #10.

FIG. 13a and FIG. 13b: Analytical High performance liquid chromatography (HPLC) chromatogram of the compound of Formula (XILb) prepared according to Example 4, Step (B).

FIG. 14: Analytical High performance liquid chromatography (HPLC) chromatogram of the sample prepared according to Example 4, Step (C), #9. FIG. 15: Analytical High performance liquid chromatography (HPLC) chromatogram of the sample prepared according to Example 4, Step (D), #31.

FIG. 16a and FIG. 16b: Analytical High performance liquid chromatography (HPLC) chromatogram of the compound of Formula (XlV-d) prepared according to Example 4, Step (D).

Detailed Description

Unless defined otherwise, all technical and scientific terms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belongs. In the event that there is a plurality of definitions for terms cited herein, those in this section prevail unless otherwise stated. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety.

As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments. As used herein, the term “alcohol” means any organic compound in which a hydroxyl group (- OH) is bound to a carbon atom, which in turn is bound to other hydrogen and/or carbon atoms. For example, the term “alcohol” means a straight or branched alkyl-OH group of 1 to 20 carbon atoms, including, but not limited to, methanol, ethanol, n-propanol, isopropanol, t-butanol, and the like. In some embodiments, the alkyl-OH chain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each optionally substituted, that is bonded through an oxygen atom. For example, the term “alkoxy” means a straight or branched -O-alkyl group of 1 to 20 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the term “alkyl” means a saturated hydrocarbon group, which is straight- chained or branched. An alkyl group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2- m ethyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2-methyl-l -pentyl, 2,2-dimethyl-l -propyl, 3 -methyl- 1 -pentyl, 4-m ethyl- 1 -pentyl, 2-methyl-2-pentyl, 3 -methyl-2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, and the like.

As used herein, the term “alkylene” or “alkylenyl” means a divalent alkyl linking group. An example of an alkylene (or alkylenyl) is methylene or methylenyl (-CH2-).

As used herein, the term “alkynyl” means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, acetylene, 1 -propylene, 2-propylene, and the like. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the terms “ambient temperature” and “room temperature” or “RT”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C to about 30° C, such as at or about 25° C. As used herein, the term “amide” means to a functional group containing a carbonyl group linked to a nitrogen atom or any compound containing the amide functional group. For example, amides are derived from carboxylic acid and an amine.

As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to:

As used herein, the term “carbocycle” means a 5-, 6, or 7-membered, saturated or unsaturated cyclic ring, optionally containing O, S, or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta- 1,3 -diene, phenyl, and any of the heterocycles recited above. As used herein, the term, “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.

As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

As used herein, the term “contacting” means bringing together of two compounds/atoms to form at least one covalent bond between the compounds or atoms.

As used herein, the term “cyano” means -CN.

As used herein, the term “cycloalkyl” means non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups can include mono- or polycyclic ring systems such as fused ring systems, bridged ring systems, and spiro ring systems. In some embodiments, polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkyl group can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6, from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-lH-indene-l-yl, or lH-inden-2(3H)-one-l-yl). As used herein, the term “cycloheteroalkyl” means as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)n (where n is 0, 1, 2 or 3). The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of the substituents for alkyl or aryl set out herein. In addition, any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

As used herein, the term “cyclic anhydride” means a variety of cyclic anhydrides, which may be employed successfully in the present disclosure, including but not limited to aryl containing cyclic anhydrides such as phthalic anhydride, substituted aryl such as tetrabromophthalic anhydride; cyclic anhydrides containing saturated cyclic groups such as tetrahydrophthalic anhydride; unsaturated cyclic anhydrides such as maleic, itaconic, allyl succinic; saturated cyclic anhydrides such as succinic, adipic; pimelic, suberic, azelaic, sebacic; other cyclic anhydrides which lead to a cyclodextrin ester with a basic group such as isatoic anhydride; and other cyclic anhydrides which lead to cyclodextrin esters with other acidic groups such as o-sulfobenzoic anhydride.

As used herein, the term “esterase” or “esterase enzyme” means a hydrolase enzyme or lipase that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis. In some embodiments, the esterase can be used for enzyme-catalyzed kinetic resolutions of secondary alcohols. In some embodiments, the esterase can achieve a high enantioselectivity for enzyme-catalyzed kinetic resolutions of secondary alcohols.

As used herein, the terms “for example” and “such as,” and grammatical equivalences thereof. As used herein, the term “halo” means halogen groups including, but not limited to fluoro, chloro, bromo, and iodo.

As used herein, the term “haloalkoxy” means an -O-haloalkyl group. An example of an haloalkoxy group is OCF₃.

As used herein, the term “haloalkyl” means a C₁-ealkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCh, CHCh, CH2CF3, and the like.

As used herein, the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which are, independently, sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms, from 3 to 6 ring-forming atoms, or from 3 to 5 ringforming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl groups, and the like. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino- 1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3 -amino- 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

As used herein, the term “heterocycle” or “heterocyclic ring” means a 5- to 7-membered mono- or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms chosen from N, O and S, and wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

As used herein, the term “heterocycloalkyl” means non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups, where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Hetercycloalkyl groups can be mono or polycyclic (e.g., fused, bridged, or spiro systems). In some embodiments, the heterocycloalkyl group has from 1 to 20 carbon atoms or from 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3 -dihydrobenzofuryl, 1,3 -benzodi oxole, benzo-1,4- dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. In addition, ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. For example, a ring-forming S atom can be substituted by 1 or 2 oxo (form a S(O) or S(O)₂). For another example, a ring-forming C atom can be substituted by oxo (form carbonyl). Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (having a bond in common with) to the nonaromatic heterocyclic ring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6- dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-l-one-3-yl, and 3,4-dihydroisoquinolin- l(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido.

As used herein, the term “heterocycloalkylalkyl” means a C₁-6 alkyl substituted by heterocycloalkyl.

As used herein, the term “hydroxy” or “hydroxyl” means an -OH group.

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” means an alkyl group substituted by a hydroxyl group. Examples of a hydroxylalkyl include, but are not limited to, - CH2OH and -CH2CH2OH.

As used herein, the term “subject” or “patient” means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.

As used herein, the term “isolating” means that separating the compounds described herein from other components of a synthetic organic chemical reaction mixture by conventional techniques, such as filtration.

As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.

As used herein, the term “nitro” means -NO2.

As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.

As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent groups, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

In some embodiments, the salt of a compound described herein is a pharmaceutically acceptable salt thereof. As used herein, the phrase “pharmaceutically acceptable salt(s),” includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, and pamoate (i.e., l,l '-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. The present embodiments also include quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moiety.

As used herein, the term “phenyl” means -C₆H₅. A phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.

As used herein, the term “purified” means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of a compound described herein by weight of the isolate.

As used herein, the phrase “quaternary ammonium salts” means derivatives of the disclosed compounds with one or more tertiary amine moieties wherein at least one of the tertiary amine moieties in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (and the cations are balanced by anions such as Cl-, CH₃COO-, and CF₃COO-), for example methylation or ethylation.

As used herein, the term “solution/suspension” means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form, in suspension in a liquid matrix.

As used herein, the term “solvent” means a usually liquid substance capable of dissolving or dispersing one or more other substances including water, inorganic nonaqueous solvent, and organic solvents. The term “inorganic nonaqueous solvent” means a solvent other than water, that is not an organic compound. Examples of the “inorganic nonaqueous solvent” include, but are not limited to: liquid ammonia, liquid sulfur dioxide, sulfuryl chloride and sulfuryl chloride fluoride, phosphoryl chloride, dinitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, pure sulfuric acid and other inorganic acids. The term “organic solvent” means carbon-based solvent. Examples of the “organic solvent” include, but are not limited to: aromatic compounds, e.g., benzene and toluene; alcohols, e.g., methanol, ethanol, and propanol; esters; ethers, e.g., tetrahydrofuran and 2-methyl tetrahydrofuran; ketones, e.g., acetone; amines, and nitrated and halogenated hydrocarbons e.g., acetonitrile. The “organic solvent” includes both polar and non-polar organic solvent. The “polar organic solvent” means an organic solvent that has large dipole moments (aka “partial charges”) and in general the organic solvent with dielectric constants greater than about 5 is considered as “polar organic solvent” while those with dielectric constants less than 5 are considered "non-polar organic solvent." Examples of the “polar organic solvent” include, but are not limited to, tetrahydrofuran, 2-methyl tetrahydrofuran, acetic acid, methanol, acetone, and acetonitrile, DMSO, and DMF. Examples of the non-polar organic solvent include, but are not limited to, benzene, carbon tetrachloride, and n-hexane. The “organic solvent” includes both protonic and non-protonic organic solvent. The term “protonic organic solvent” means an organic solvent having a hydrogen atom bonded to oxygen or nitrogen (an acidic hydrogen atom). Examples of the “protonic organic solvent” include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, hexanol, phenol, acetic acid, benzoic acid and partly fluorinated compounds thereof. Examples of the “non-protonic organic solvent” or “non-protonic solvent” include, but are not limited to: 2-methyl-tetrahydrofuran, tetrahydrofuran, acetonitrile, acetone, dicholoromethane, chloroform, ethyl acetate, diethyl ether, tert-butylmethyl ether, and N,N-Dimethylformamide.

As used herein, the phrase “substantially isolated” means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

As used herein, the phrase “suitable substituent” or “substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds described herein or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₅-C₆aryl, C₁-C₆alkoxy, C₃-C₅heteroaryl, C₃- C₆cycloalkyl, C₅-C₆aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C₁- C₈alkyl), -N(C₁- C₈alkyl)₂, -NH(C₆aryl), -N(C₅-C₆aryl)2, -CHO, -CO(C₁-C₆alkyl), -CO((C₅-C₆)aryl), -CO2((C₁-C₆)alkyl), and -CO2((C₅-C₆)aryl). One of skill in art can readily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compounds described herein.

As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic measures wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Thus, “treatment of pain” or “treating pain” means an activity that alleviates or ameliorates any of the primary phenomena or secondary symptoms associated with the pain or other condition described herein.

At various places in the present specification, substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁-C₆ alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties selected from the Markush groups defined for R. In another example, when an optionally multiple substituent is designated in the form, for example,

, then it is understood that substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence. In the above example, where the variable T¹ is defined to include hydrogens, such as when T¹ is CH₂, NH, etc., any H can be replaced with a substituent. It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. It is understood that the present embodiments encompass the process, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof, are within the scope of the embodiments. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the compounds can be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated. Compounds that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparation of optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included within the present embodiments and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.

In some embodiments, the composition comprises a compound, or a pharmaceutically acceptable salt thereof, that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomeric pure, which means that the ratio of one enantiomer to the other in the composition is at least 90: 1 at least 95: 1, at least 98: 1, or at least 99: 1, or is completely in the form of one enantiomer over the other.

Compounds may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-l,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms.

Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation can include, for example, a composition enriched in the compound. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

Although the disclosed compounds are suitable, other functional groups can be incorporated into the compound with an expectation of similar results. In particular, thioamides and thioesters are anticipated to have very similar properties. The distance between aromatic rings can impact the geometrical pattern of the compound and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine. The distance between and the relative orientation of monomers within the compounds can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacing a carbonyl group with a dicarbonyl alters the distance between the monomers and the propensity of dicarbonyl unit to adopt an antiarrangement of the two carbonyl moiety and alter the periodicity of the compound. Pyromellitic anhydride represents still another alternative to simple amide linkages which can alter the conformation and physical properties of the compound. Modern methods of solid phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 Daltons. Other substitution patterns are equally effective.

Embodiments of various processes of preparing compounds of any one of the Formulae as described herein including Formula (I), Formula (Il-a), Formulae (III) — (XIV), Formulae (XlV-a) — (XlV-d), Formulae (X-a) — (X-b), Formulae (XVI-a) — (XVI-c), and Formula (XVII), and salts thereof are provided. Where a variable is not specifically recited, the variable can be any option described herein, except as otherwise noted or dictated by context.

In some embodiments, processes of preparing compounds of Formula (I) or a pharmaceutically acceptable salt thereof are as described in the appended exemplary, nonlimiting claims.

and

Formula (I) in a substantially enantiopure form, wherein: R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)_nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl; and n is 0-10.

In some embodiments, provided are processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the contacting is reacting. In some embodiments, the contacting is condensing. In some embodiments, the contacting is coupling. In some embodiments, the contacting is cyclizing.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)_nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl. In some embodiments, R₁ is a protecting group. In some embodiments, R₁ is C(=O)OR₅. In some embodiments, R₁ is C(=O)R₅. In some embodiments, R₁ is H. In some embodiments, R₁ is optionally substituted aryl. In some embodiments, R₁ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₁ is optionally substituted C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁ is optionally substituted C₂-C₆ alkenyl. In some embodiments, R₁ is optionally substituted C₂-C₆ haloalkenyl -(CH₂)_nR₈. In some embodiments, R₁ is optionally substituted heterocycle. In some embodiments, R₁ is optionally substituted C₁-C₆ ester. In some embodiments, R₁ is optionally substituted cycloalkyl. In some embodiments, R₁ is optionally substituted C₁-C₆ alkoxy. In some embodiments, R₁ is optionally substituted pyrrolinyl. In some embodiments, R₁ is optionally substituted morpholinyl. In some embodiments, R₁ is optionally substituted C₃-C₆ cyclic ether. In some embodiments, R₁ is optionally substituted piperidyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C₁-C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₂ is H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C₁-C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₂ is H. In some embodiments, R₂ is halo. In some embodiments, R₂ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₂ is -SO₂C₁-C₆alkyl. In some embodiments, R₂ is -OCF₃. In some embodiments, R₂ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₂ is -OR₆. In some embodiments, R₃ is H, halo, optionally substituted C₁- C₆ haloalkyl, -SO₂C₁-C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₃ is H. In some embodiments, R₃ is halo. In some embodiments, R₃ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₃ is -SO₂C₁-C₆alkyl. In some embodiments, R₃ is -OCF₃. In some embodiments, R₃ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₃ is -OR₆. In some embodiments, R₆ is H or optionally substituted C₁-C₆ alkyl. In some embodiments, R₆ is H. In some embodiments, R₆ is optionally substituted C₁-C₆ alkyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₄ is H. In some embodiments, R₄ is optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₄ is optionally substituted unbranched C₁-C₆ alkyl. In some embodiments, R₄ is optionally substituted branched C₁-C₆ alkyl. In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₅ isH. In some embodiments, R₅ is optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₅ is optionally substituted unbranched C₁-C₆ alkyl. In some embodiments, R₅ is optionally substituted branched C₁-C₆ alkyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl. In some embodiments, R₈ is H. In some embodiments, R₈ is -C(=O)R₉. In some embodiments, R₈ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₈ is optionally substituted nitrogen. In some embodiments, R₈ is optionally substituted C₁-C₆ branched or unbranched alkyl. In some embodiments, R₈ is optionally substituted aryl. In some embodiments, R₈ is optionally substituted heteroaryl. In some embodiments, R₈ is optionally substituted C₂-C₆ alkenyl. In some embodiments, R₈ is optionally substituted cycloalkyl. In some embodiments, R₈ is optionally substituted heterocycle. In some embodiments, R₈ is -OH. In some embodiments, R₈ is optionally substituted alkoxy. In some embodiments, R₈ is optionally substituted pyrrolinyl. In some embodiments, R₈ is optionally substituted phenyl. In some embodiments, R₈ is optionally substituted pyrrolidinyl. In some embodiments, R₈ is optionally substituted imidazolidinyl. In some embodiments, R₈ is optionally substituted morpholinyl. In some embodiments, R₈ is optionally substituted piperidyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₉ is phenyl or C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is phenyl. In some embodiments, R₉ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is C₁-C₆ unbranched alkyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₁₀ is H or C₁-C₆ branched alkyl. In some embodiments, R₁₀ is H. In some embodiments, R₁₀ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁₀ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁₀ is C₁-C₆ unbranched alkyl.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein n is 0-6. In some embodiments, n is 0-5 In some embodiments, n is 0-4. In some embodiments, n is 0-3. In some embodiments, n is 0-2 In some embodiments, n is 0-1. In some embodiments, n is 1-6. In some embodiments, n is 1-5. In some embodiments, n is 1-4. In some embodiments, n is 1-3. In some embodiments, n is 1-2. In some embodiments, n is 2-6. In some embodiments, n is 2-5. In some embodiments, n is 2-4. In some embodiments, n is 2-3. In some embodiments, n is 3-6. In some embodiments, n is 3-5. In some embodiments, n is 3-4. In some embodiments, n is 4-6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the esterase enzyme is a lipase.

In some embodiments, the lipase is an immobilized lipase. In some embodiments, the immobilized lipase is Novozym 435.

In some embodiments, the ratio of the esterase enzyme to the racemic compound is in any range from about 0.01 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of about 0.01 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.02: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.03 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.05 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.05:1 w/w to about 1 :1 w/w. In some embodiments, the ratio is in a range of 0.05: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.07: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.08: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.09: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of about 0.1 :1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.2: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.3 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.5:1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.5: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.5 : 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.7: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.8: 1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is in a range of 0.9:1 w/w to about 1 : 1 w/w. In some embodiments, the ratio is about 0.1 : 1 w/w. In some embodiments, the ratio is about 0.2: 1 w/w. In some embodiments, the ratio is about 0.3: 1 w/w. In some embodiments, the ratio is about 0.4: 1 w/w. In some embodiments, the ratio is about 0.5:1 w/w. In some embodiments, the ratio is about 0.6: 1 w/w. In some embodiments, the ratio is about 0.7: 1 w/w. In some embodiments, the ratio is about 0.8: 1 w/w. In some embodiments, the ratio is about 0.9: 1 w/w. In some embodiments, the ratio is about 1 : 1 w/w. In some embodiments, the ratio is about 0.01 : 1 w/w. In some embodiments, the ratio is about 0.02: 1 w/w. In some embodiments, the ratio is about 0.03: 1 w/w. In some embodiments, the ratio is about 0.04: 1 w/w. In some embodiments, the ratio is about 0.05: 1 w/w. In some embodiments, the ratio is about 0.06: 1 w/w. In some embodiments, the ratio is about 0.07: 1 w/w. In some embodiments, the ratio is about 0.08: 1 w/w. In some embodiments, the ratio is about 0.09: 1 w/w.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the activation agent is an ester or an anhydride. In some embodiments, the activation agent is an ester. In some embodiments, the ester is a vinyl alcohol ester. In some embodiments, the vinyl alcohol ester is vinyl propionate or vinyl acetate. In some embodiments, the vinyl alcohol ester is vinyl propionate. In some embodiments, the vinyl alcohol ester is vinyl acetate. In some embodiments, the vinyl alcohol ester is vinyl propionate. In some embodiments, the activation agent is an anhydride. In some embodiments, the anhydride is propionic anhydride.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the molar ratio of the activation agent to the racemic compound is in any range from about 0.1 :1 to about 20: 1. In some embodiments, the ratio is in a range of about 0.1 : 1 to about 20: 1. In some embodiments, the ratio is in a range of about 0.1 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.2: 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.3 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.5 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.5: 1 to about 8:1. In some embodiments, the ratio is in a range of about 0.5:1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.7:1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.55: 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.8: 1 to about 8: 1. In some embodiments, the ratio is in a range of about 0.9: 1 to about 8: 1. In some embodiments, the ratio is in a range of about 1 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 2: 1 to about 8: 1. In some embodiments, the ratio is in a range of about 3 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 5 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 5 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 5 : 1 to about 8: 1. In some embodiments, the ratio is in a range of about 7: 1 to about 8: 1. In some embodiments, the ratio is about 7: 1. In some embodiments, the ratio is about 1 : 1. In some embodiments, the ratio is about 2:1. In some embodiments, the ratio is about 3: 1. In some embodiments, the ratio is about 4: 1. In some embodiments, the ratio is about 5:1. In some embodiments, the ratio is about

6: 1. In some embodiments, the ratio is about 7: 1. In some embodiments, the ratio is about 8: 1.

In some embodiments, the ratio is about 9: 1. In some embodiments, the ratio is about 10: 1. In some embodiments, the ratio is about 11 : 1. In some embodiments, the ratio is about 12:1. In some embodiments, the ratio is about 13: 1. In some embodiments, the ratio is about 14:1. In some embodiments, the ratio is about 15: 1. In some embodiments, the ratio is about 16:1. In some embodiments, the ratio is about 17: 1. In some embodiments, the ratio is about 18:1. In some embodiments, the ratio is about 19: 1. In some embodiments, the ratio is about 20:1.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the volume ratio of the activation agent to the racemic compound is in any range from about 1 : 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 1 : 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 9: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 8: 1 v/v. some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 7: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 6: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 5: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 4: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 3 : 1 v/v. In some embodiments, the volume ratio is in a range of about 3: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 4: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 5: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 6: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 7: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 8: 1 v/v to about 10:1 v/v. some embodiments, the volume ratio is in a range of about 9: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about

2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about

7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v. In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the solvent is an organic solvent. In some embodiments, the organic solvent is a non-protic organic solvent. In some embodiments, the solvent is the non-protic organic solvent is acetonitrile, acetone, toluene, or tetrahydrofuran, or a combination thereof. In some embodiments, the solvent is the non-protic organic solvent is acetonitrile. In some embodiments, the solvent is acetone. In some embodiments, the solvent is toluene. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is any combination of acetonitrile, acetone, toluene, and tetrahydrofuran.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the volume ratio of the solvent to the racemic compound is in any range from about 1 : 1 v/v to about 20: 1 v/v. In some embodiments, the volume ratio is in a range of about 1 : 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 3 : 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 4: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 5: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 6: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 7: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 8: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 9: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about 2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about 7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v. In some embodiments, the volume ratio is about 11 : 1 v/v. In some embodiments, the volume ratio is about 12:1 v/v. In some embodiments, the volume ratio is about 13: 1 v/v. In some embodiments, the volume ratio is about 14: 1 v/v. In some embodiments, the volume ratio is about 15: 1 v/v. In some embodiments, the volume ratio is about 16:1 v/v. In some embodiments, the volume ratio is about 17: 1 v/v. In some embodiments, the volume ratio is about 18: 1 v/v. In some embodiments, the volume ratio is about 19:1 v/v. In some embodiments, the volume ratio is about 20: 1 v/v.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the process produces a suspension. In some embodiments, the suspension is heated to a temperature in any range from about 20 to about 55 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 55 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 50 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 45 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 40 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 35 °C. In some embodiments, the suspension is heated to a temperature in a range of about 25 to about 30 °C. In some embodiments, the suspension is heated under an inert gas. In some embodiments, the inert gas is nitrogen. In some embodiments, the inert gas is Argon. In some embodiments, the suspension is stirred at the heated temperatures as described herein for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours. In some embodiments, the suspension is stirred for about 0.1 hour. In some embodiments, the suspension is stirred for about 0.25 hour. In some embodiments, the suspension is stirred for about 0.5 hour. In some embodiments, the suspension is stirred for about 1 hour. In some embodiments, the suspension is stirred for about 2 hours. In some embodiments, the suspension is stirred for about 3 hours. In some embodiments, the suspension is stirred for about 4 hours. In some embodiments, the suspension is stirred for about 5 hours. In some embodiments, the suspension is stirred for about 6 hours. In some embodiments, the suspension is stirred for about 7 hours. In some embodiments, the suspension is stirred for about 8 hours. In some embodiments, the suspension is stirred for about 9 hours. In some embodiments, the suspension is stirred for about 10 hours. In some embodiments, the suspension is stirred for about 11 hours. In some embodiments, the suspension is stirred for about 12 hours. In some embodiments, the suspension is stirred for about 13 hours. In some embodiments, the suspension is stirred for about 14 hours. In some embodiments, the suspension is stirred for about 15 hours. In some embodiments, the suspension is stirred for about 16 hours. In some embodiments, the suspension is stirred for about 17 hours. In some embodiments, the suspension is stirred for about 18 hours. In some embodiments, the suspension is stirred for about 19 hours. In some embodiments, the suspension is stirred for about 20 hours.

In some embodiments, processes of preparing compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the heated suspension as described herein is filtered to produce a filtrate comprising the compound of Formula (I) and the compound of Formula (Il-b). In some embodiments, the process further comprises isolating the compound of Formula (I) from the filtrate. In some embodiments, the isolation of the compound of Formula (I) from the filtrate comprises isolating the compound Formula (I) with a High- performance liquid chromatography (HPLC) or silica gel flash chromatography. In some embodiments, the isolation of the compound of Formula (I) comprises contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture.

In some embodiments, the cyclic anhydride as described herein is an aryl containing cyclic anhydride a saturated cyclic anhydride, or unsaturated cyclic anhydride, or a combination thereof. In some embodiments, the cyclic anhydride has a formula of

Formula (XV-a),

Formula (XV-c),

wherein R₁₂, R₁₃, R₁₄, R₁₅, R₁₂ , R₁₃ , R₁₄ , and R₁₅’ are each independently D, H, optionally substituted C₁- C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; optionally, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form a optionally substituted carbocycle; m is 0-6; and p is 0-6.

In some embodiments, the cyclic anhydride has a formula of

Formula (XV-a). In some embodiments, the cyclic anhydride has a formula of

Formula (XV-b). In some embodiments, the cyclic anhydride has a formula

Formula (XV-c). In some embodiments, the cyclic anhydride has a

In some embodiments, R₁₂ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₂ is D. In some embodiments, R₁₂ is H. In some embodiments, R₁₂ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₂ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₂ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₂ is R₁₂ is D. In some embodiments, R₁₂ is H. In some embodiments, R₁₂ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₂ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₂ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₂’ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₂’ is D. In some embodiments, R₁₂’ is H. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₂’ is R₁₂’ is D. In some embodiments, R₁₂’ is H. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₂’ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₃ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₃ is D. In some embodiments, R₁₃ is H. In some embodiments, R₁₃ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₃ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₃ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₃ is R₁₃ is D. In some embodiments, R₁₃ is H. In some embodiments, R₁₃ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₃ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₃ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₃’ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₃’ is D. In some embodiments, R₁₃’ is H. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₃’ is R₁₃’ is D. In some embodiments, R₁₃’ is H. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₃’ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₄ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₄is D. In some embodiments, R₁₄is H. In some embodiments, R₁₄is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₄is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₄is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₄is R₁₄is D. In some embodiments, R₁₄is H. In some embodiments, R₁₄is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₄is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₄is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₄’ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₄’ is D. In some embodiments, R₁₄’ is H. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₄’ is R₁₄’ is D. In some embodiments, R₁₄’ is H. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₄’ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₅ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₅ is D. In some embodiments, R₁₅ is H. In some embodiments, R₁₅ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₅ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₅ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₅ is R₁₅ is D. In some embodiments, R₁₅ is H. In some embodiments, R₁₅ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₅ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₅ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₅’ is D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R₁₅’ is D. In some embodiments, R₁₅’ is H. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ alkoxy. In some embodiments. In some embodiments, R₁₅’ is R₁₅’ is D. In some embodiments, R₁₅’ is H. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₁₅’ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C_3-7 spirocyclic ring. In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C₃ spirocyclic ring. In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C4 spirocyclic ring. In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C₅ spirocyclic ring. In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C₆ spirocyclic ring. In some embodiments, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form an optionally substituted C₇ spirocyclic ring.

In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C_3-7 spirocyclic ring. In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C₃ spirocyclic ring. In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C4 spirocyclic ring. In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C₅ spirocyclic ring. In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C₆ spirocyclic ring. In some embodiments, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form an optionally substituted C₇ spirocyclic ring.

In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C_3-7 spirocyclic ring. In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C₃ spirocyclic ring. In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C4 spirocyclic ring. In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C₅ spirocyclic ring. In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C₆ spirocyclic ring. In some embodiments, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form an optionally substituted C₇ spirocyclic ring.

In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C_3-7 spirocyclic ring. In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C₃ spirocyclic ring. In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C4 spirocyclic ring. In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C₅ spirocyclic ring. In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C₆ spirocyclic ring. In some embodiments, R₁₅ and R₁₅’ together with the carbon atom to which they are both attached form an optionally substituted C₇ spirocyclic ring.

In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C_3-7 spirocyclic ring. In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C₃ spirocyclic ring. In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C4 spirocyclic ring. In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C₅ spirocyclic ring. In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C₆ spirocyclic ring. In some embodiments, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form an optionally substituted C₇ spirocyclic ring.

In some embodiments, m is 0-6. In some embodiments, m is 0-5. In some embodiments, m is O-4. In some embodiments, m is 0-3. In some embodiments, m is 0-2. In some embodiments, m is 0-1. In some embodiments, m is 1-6. In some embodiments, m is 1-5. In some embodiments, m is 1-4. In some embodiments, m is 1-3. In some embodiments, m is 1-2. In some embodiments, m is 2-6. In some embodiments, m is 2-5. In some embodiments, m is 2-

4. In some embodiments, m is 2-3. In some embodiments, m is 3-6. In some embodiments, m is

3-5. In some embodiments, m is 3-4. In some embodiments, m is 4-6. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

In some embodiments, p is 0-6. In some embodiments, p is 0-5. In some embodiments, p is 0-4. In some embodiments, p is 0-3. In some embodiments, p is 0-2. In some embodiments, p is 0-1. In some embodiments, p is 1-6. In some embodiments, p is 1-5. In some embodiments, p is 1-4. In some embodiments, p is 1-3. In some embodiments, p is 1-2. In some embodiments, p is 2-6. In some embodiments, p is 2-5. In some embodiments, p is 2-4. In some embodiments, p is 2-3. In some embodiments, p is 3-6. In some embodiments, p is 3-5. In some embodiments, p is 3-4. In some embodiments, p is 4-6. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, processes of isolating compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, the process further comprising contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture, wherein the cyclic anhydride together with the compound of Formula

(Il-b) forms an acid having a formula of

Formula (XVI-a),

wherein the variables are described and provided herein. In some embodiments, the acid has a

Formula (XVI-a). In some embodiments, the acid has a formula of

Formula (XVI-b). In some embodiments, the acid has a

Formula (XVI-c). In some embodiments, m is 0. In

some embodiments, p is 0. In some embodiments, m is 0. In some embodiments, R₁₂ is H. In some embodiments, R₁₂’ is H. In some embodiments, R₁₃ is H. In some embodiments, R₁₃’ is H.

In some embodiments, the cyclic anhydride has a formula of . In some

embodiments, the acid has a formula of

Formula (XVII), wherein the variables are described and provided herein.

In some embodiments, processes of isolating compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, the process further comprising contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture, wherein the molar ratio of the anhydride activating reagent to the racemic compound is in any range from about 0.01 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.01 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.02: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.03 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.05: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.05 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.05 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.07: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.08: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.09: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.1 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.2: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.3 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.5 : 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.5: 1 to about 1 :1. In some embodiments, the ratio is in a range of about 0.5:1 to about 1 : 1. In some embodiments, the ratio is in a range of about

0.7:1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.8: 1 to about 1 : 1. In some embodiments, the ratio is in a range of about 0.9: 1 to about 1 : 1. In some embodiments, the ratio is about 0.1 : 1. In some embodiments, the ratio is about 0.2: 1. In some embodiments, the ratio is about 0.3: 1. In some embodiments, the ratio is about 0.4: 1. In some embodiments, the ratio is about 0.5: 1. In some embodiments, the ratio is about 0.6: 1. In some embodiments, the ratio is about 0.7: 1. In some embodiments, the ratio is about 0.8: 1. In some embodiments, the ratio is about 0.9: 1. In some embodiments, the ratio is about 1 :1. In some embodiments, the ratio is about 0.01 : 1. In some embodiments, the ratio is about 0.02: 1. In some embodiments, the ratio is about 0.03 : 1. In some embodiments, the ratio is about 0.04: 1. In some embodiments, the ratio is about 0.05: 1. In some embodiments, the ratio is about 0.06: 1. In some embodiments, the ratio is about 0.07: 1. In some embodiments, the ratio is about 0.08: 1. In some embodiments, the ratio is about 0.09: 1.

In some embodiments, processes of isolating compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, the process further comprising contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture, wherein the anhydride activating reagent is 4-dimethylaminopyridine (DMAP).

In some embodiments, processes of isolating compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, the process further comprising contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture, the process further comprising heating the mixture to a temperature in any range from about 30 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 30 °C to about 80 °C. In some embodiments, the temperature is in a range of about 30 °C to about 75 °C. In some embodiments, the temperature is in a range of about 30 °C to about 70 °C. In some embodiments, the temperature is in a range of about 30 °C to about 65 °C. In some embodiments, the temperature is in a range of about 30 °C to about 60 °C. In some embodiments, the temperature is in a range of about 30 °C to about 55 °C. In some embodiments, the temperature is in a range of about 30 °C to about 50 °C. In some embodiments, the temperature is in a range of about 30 °C to about 45 °C. In some embodiments, the temperature is in a range of about 30 °C to about 40 °C. In some embodiments, the temperature is in a range of about 30 °C. In some embodiments, the temperature is in a range of about 35 °C. In some embodiments, the temperature is in a range of about 40 °C. In some embodiments, the temperature is in a range of about 45 °C. In some embodiments, the temperature is in a range of about 50 °C. In some embodiments, the temperature is in a range of about 55 °C. In some embodiments, the temperature is in a range of about 60 °C. In some embodiments, the temperature is in a range of about 65 °C. In some embodiments, the temperature is in a range of about 70 °C. In some embodiments, the temperature is in a range of about 75 °C. In some embodiments, the temperature is in a range of about 80 °C. In some embodiments, the mixture is stirred at the heated temperatures as described herein for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours. In some embodiments, the mixture is stirred for about 0.1 hour. In some embodiments, the mixture is stirred for about 0.25 hour. In some embodiments, the mixture is stirred for about 0.5 hour. In some embodiments, the mixture is stirred for about 1 hour. In some embodiments, the mixture is stirred for about 2 hours. In some embodiments, the mixture is stirred for about 3 hours. In some embodiments, the mixture is stirred for about 4 hours. In some embodiments, the mixture is stirred for about 5 hours. In some embodiments, the mixture is stirred for about 6 hours. In some embodiments, the mixture is stirred for about 7 hours. In some embodiments, the mixture is stirred for about 8 hours. In some embodiments, the mixture is stirred for about 9 hours. In some embodiments, the mixture is stirred for about 10 hours. In some embodiments, the mixture is stirred for about 11 hours. In some embodiments, the mixture is stirred for about 12 hours. In some embodiments, the mixture is stirred for about 13 hours. In some embodiments, the mixture is stirred for about 14 hours. In some embodiments, the mixture is stirred for about 15 hours. In some embodiments, the mixture is stirred for about 16 hours. In some embodiments, the mixture is stirred for about 17 hours. In some embodiments, the mixture is stirred for about 18 hours. In some embodiments, the mixture is stirred for about 19 hours. In some embodiments, the mixture is stirred for about 20 hours.

In some embodiments, processes are described and provided herein for isolating compounds of Formula (I) from the mixture further comprising concentrating the mixture under vacuum to form a residue comprising the compound of Formula (I) and the acid. In some embodiments, the process for isolating compounds of Formula (I) further comprises removing the acid as described herein from the residue to produce the compound of Formula (I).

In some embodiments, processes are described and provided herein for removing the acid as described herein further comprising stirring the residue with a first basic solution to form a mixture. In some embodiments, the first basic solution is a K₂CO₃ aqueous solution. In some embodiments, the first basic solution is a 5% K₂CO₃ aqueous solution. In some embodiments, wherein the volume ratio of the first basic solution to the racemic compound is in any range from about 1 : 1 v/v to about 10:1 v/v. In some embodiments, the ratio is in a range of about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 9: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 8: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 7: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 6: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 5: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 4: 1 v/v. In some embodiments, the ratio is in a range of about 2: 1 v/v to about 3 : 1 v/v. In some embodiments, the ratio is in a range of about 3 : 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 4: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 5: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 6: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 7: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 8:1 v/v to about 10: 1 v/v. In some embodiments, the ratio is in a range of about 9: 1 v/v to about 10: 1 v/v. In some embodiments, the ratio is about 1 : 1 v/v. In some embodiments, the ratio is about 2: 1 v/v. In some embodiments, the ratio is about 3 : 1 v/v. In some embodiments, the ratio is about 4: 1 v/v. In some embodiments, the ratio is about 5: 1 v/v. In some embodiments, the ratio is about 6: 1 v/v. In some embodiments, the ratio is about 7: 1 v/v. In some embodiments, the ratio is about 8: 1 v/v. In some embodiments, the ratio is about 9: 1 v/v. In some embodiments, the ratio is about 10: 1 v/v. In some embodiments, the mixture as described herein is stirred for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours. In some embodiments, the mixture is stirred for about 0.1 hour. In some embodiments, the mixture is stirred for about 0.25 hour. In some embodiments, the mixture is stirred for about 0.5 hour. In some embodiments, the mixture is stirred for about 1 hour. In some embodiments, the mixture is stirred for about 2 hours. In some embodiments, the mixture is stirred for about 3 hours. In some embodiments, the mixture is stirred for about 4 hours. In some embodiments, the mixture is stirred for about 5 hours. In some embodiments, the mixture is stirred for about 6 hours. In some embodiments, the mixture is stirred for about 7 hours. In some embodiments, the mixture is stirred for about 8 hours. In some embodiments, the mixture is stirred for about 9 hours. In some embodiments, the mixture is stirred for about 10 hours. In some embodiments, the mixture is stirred for about 11 hours. In some embodiments, the mixture is stirred for about 12 hours. In some embodiments, the mixture is stirred for about 13 hours. In some embodiments, the mixture is stirred for about 14 hours. In some embodiments, the mixture is stirred for about 15 hours. In some embodiments, the mixture is stirred for about 16 hours. In some embodiments, the mixture is stirred for about 17 hours. In some embodiments, the mixture is stirred for about 18 hours. In some embodiments, the mixture is stirred for about 19 hours. In some embodiments, the mixture is stirred for about 20 hours.

In some embodiments, processes are described and provided herein for removing the acid as described herein further comprising adding a non-protonic organic solvent to the mixture of the residue and a first basic solution as described herein to form a biphasic mixture comprising an organic phase and an aqueous phase. In some embodiments, the volume ratio of the non- protic organic solvent to the racemic compound in any range from about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 9: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 8: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 7: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 6: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 5: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 4: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 3 : 1 v/v. In some embodiments, the volume ratio is in a range of about 3: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 4: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 5: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 6: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 7: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 8: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 9: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about

2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about 7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v. In some embodiments, the non-protic organic solvent is 2-methyl tetrahydrofuran or tetrahydrofuran. In some embodiments, the non-protic organic solvent is 2-methyl tetrahydrofuran. In some embodiments, the non-protic organic solvent is tetrahydrofuran. In some embodiments, processes are described and provided herein for removing the acid as described and provided herein further comprising separating the organic phase from the biphasic mixture as described herein and washing the organic phase with the first basic solution as described herein. In some embodiments, the volume ratio of the first basic solution to the racemic compound is in any range from about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 2:1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 9: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 8: 1 v/v. In some embodiments, the volume ratio is in a range of about 2:1 v/v to about 7 : 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 6: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 5: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 4: 1 v/v. In some embodiments, the volume ratio is in a range of about 2: 1 v/v to about 3 : 1 v/v. In some embodiments, the volume ratio is in a range of about 3 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is in a range of about 4: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 5: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 6: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 7: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 8: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is in a range of about 9: 1 v/v to about 10:1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about 2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about 7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v. In some embodiments, the organic phase is washed with the first basic solution for at least once. In some embodiments, the organic phase is washed with the first basic solution for once. In some embodiments, the organic phase is washed with the first basic solution for two times. In some embodiments, the organic phase is washed with the first basic solution for three times. In some embodiments, the organic phase is washed with the first basic solution for four times. In some embodiments, the organic phase is washed with the first basic solution for five times.

In some embodiments, processes are described and provided herein for removing the acid as described herein further comprising concentrating the washed organic phase as described herein to produce compounds of Formula (I). In some embodiments, the washed organic phase is concentrated under vacuum below about 50 °C. In some embodiments, the washed organic phase is concentrated under vacuum below about 40 °C. In some embodiments, the washed organic phase is concentrated under vacuum below about 30 °C. In some embodiments, the washed organic phase is concentrated under vacuum below about 25 °C.

In some embodiments, processes are described and provided herein for preparing compounds of Formula (I), wherein the compound of Formula (I) is produced in a substantially enantiopure form. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 90%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 95%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 98%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 99%.

In some embodiments, processes are described and provided herein for preparing compounds of Formula (I), the process further comprising recrystallizing the compound to improve enantiopurity with the known methods and/or technique in the art.

In some embodiments, processes of preparing compounds of Formula (Il-a) or a pharmaceutically acceptable salt thereof are as described in the appended exemplary, nonlimiting claims.

In some embodiments, processes are described and provided herein for preparing a compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, in the crystalline form. In some embodiments, the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is produced in a substantially enantiopure form. In some embodiments, the substantially enantiopure form is a crystalline form. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 90%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 91%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 92%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 93%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 94%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 95%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 96%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 97%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 98%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.5%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.7%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.8%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of about 90%, 91%, 92%, 93%, 94%, 95%, 95%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of about 99.9%.

In some embodiments, processes are described and provided herein for preparing a highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is in the crystalline form. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 90%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 91%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 92%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 93%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 94%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 95%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 96%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 97%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 98%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 99%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 99.5%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 99.6%. In some embodiments, the highly pure compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has a purity of at least about 99.7%. In some embodiments, the highly pure compound of Formula (I) has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the purity of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is about 99.7%.

In some embodiments, processes are described and provided herein for preparing a highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is stored at 5 °C or room temperature (25 °C). In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 6 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 5 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 4 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 3 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 2 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, remains in the substantially enantiopure form for 1 month. In some embodiments, the substantially enantiopure form is a crystalline form. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 90%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 91%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 92%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 93%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 94%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 95%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 96%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 97%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 98%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.5%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.7%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of at least about 99.8%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of about 90%, 91%, 92%, 93%, 94%, 95%, 95%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the substantially enantiopure form of the compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, has an enantiomeric excess of about 99.9%. In some embodiments, processes are described and provided herein for preparing a highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is stored at 5 °C or room temperature (25 °C). In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 6 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 5 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 4 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 3 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 2 months. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is of high purity for 1 month. In some embodiments, the highly stable compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, is in the crystalline form. In some embodiments, the high purity refers to a purity of at least about 90%. In some embodiments, the high purity refers to a purity of at least about 91%. In some embodiments, the high purity refers to a purity of at least about 92%. In some embodiments, the high purity refers to a purity of at least about 93%. In some embodiments, the high purity refers to a purity of at least about 94%. In some embodiments, the high purity refers to a purity of at least about 95%. In some embodiments, the high purity refers to a purity of at least about 96%. In some embodiments, the high purity refers to a purity of at least about 97%. In some embodiments, the high purity refers to a purity of at least about 98%. In some embodiments, the high purity refers to a purity of at least about 99%. In some embodiments, the high purity refers to a purity of at least about 99.5%. In some embodiments, the high purity refers to a purity of at least about 99.6%. In some embodiments, the high purity refers to a purity of at least about 99.7%. In some embodiments, the high purity refers to a purity of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the high purity refers to a purity of at least about 99.7%.

In some embodiments, processes of preparing compounds of Formula (Il-a), or a pharmaceutically acceptable salt thereof, are provided, the process comprises hydrolyzing the compound of Formula (I) as described herein to form the compound of

Formula (Il-a) in a substantially enantiopure form, wherein the variables are as defined as described and provided herein. In some embodiments, the hydrolysis condition is a suitable condition for removing

of Formula (I) to form the compound of Formula (Il-a). the suitable condition comprising adding a second basic solution to the compound of Formula (I) to form a mixture. In some embodiments, the second basic solution comprises sodium hydroxide and water. In some embodiments, the molar ratio of the sodium hydroxide to the racemic compound is in any range from about 10: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 10: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 9: 1 to about 1 :1. In some embodiments, the molar ratio is in a range of about 8: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 7: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 6: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 5.5 : 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 5 : 1 to about 1 :1. In some embodiments, the molar ratio is in a range of about 4.5:1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 4: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 3.5: 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 3 : 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 2.5 : 1 to about 1 : 1. In some embodiments, the molar ratio is in a range of about 2: 1 to about 1 :1. In some embodiments, the molar ratio is in a range of about 1.5:1 to about 1 : 1. In some embodiments, the molar ratio is about 1 : 1. In some embodiments, the molar ratio is about 1.5: 1. In some embodiments, the molar ratio is about 2: 1. In some embodiments, the molar ratio is about 2.5: 1. In some embodiments, the molar ratio is about 3: 1. In some embodiments, the molar ratio is about 3.5:1. In some embodiments, the molar ratio is about 4: 1. In some embodiments, the molar ratio is about 4.5: 1. In some embodiments, the molar ratio is about 5: 1. In some embodiments, the molar ratio is about 5.5: 1. In some embodiments, the molar ratio is about 6: 1. In some embodiments, the molar ratio is about 6.5: 1. In some embodiments, the molar ratio is about 7: 1. In some embodiments, the molar ratio is about 7.5: 1. In some embodiments, the molar ratio is about 8:1. In some embodiments, the molar ratio is about 8.5: 1. In some embodiments, the molar ratio is about 9: 1. In some embodiments, the molar ratio is about 9.5: 1. In some embodiments, the molar ratio is about 10: 1. In some embodiments, the volume ratio of the water to the racemic compound is in any range from about 5 : 1 to about 1 : 1. In some embodiments, the volume ratio is in a range of about 5 : 1 to about 1 : 1. In some embodiments, the volume ratio is in a range of about 4: 1 to about 1 : 1. In some embodiments, the volume ratio is in a range of about 3 : 1 to about 1 : 1. In some embodiments, the volume ratio is in a range of about 2: 1 to about 1 : 1. In some embodiments, the volume ratio is about 5: 1. In some embodiments, the volume ratio is about 4: 1. In some embodiments, the volume ratio is about 3: 1. In some embodiments, the volume ratio is about 2: 1. In some embodiments, the volume ratio is about 1 : 1.

In some embodiments, processes as described herein for preparing compounds of Formula (Il-a), or a pharmaceutically acceptable salt thereof, comprising hydrolyzing the compound of Formula (I) further comprise heating the mixture of the compound of Formula (I), the second base solution, and the water as described and provided herein to a temperature in any range from about 30 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 30 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 40 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 45 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 50 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 55 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 60 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 65 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 65 °C to about 75 °C. In some embodiments, the mixture is heated to a temperature in a range of about 65 °C to about 70 °C. In some embodiments, the mixture is heated to a temperature in a range of about 65 °C to about 65 °C. In some embodiments, the mixture is heated to a temperature in a range of about 70 °C to about 80 °C. In some embodiments, the mixture is heated to a temperature in a range of about 75 °C to about 80 °C. In some embodiments, the temperature is in a range of about 30 °C to about 75 °C. In some embodiments, the temperature is in a range of about 30 °C to about 70 °C. In some embodiments, the temperature is in a range of about 30 °C to about 65 °C. In some embodiments, the temperature is in a range of about 30 °C. In some embodiments, the temperature is in a range of about 35 °C. In some embodiments, the temperature is in a range of about 40 °C. In some embodiments, the temperature is in a range of about 45 °C. In some embodiments, the temperature is in a range of about 50 °C. In some embodiments, the temperature is in a range of about 55 °C. In some embodiments, the temperature is in a range of about 60 °C. In some embodiments, the temperature is in a range of about 65 °C. In some embodiments, the temperature is in a range of about 70 °C. In some embodiments, the temperature is in a range of about 75 °C. In some embodiments, the temperature is in a range of about 80 °C. In some embodiments, the mixture is stirred at the heated temperatures as described herein for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours. In some embodiments, the mixture is stirred for about 0.1 hour. In some embodiments, the mixture is stirred for about 0.25 hour. In some embodiments, the mixture is stirred for about 0.5 hour. In some embodiments, the mixture is stirred for about 1 hour. In some embodiments, the mixture is stirred for about 2 hours. In some embodiments, the mixture is stirred for about 3 hours. In some embodiments, the mixture is stirred for about 4 hours. In some embodiments, the mixture is stirred for about 5 hours. In some embodiments, the mixture is stirred for about 6 hours. In some embodiments, the mixture is stirred for about 7 hours. In some embodiments, the mixture is stirred for about 8 hours. In some embodiments, the mixture is stirred for about 9 hours. In some embodiments, the mixture is stirred for about 10 hours. In some embodiments, the mixture is stirred for about 11 hours. In some embodiments, the mixture is stirred for about 12 hours. In some embodiments, the mixture is stirred for about 13 hours. In some embodiments, the mixture is stirred for about 14 hours. In some embodiments, the mixture is stirred for about 15 hours. In some embodiments, the mixture is stirred for about 16 hours. In some embodiments, the mixture is stirred for about 17 hours. In some embodiments, the mixture is stirred for about 18 hours. In some embodiments, the mixture is stirred for about 19 hours. In some embodiments, the mixture is stirred for about 20 hours. In some embodiments, the heated mixture as described and provided here is further cooled. In some embodiments, the temperature is in a range of about 20 °C to about 30 °C. In some embodiments, the temperature is about 20 °C. In some embodiments, the temperature is about 25 °C. In some embodiments, the temperature is about 30 °C.

In some embodiments, processes as described herein for preparing compounds of Formula (Il-a), or a pharmaceutically acceptable salt thereof, comprising hydrolyzing the compound of Formula (I) further comprise adding a non-protonic organic solvent to the cooled mixture as described herein to form a biphasic mixture comprising an organic phase and an aqueous phase. In some embodiments, the volume ratio of the non-protic organic solvent to the racemic compound is in any range from about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio a range of about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about 2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about 7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v. In some embodiments, the process further comprises separating the organic phase from the biphasic mixture as described herein and washing the organic phase with water. In some embodiments, the organic phase is washed with water for at least once. In some embodiments, the organic phase is washed with water for two times. In some embodiments, the organic phase is washed with water for three times. In some embodiments, the organic phase is washed with water for four times. In some embodiments, the organic phase is washed with water for five times. In some embodiments, the volume ratio of the water to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about 1 : 1 v/v. In some embodiments, the volume ratio is about 2: 1 v/v. In some embodiments, the volume ratio is about 3 : 1 v/v. In some embodiments, the volume ratio is about 4: 1 v/v. In some embodiments, the volume ratio is about 5: 1 v/v. In some embodiments, the volume ratio is about 6: 1 v/v. In some embodiments, the volume ratio is about 7: 1 v/v. In some embodiments, the volume ratio is about 8: 1 v/v. In some embodiments, the volume ratio is about 9: 1 v/v. In some embodiments, the volume ratio is about 10: 1 v/v.

In some embodiments, processes are described and provided herein for preparing compounds of Formula (Il-a), wherein the compound of Formula (I) is produced in a substantially enantiopure form. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 90%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 95%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 98%. In some embodiments, the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 99%.

In some embodiments, processes are described and provided herein for preparing compounds of Formula (I) or Formula (Il-a), wherein R₁₀ is C₁-C₆ alkyl. In some embodiments, R₁₀ is CHs In some embodiments, R₃ is H. In some embodiments, the compound of Formula (I) has a formula of

Formula (III). In some embodiments, the compound of Formula (I) has a formula of

Formula (IV). In some embodiments, the compound of

Formula (I) has a formula of Formula (V). In some embodiments, the

compound of Formula (I) has a formula of

Formula (VI). In some embodiments, the compound of Formula (I) has a formula of

Formula (VII). In some embodiments, the compound of Formula

(I) has a formula of

embodiments, the compound of Formula (Il-a) in a substantially enantiopure form has a formula of

Formula (X-a).

In some embodiments, processes of preparing compounds of Formula (XI) or a pharmaceutically acceptable salt thereof are as described in the appended exemplary, nonlimiting claims.

In some embodiments, processes of preparing compounds of Formula (XI), or a pharmaceutically acceptable salt thereof, are provided. In some embodiments, the process comprises contacting the compound of Formula (Il-a) with a suitable substance to form a compound having a formula of

Formula (XI), wherein: R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl; Rn is I, Br, Cl, OMs, and OTf; and n is 0-6.

In some embodiments, Rn is I. In some embodiments, Rn is Br. In some embodiments,

Rn is Cl. In some embodiments, Rn is OMs. In some embodiments, Rn is OTf. In some embodiments, processes as described herein for preparing compounds of

Formula (XI), or a pharmaceutically acceptable salt thereof, the process further comprises contacting the compound of Formula (XI) with 6-hydroxy-2,3-dihydro-lH-isoindol-l-one to form a compound having a formula of

Formula (XIII). In some embodiments, the deprotection agent is an acid, In some embodiments, the acid is hydrochloride acid. In some embodiments, the process as described and provided herein further comprises contacting the compound of Formula (XIII) with 1 -(2 -bromomethyl)- IH-pyrrole to form a compound having a formula of

Formula (XlV-a). In some embodiments, the

compound of Formula (XIV) has a formula of

Formula (XlV-b).

In some embodiments, the compound of Formula (XIV) has a formula of

Formula (XIV-c). In some embodiments, the compound of Formula (XIV) has a formula of Formula (XlV-d). The

variables R₂, R₆, R7, are defined as described and provided herein.

Formula (X-b); b) isolating the compound of Formula (IX) from the suspension of step a); c) hydrolyzing the compound of Formula (IX) isolated from step b) with a first base under a suitable condition to form the compound of Formula (X-a) in a

substantially enantiopure form; d) contacting the compound of Formula (X-a) of step c) with methanesulfonyl chloride and a second base under a suitable condition to form a compound of

Formula

(XlV-d). In some embodiments, the activation agent is vinyl acetate. In some embodiments, the esterase enzyme is Novozym 435. In some embodiments, the solvent is acetonitrile. In some embodiments, the isolating the compound of Formula (IX) comprises: i) filtering the suspension of step a) to form a filtrate comprising compound of Formula (IX) and the compound of Formula (X-b); ii) contacting the filtrate of step i) with a cyclic anhydride having a formula of

and 4-dimethylaminopyridine to form a mixture comprising a compound of Formula (XVII-a) and the compound of Formula (IX);

iii) concentrating the mixture of step ii) to form a residue comprising the compound of Formula (XVII-a) and the compound of Formula (IX); iv) dissolving the residue of step iii) in 2-Me-tetrahydrofuran to from a solution and washing the solution with 5% K₂CO₃ aqueous solution at least once to remove the compound of Formula (XVII-a) from the mixture; and v) concentrating the washed solution of step iv) to produce the compound of Formula (IX). In some embodiments, the first base of step c) is sodium hydroxide. In some embodiments, the base is a sodium hydroxide aqueous solution. In some embodiments, the acid of step f) is hydrochloride acid. In some embodiments, the second base of step d) is triethylamine. In some embodiments, the third base of step e) is K₂CO₃. In some embodiments, the fourth base of step g) is K₂CO₃.

In some embodiments, processes of preparing compounds of Formula (XlV-d), or pharmaceutically acceptable salts thereof, are provided, the process comprising: a) contacting a racemic compound having formulae of Formula (X-a)

Formula (X-b) with vinyl acetate in the presence of Novozym 435 in acetonitrile under suitable conditions to produce a suspension comprising a compound having

Formula (IX) and

Formula (X-b); b) isolating the compound of Formula (IX) from the suspension of step a) comprising: i) filtering the suspension of step a) to form a filtrate comprising compound of Formula (IX) and the compound of Formula (X-b); ii) contacting the filtrate of step i) with a cyclic anhydride having a formula of

and 4-dimethylaminopyridine to form a mixture comprising a compound of

Formula (XVII-a) and the compound of Formula (IX); iii) concentrating the mixture of step ii) to form a residue comprising the compound of Formula (XVII-a) and the compound of Formula (IX); iv) dissolving the residue of step iii) in 2-Me-tetrahydrofuran to from a solution and washing the solution with K₂CO₃ aqueous solution at least once to remove the compound of Formula (XVII-a) from the mixture; and v) concentrating the washed solution of step iv) to produce the compound of Formula

(IX); c) hydrolyzing the compound of Formula (IX) isolated from step b) with a sodium hydroxide solution under a suitable condition to form the compound of

Formula

(X-a) in a substantially enantiopure form; d) contacting the compound of Formula (X-a) of step c) with methanesulfonyl chloride and triethylamine under a suitable condition to form a compound of

Formula (Xl-a); e) contacting the compound of Formula (Xl-a) of step d) with 6-hydroxy-2,3-dihydro-lH- isoindol-l-one and K₂CO₃ under a suitable condition to produce a compound of

Formula (Xll-b); f) contacting the compound of Formula (Xll-b) with hydrochloride acid under a suitable condition to produce a compound of

Formula (Xlll-a); and g) contacting the compound of Formula (Xlll-a) with 1 -(2 -bromomethyl)- IH-pyrrole and K₂CO₃

In some embodiments, compounds having a formula of the formula of

Formula (I) are provided, wherein: R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl; and n is 0-6.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl - (CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl. In some embodiments, R₁ is a protecting group. In some embodiments, R₁ is C(=O)OR₅. In some embodiments, R₁ is C(=O)R₅. In some embodiments, R₁ is H. In some embodiments, R₁ is optionally substituted aryl. In some embodiments, R₁ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₁ is optionally substituted C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁ is optionally substituted C₂-C₆ alkenyl. In some embodiments, R₁ is optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈. In some embodiments, R₁ is optionally substituted heterocycle. In some embodiments, R₁ is optionally substituted C₁- C₆ ester. In some embodiments, R₁ is optionally substituted cycloalkyl. In some embodiments, R₁ is optionally substituted C₁-C₆ alkoxy. In some embodiments, R₁ is optionally substituted pyrrolinyl. In some embodiments, R₁ is optionally substituted morpholinyl. In some embodiments, R₁ is optionally substituted C₃-C₆ cyclic ether. In some embodiments, R₁ is optionally substituted piperidyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C₁-C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₂ is H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C₁-C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₂ is H. In some embodiments, R₂ is halo. In some embodiments, R₂ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₂ is -SO₂C₁-C₆alkyl. In some embodiments, R₂ is -OCF₃. In some embodiments, R₂ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₂ is -OR₆. In some embodiments, R₁ is H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C₁-C₆alkyl, - OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆. In some embodiments, R₃ is H. In some embodiments, R₃ is halo. In some embodiments, R₃ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₃ is -SO₂C₁-C₆alkyl. In some embodiments, R₃ is -OCF₃. In some embodiments, R₃ is optionally substituted C₁-C₆ alkyl. In some embodiments, R₃ is -OR₆. In some embodiments, R₆ is H or optionally substituted C₁-C₆ alkyl. In some embodiments, R₆ is H. In some embodiments, R₆ is optionally substituted C₁-C₆ alkyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₄ is H. In some embodiments, R₁ is optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₁ is optionally substituted unbranched C₁-C₆ alkyl. In some embodiments, R₁ is optionally substituted branched C₁-C₆ alkyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₅ isH. In some embodiments, R₅ is optionally substituted branched or unbranched C₁-C₆ alkyl. In some embodiments, R₅ is optionally substituted unbranched C₁-C₆ alkyl. In some embodiments, R₅ is optionally substituted branched C₁-C₆ alkyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl. In some embodiments, R₈ is H. In some embodiments, R₈ is -C(=O)R₉. In some embodiments, R₈ is optionally substituted C₁-C₆ haloalkyl. In some embodiments, R₈ is optionally substituted nitrogen. In some embodiments, R₈ is optionally substituted C₁-C₆ branched or unbranched alkyl. In some embodiments, R₈ is optionally substituted aryl. In some embodiments, R₈ is optionally substituted heteroaryl. In some embodiments, R₈ is optionally substituted C₂-C₆ alkenyl. In some embodiments, R₈ is optionally substituted cycloalkyl. In some embodiments, R₈ is optionally substituted heterocycle. In some embodiments, R₈ is -OH. In some embodiments, R₈ is optionally substituted alkoxy. In some embodiments, R₈ is optionally substituted pyrrolinyl. In some embodiments, R₈ is optionally substituted phenyl. In some embodiments, R₈ is optionally substituted pyrrolidinyl. In some embodiments, R₈ is optionally substituted imidazolidinyl. In some embodiments, R₈ is optionally substituted morpholinyl. In some embodiments, R₈ is optionally substituted piperidyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₉ is phenyl or C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is phenyl. In some embodiments, R₉ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₉ is C₁-C₆ unbranched alkyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₁₀ is H or C₁-C₆ branched alkyl. In some embodiments, R₁₀ is H.

In some embodiments, R₁₀ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁₀ is C₁-C₆ branched or unbranched alkyl. In some embodiments, R₁₀ is C₁-C₆ unbranched alkyl.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein n is 0-6. In some embodiments, n is 0-5. In some embodiments, n is 0-4 In some embodiments, n is 0-3. In some embodiments, n is 0-2. In some embodiments, n is 0-1 In some embodiments, n is 1-6. In some embodiments, n is 1-5. In some embodiments, n is 1-4. In some embodiments, n is 1-3. In some embodiments, n is 1-2. In some embodiments, n is 2-6. In some embodiments, n is 2-5. In some embodiments, n is 2-4. In some embodiments, n is 2-3. In some embodiments, n is 3-6. In some embodiments, n is 3-5. In some embodiments, n is 3-4. In some embodiments, n is 4-6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, n is 5. In some embodiments, n is 6.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₁₀ is C₁-C₆ alkyl. In some embodiments, R₁₀ is CH3.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein R₃ is H.

In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the compound of Formula (I) has a formula of

Formula (III), wherein the variables are as defined as described and provided herein. In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the compound of Formula (I) has a formula of

Formula (IV), wherein the variables are as defined as described and provided herein. In some embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are provided, wherein the compound of Formula (I) has a formula of

Formula (V), wherein the variables are as defined as described and provided herein.

Formula (VI), wherein the variables are as defined as described and provided herein.

Formula (VII), wherein the variables are as defined as described and provided herein.

Formula (VIII), wherein the variables are as defined as described and provided herein.

Although the compounds as described herein may be shown with specific stereochemistries around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture. Such isomers or racemic mixtures are encompassed by the present disclosure. Additionally, although the compounds are shown collectively in a table, any compounds, or a pharmaceutically acceptable salt thereof, can be chosen from the table and used in the embodiments provided for herein.

In some embodiments, pharmaceutical compositions comprising a compound or pharmaceutically salt thereof of any compound described herein are provided. In some embodiments, pharmaceutical composition comprising a compound of Formula (XIV) as described and provided herein are provided.

The compounds described herein can be made by can be made according to the processes described herein and in the examples. The processes described herein can be adapted based upon the compounds desired and described herein. In some embodiments, this process can be used to make one or more compounds as described herein and will be apparent to one of skill in the art which compounds can be made according to the processes described herein.

The conditions and temperatures can be varied, such as shown in the examples described herein. These schemes are non-limiting synthetic schemes and the synthetic routes can be modified as would be apparent to one of skill in the art reading the present specification. The compounds can also be prepared according to the schemes described in the Examples.

The compounds can be used to modulate the Delta receptor. Thus, in some embodiments, the compounds can be referred to as Delta receptor modulating compounds.

PHARMACEUTICAL COMPOSITIONS/FORMULATIONS

Embodiments described herein can be used in pharmaceutical compositions and can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. In some embodiments, the formulations may contain a buffer and/or a preservative. The compounds of any of the formulae described herein including Formula (XIV) and Formulae (XlV-a) — (XlV-d) and their physiologically acceptable salts, anhydrates, hydrates and/or solvates, can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally (for example, intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the route of administration and standard biological practice. Other routes of administration are also described herein and can be used as well.

In some embodiments, pharmaceutical compositions are provided comprising effective amounts of the compound of Formula (XIV), for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such compositions are known to one skilled in the art and the compositions can be formulated using standard techniques. For example, diluents of various buffer content such as, but not limited to, TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc. or TRIS-HC1 or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes may be used. Hyaluronic acid may also be used. Such compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a composition comprising the compound of Formula (XIV), as described herein. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. Where a buffer is to be included in the formulations, the buffer can be, for example, but not limited to, sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, di sodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)- aminomethan, or mixtures thereof. Each buffer can be used independently or in combination with another buffer. In some embodiments, the buffer is glycylglycine, sodium dihydrogen phosphate, di sodium hydrogen phosphate, sodium phosphate or mixtures thereof. Where a pharmaceutically acceptable preservative is to be included in the formulations, the preservative can be, but is not limited to, phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. In some embodiments, the preservative is phenol and/or m-cresol.

In some embodiments, the preservative is present in a concentration from about 0.1 mg/ml to about 100 mg/ml, more preferably in a concentration from about 0.1 mg/ml to about 50 mg/ml, about 0.1 mg/ml to about 25 mg/ml. In some embodiments, the preservative is present in a concentration from about 0.1 mg/ml to about 10 mg/ml.

The use of a preservative in pharmaceutical compositions is well known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

In some embodiments, the formulation may further comprise a chelating agent where the chelating agent may be salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.

In some embodiments, the chelating agent is present in a concentration from 0.1 mg/ml to 10 mg/ml, particularly in a concentration from 0.1 mg/ml to 5 mg/ml. In some embodiments, the chelating agent is present in a concentration from 0.1 mg/ml to 2 mg/ml. In some embodiments, the chelating agent is present in a concentration from 2 mg/ml to 5 mg/ml.

The use of a chelating agent in pharmaceutical compositions is well known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

In some embodiments, the formulation may further comprise a stabilizer selected from the group of high molecular weight polymers or low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol (e.g., PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L- glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and mixtures thereof. In some embodiments, the stabilizer is L-histidine, imidazole, arginine, or any combination thereof.

In some embodiments, the high molecular weight polymer is present in a concentration from 0.1 mg/ml to 100 mg/ml, in a concentration from 0.1 mg/ml to 50 mg/ml. In some embodiments, the high molecular weight polymer is present in a concentration from 0.1 mg/ml to 5 mg/ml. In some embodiments, the high molecular weight polymer is present in a concentration from 5 mg/ml to 10 mg/ml. In some embodiments, the high molecular weight polymer is present in a concentration from 10 mg/ml to 20 mg/ml. In some embodiments, the high molecular weight polymer is present in a concentration from 20 mg/ml to 30 mg/ml. In some embodiments, the high molecular weight polymer is present in a concentration from 30 mg/ml to 50 mg/ml.

In some embodiments, the low molecular weight polymer is present in a concentration from 0.1 mg/ml to 100 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 0.1 mg/ml to 50 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 0.1 mg/ml to 5 mg/ml. In some embodiments, the low molecular weight polymer compound is present in a concentration from 5 mg/ml to 10 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 10 mg/ml to 20 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 20 mg/ml to 30 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 30 mg/ml to 50 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 50 mg/ml to 60 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 60 mg/ml to 80 mg/ml. In some embodiments, the low molecular weight polymer is present in a concentration from 80 mg/ml to 100 mg/ml.

The use of a stabilizer in pharmaceutical compositions is well known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995. In some embodiments, the formulation may comprise a surfactant where a surfactant can be a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g., Tween-20, or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3-ammonio-l -propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g., l-acyl-sn-glycero-3 -phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g., lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g., N-alkyl-N,N-dimethylammonio-l- propanesulfonates, 3 -cholamido- 1 -propyldimethylammonio- 1 -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g., cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-100, Dodecyl P-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acid derivatives — (e.g., sodium tauro- dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (e.g., oleic acid and caprylic acid), acylcarnitines and derivatives, Na-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, Na-acylated derivatives of dipeptide comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, Na-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, imidazoline derivatives, or any mixture thereof. The use of a surfactant in pharmaceutical compositions is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulations may also comprise a pharmaceutically acceptable sweetener. In some embodiments, the sweetener comprises at least one intense sweetener such as, but not limited to, saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4,l ',6'-trichloro-4,r,6'- trideoxygalactosucrose), preferably saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners are conveniently employed in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, or from about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones. The bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35% or from about 10% to 15% (w/v).

The formulations may be prepared by conventional techniques, for example, as described in Remington’s Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.

Administration of the compound or the formulations described herein may be carried out using any method known in the art. For example, administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, inhalation, or by oral administration. In some embodiments, the compound or formulation is administered intravenously or by injection.

For oral administration, the compound of Formula (XIV), or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as gel caps, caplets, granules, lozenges, bulk powders, capsules or tablets. The tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients, including binding agents, for example, pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose; fillers, for example, lactose, microcrystalline cellulose, or calcium hydrogen phosphate; lubricants, for example, magnesium stearate, talc, or silica; disintegrants, for example, potato starch or sodium starch glycolate; or wetting agents, for example, sodium lauryl sulphate. Tablets can be coated by methods well known in the art.

Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p- hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.

For topical administration, the compound of Formula (XIV), can be formulated in a pharmaceutically acceptable vehicle containing 0.1 to 10 percent, preferably 0.5 to 5 percent, of the active compound(s). Such formulations can be in the form of a cream, lotion, sublingual tablet, aerosols and/or emulsions and can be included in a transdermal or buccal patch of the matrix or reservoir type as are conventional in the art for this purpose. For parenteral administration, the compound of Formula (XIV), or an amorphous form of the compound can be administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. Form I can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents. Additionally, the compound can be precipitated and stored in an ampule or other container and then dissolved in a solution prior to being administered to a subject.

For administration by injection, the compound can be used in solution, and, for example, in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic. In some embodiments, the pharmaceutical compositions may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration. In particular, injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g., liposomes) may be utilized. Suitable pharmaceutical carriers are described in “Remington’s pharmaceutical Sciences” by E. W. Martin.

For administration by inhalation, the compound may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch. For intranasal administration, the compound may be used, for example, as a liquid spray, as a powder or in the form of drops.

The compound can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.

Furthermore, the compound can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack can, for example, comprise metal or plastic foil, for example, a blister pack. The pack can also contain individual vials or other containers. The pack or dispenser device can be accompanied by instructions for administration.

DOSAGES

The compound of Formula (XIV), may be administered to a patient at therapeutically effective doses to prevent, treat, or control diseases and disorders mediated, in whole or in part, by a GPCR-ligand interaction described herein. Pharmaceutical compositions comprising the compound of Formula (XIV), may be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient. The dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.

The amount and frequency of administration of the compound comprising the compound of Formula (XIV) prepared according to a method described herein and/or the pharmaceutically acceptable salts thereof can be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In general, it is contemplated that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in particular from 0.01 mg/kg to 1 mg/kg body weight. More specifically, it is contemplated that an effective amount would be to continuously infuse by intravenous administration from 0.01 micrograms/kg body weight/min to 100 micrograms/kg body weight/min for a period of 12 hours to 14 days. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Sub-doses may be formulated as unit dosage forms, for example, containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form.

In some embodiments, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

MEDICAL USE A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof.

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof.

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating or preventing hyperalgesia. In some embodiments, the hyperalgesia is opioid induced hyperalgesia. In some embodiments, the opioid induced hyperalgesia is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin induced hyperalgesia. In some embodiments, the subject has been administered an opioid prior to being administered the compound of Formula (XIV) or a pharmaceutical composition thereof.

A composition comprising the compound of Formula (XI V) prepared according to a process described herein, can be used for treating pain in a subject comprising: administering an opioid agonist to the subject until the opioid increases nociceptive sensitization in the subject; and administering to a patient in need thereof, the compound of Formula (XIV), or a pharmaceutical composition thereof.

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating pain in an opioid exposed subject comprising: a) administering an opioid agonist to the subject; b) administering to the subject of step a), in the absence of the opioid administered in step a), the compound of Formula (XIV) or a pharmaceutical composition thereof. In some embodiments, In some embodiments, the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or a pharmaceutically acceptable salt thereof

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for decreasing nociceptive sensitization in a subject. In some embodiments, the subject has opioid induced nociceptive sensitization.

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating medication overuse headache in a subject comprising administering to a patient in need thereof, the compound of Formula (XIV) or a pharmaceutical composition thereof. In some embodiments, the medication overuse headache is caused by acetaminophen, aspirin, a mu-opioid agonist, a non-steroidal anti-inflammatory drug (NS AID), or a triptan. In some embodiments, the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan, or donitriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the mu-opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, or heroin, or a pharmaceutically acceptable salt thereof.

A composition comprising the compound of Formula (XIV) prepared according to a process described herein can be used for treating a migraine in a subject, the method comprising: administering a triptan to a subject; and administering to a patient in need thereof, the compound of Formula (XIV) or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (XIV) or a pharmaceutical composition thereof is administered in the absence of the triptan. In some embodiments, the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan, or donitriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject develops medication overuse headache prior to being administered the compound of Formula (XIV) or a pharmaceutical composition thereof.

COMBINATION THERAPIES Methods are also provided for treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof by administering the compound of Formula (XIV) prepared according to a method described herein, and/or pharmaceutically acceptable salts thereof, in combination with other drags for the treatment of pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof In the combination therapies, the compound of Formula (XIV) prepared according to a process described herein is co-administered with one or more drugs for the treatment of pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof to increase efficacy and to reduce side effects associated with high doses of these therapeutics. The combination therapies described above have synergistic and additive therapeutic effects. An improvement in the drug therapeutic regimen can be described as the interaction of two or more agents so that their combined effect reduces the incidence of adverse event (AE) of either or both agents used in co-therapy. This reduction in the incidence of adverse effects can be a result of, e.g., administration of lower dosages of either or both agent used in the co-therapy. For example, if the effect of Drug A alone is 25% and has an adverse event incidence of 45% at labeled dose; and the effect of Drug B alone is 25% and has an adverse event incidence of 30% at labeled dose, but when the two drugs are combined at lower than labeled doses of each, if the overall effect is 35% (an improvement, but not synergistic or additive) and the adverse incidence rate is 20%, there is an improvement in the drug therapeutic regimen.

In some embodiments, the compounds described herein are administered as a monotherapy. In some embodiments, the compounds described herein are administered as part of a combination therapy. For example, a compound may be used in combination with other drugs or therapies that are used in the treatment/prevention/suppression and/or amelioration of the diseases or conditions for which compounds are useful.

Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compounds described herein. When a compound described herein is used contemporaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs in addition to the compound described herein may be employed. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to the compounds described herein.

A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is often a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods, compound and compositions are particularly suited to administration to any animal, such as a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.

The following examples are merely illustrative and should not be construed as limiting the scope of the embodiments in any way as many variations and equivalents that are encompassed by these embodiments will become apparent to those skilled in the art upon reading the present disclosure.

In order that the embodiments disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the embodiments in any manner.

The following examples are illustrative, but not limiting, of the processes described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy, synthesis, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

Examples

Certain synthetic schemes, both general and specific, are provided herein. The compounds disclosed herein can be made according to the processes described herein or intermediates that lead to the compounds disclosed herein can be made according to the processes described herein. The substitutions can be varied according to the compound or intermediate being made based upon the following examples and other modifications known to one of skill in the art.

The processes disclosed herein were used to prepare the following compounds in the following examples or the examples were varied according to one of skill in the art to prepare the compounds.

Example 1: Processes of preparing compounds of Formula (I)

General Procedure A:

Synthesis

Compounds of Formula (I) can be prepared as shown by the processes outlined in Scheme 1. The racemic compounds having Formulae (Il-a) and (Il-b) contact with an ester having a formula of

or an anhydride having a formula of in the

presence of an esterase enzyme described herein can yield the compound having the Formula (I) in a mixture with the unreacted enantiomer of Formula (Il-b). The unreacted enantiomer of Formula (Il-b) in the mixture contacts a cyclic anhydride described herein to form an acid of

Formula (XVI), wherein X is The acid

described herein in the mixture is removed by washing the mixture with a basic solution as described and provided herein. R₁6 is optionally substituted branched or unbranched C₁-C₆ alkyl, C₂-C₆ alkenyl or C₁-C₆ alkynyl; and the rest variables are as defined in the embodiments as described and provided herein.

Scheme 1

Example 1- 1. Synthesis of the compound of Formula (IX): tert-butyl (2R,3S,4R)-3-

(acetoxymethyl)-4-(3-(2-methoxyethoxy)phenyl)-2-methylpiperidine-l-carboxylate

Scheme 2

First kinetic resolution:

To a solution of the racemic compound having Formulae (X-a) and (X-b) (8.0 kg, 1.00 eq.) in acetonitrile (ACN) (24 L, 3-fold volume of the racemic compound (3.00 V)) was added vinyl acetate (16 L, 2.00 V), Novozyme 435 (1.6 kg, 0.20 w/w) to form a suspension mixture.

The suspension mixture was allowed to stir at 25 °C -30 °C under nitrogen for about 16 h. Liquid Chromatography-Mass Spectrometry analysis (LC-MS) results in FIG. 1 showed the percentage of the compound of Formula (IX) in the suspension mixture was 47.6%. In FIG. 1. the peak at about 14.3 min has a mass peak corresponding to the compound of Formula (IX) (UPLC-qDa (C₂₃H₃₅NO₆) calcd 422.25, [M + H]⁺, found 444, 3 [M + Na]⁺); the peak at about 12.0 min has a mass peak corresponding to the racemic compound (UPLC-qDa (C₂₁H₃₃NO₅) calcd 380.24, [M + H]⁺, found 402.3 [M + Na]⁺). Then, the suspension mixture was then filtered and the filtered cake was washed with ACN (16 L, 2.00 V). The filtrates were collected and charged back to a reactor to which was added succinic anhydride (5.27 kg, 2.50 eq.) and 4-Dimethylaminopyridine (DMAP) (0.26 kg, 0.10 eq.). The resulting mixture was heated to an internal temperature of about 65 -70 °C and stirred for 6 h. LC-MS analysis results in FIG. 2 showed that the racemic compound having Formulae (X-a) and (X-b) in the heated mixture was consumed completely and the peak at about 6.8 min has a mass peak corresponding to the compound of Formula (XVII-a)(UPLC-qDa (C₂₅H₃₇NO₈) calcd 480.24, [M + H]⁺, found 502.3 [M + Na]⁺). The solvents were concentrated in vacuum to form a residue 1.5V-2.0V(12L-16L). To the residue was added 5% K₂CO₃ aqueous solution (64 L, 8.00 V) to form a mixture and the resulting mixture was stirred for 1 h at about 20-30 °C. Then, to the mixture 2-Me-THF (40 L, 5.00 V) was added to form a biphasic mixture and the biphasic mixture was stirred at 20-30 °C for 0.5 h. The organic phase of the biphasic mixture was separated and washed with 5% K₂CO₃ aqueous solution (64 L, 8.00 V) for three times. The organic phase was then concentrated in vacuum below 50 °C to 1.5V-2.0V(12L-16L), to which an additional THF (40 L, 5.00 V) was added, and the solvents were again concentrated below 50 °C to a solution of the compound of Formula (I) 2.0V- 2.5V(16L-20L), which was repeated for two more times. To the resulting solution was added water (16 L, 2.00 V) and NaOH (2.95 kg, 3.5 eq.), the reaction mixture was heated to an internal temperature of 60-65 °C and stirred for 18 h. HPLC analysis results in FIG. 3 showed the content of the compound of Formula (IX) in the reaction mixture was 0.7 %. The solution was cooled to an internal temperature of 20-30 °C and added MTBE (40 L, 5.00 V), water (40 L, 5.00 V) to form a biphasic mixture from which the organic phase was then separated and washed with water (40 L, 5.00 V) for three times. The organic phase was then concentrated in vacuum below 50 °C until no fraction flow out.

Second kinetic resolution:

To above concentrated organic phase was added ACN (8 L, 1.00 V), vinyl acetate (5.6 L, 0.70 V), Novozyme 435 (1.2 kg, 0.15w/w) to form a suspension. The resulting suspension was allowed to stir at 25-30 °C under nitrogen for 15 h. HPLC analysis results in FIG. 4 showed the percentage of the compound of Formula (IX) in the suspension mixture was 81.8%. Then, the suspension mixture filtered and the filtered cake was washed the cake with ACN (8 L, 1.00 V). The filtrates were collected and charged back to a reactor to which was added succinic anhydride (3.16 kg, 1.50 eq.) and DMAP (0.155 kg, 0.06 eq.). The resulting mixture was heated to an internal temperature of about 65 -70 °C and stirred for 2 h. HPLC analysis results in FIG. 5 showed that the racemic compound was consumed completely. The solvents were concentrated in vacuum until no fraction flow out form a residue. To the residue was added 5% K₂CO₃ aqueous solution (24 L, 3.00 V) to form a mixture and the resulting mixture was stirred for 1 h at 20-30 ⁰ C. Then, to the mixture 2-Me-THF (16 L, 2.00 V) was added to form a biphasic mixture and the biphasic mixture was stirred at 20-30°C for 0.5 h. The organic phase of the biphasic mixture was separated and washed with 5% K₂CO₃ aqueous solution (24 L, 3.00 V) for three times. The organic phase was then concentrated in vacuum below 50 °C until no fraction flow out, to which was added water (4 L, 0.50 V) and NaOH (1.27 kg, 1.5 eq.). The resulting reaction mixture was heated to an internal temperature of 60-65 °C and stirred for 16 h (HPLC showed the content of compound of Formula (IX) was 0.15%). The solution was cooled to an internal temperature of 20-30 °C and added MTBE (16 L, 2.00 V) and water (16 L, 2.00 V) to form a biphasic mixture, of which the organic layer was separated and washed with water (16 L, 2.00 V) for three times. The organic phase was then concentrated under vacuum below 50 °C until no fraction flow out to afford the compound of Formula (ILa) as light yellow oil in 31.0% yield with a 99.4% chemical purity and a 98.9% enantiomeric purity.

High-performance liquid chromatography (HPLC)

Compounds as described and provided herein as well as the reactions mixtures thereof described herein were analyzed with High-performance liquid chromatography for their purities and the reaction conversion rates and yields. The general experimental conditions for HPLC are as follows:

The chemical purity of the compound of Formula (ILa) is determined by an analytic method described herein by HPLC. The HPLC analysis results on Agilent 1260 (HPLC-112) in FIG. 6 demonstrated that the compounds of Formula (XVILa), Formula (IX) and Formula (X-a) have different retention times at about 7.9 min, at about 13.1, and at about 15.3 min respectively. The HPLC analysis results on Agilent 1260 (TJ-HPLC-018) in FIGs. 1-5 demonstrated that the reaction conversions as indicate above. Any differences in retention times see in FIG. 1-5 as compared to FIG. 6 for the compounds of Formula (XVII-a), Formula (IX) and Formula (X-a) are due to the system variations between the different instruments HPLC-112 and TJ-HPLC-018, which is understood and appreciate by one of skill in the art.

The analysis result in FIG. 7 showed that the chemical purity of the compound of Formula (X-a) is 99.4%. The HPLC conditions and methods are as follows:

Instrument: Agilent 1260

Gradient Table:

The enantiomeric purity of the compound of Formula (ILa) is determined by an analytic method described herein by chiral HPLC. The chiral HPLC conditions and methods are as follows: Instrument: Agilent 1260

Gradient Table:

The chiral HPLC analysis results in FIG. 8 demonstrated that the racemic compounds of Formula (IX-a) and Formula (IX) have different retention times at about 13.4 min and at about 16.6 min respectively and the racemic compounds of Formula (X-b) and Formula (X-a) have different retention times at about 32.9 min and at about 37.0 min respectively. As a result, the analysis result in FIG. 9 showed that the enantiomeric purity of the compound of Formula (IX) prepared herein is 98.9%.

The chiral HPLC analysis were used to determine the chiral purity of the compound of Formula (IX) described and provided in Examples 1-2 to 1-8.

Additionally, the kinetic resolution steps described and provided herein can be repeated to obtain high enantiomeric purity of the compound of Formula (I) or Formula (Il-a) as needed. In some embodiments, recrystallization can also be used in combination with the kinetic resolution steps described and provided herein to obtain high enantiomeric purity of the compound of Formula (I) or Formula (Il-a). Example 1-2. Screening solvents for synthesis of the compound of Formula (IX)

Various organic solvents were screened for synthesis of the compound of Formula (IX). Based on the results seen in Table 1, acetonitrile was found to be the preferred solvent for the synthesis of the compound of Formula (IX). Table 1.

Example 1-3. Screening volumes of acetonitrile for synthesis of the compound of Formula (IX)

Next, volumes of acetonitrile were screened for synthesis of the compound of Formula (IX). Based on the results seen in Table 2, the 3-fold volume ratio (3 V) of acetonitrile to the racemic compound was found to be the preferred for the synthesis of the compound of Formula (IX). Table 2.

- Ill -

Example 1-4. Temperature screen for synthesis of the compound of Formula (IX)

Different ranges were screened for synthesis of the compound of Formula (IX). Based on the results seen in Table 3, the temperature range from about 25 °C to 30 °C was found to be the preferred for the synthesis of the compound of Formula (IX).

Table 3.

Example 1-5. Screening amounts of Novozyme 435 for synthesis of the compound of Formula (IX) Various amounts of Novozyme 435 were screened for synthesis of the compound of

Formula (IX). Based on the results seen in Table 4, the amount of Novozyme used in a ratio of 0.2 w/w to the racemic compound was found to be the preferred for the synthesis of the compound of Formula (IX).

Table 4.

( ) ( )

Example 1-6. Screening activation reagents for synthesis of the compound of Formula (IX)

Various activation reagents were screened for synthesis of the compound of Formula (IX). Based on the results seen in Table 5, vinyl acetate was found to be the preferred activation reagent for the synthesis of compound of Formula (IX).

Table 5.

Example 1-7. Screening amounts of vinyl acetate for synthesis of the compound of Formula (IX) Next, various amounts of vinyl acetate were screened for synthesis of the compound of

Formula (IX). Based on the results seen in Table 6, the amount of vinyl acetate used in a molar ratio of about 1 : 1 to the racemic compound was found to be the preferred for the synthesis of compound of Formula (IX).

Table 6.

Example 1-8. Screening amounts of vinyl propionate for synthesis of the compound of Formula (IX)

Various amounts of vinyl propionate were screened for synthesis of the compound of Formula (IX). Based on the results seen in Table 7, the amount of vinyl acetate used in a molar ratio of about 8: 1 to the racemic compound was found to be the preferred for the synthesis of the compound of Formula (IX).

Table 7.

Example 2: Processes of preparing compounds of Formula (XIV) General Procedure B:

Synthesis

Compounds of Formula (XIV) can be prepared as shown by the processes outlined in

Scheme 3. The compound of Formulae (II-c) contact with a suitable reagent to form the compound of Formula (XI

Scheme 3

Example 2-1. Synthesis of the compound of Formula (XlV-d): 6-(((2R,3S,4R)-l-(2-(lH- pyrrol-l-yl)ethyl)-4-(3-(2-methoxyethoxy)phenyl)-2-methylpiperidin-3- yl)methoxy)isoindolin-l-one and the hydrochloride salt thereof Scheme 4

Preparation of (-)-tert-Butyl (trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-3-{[(3- oxo-2, 3-dihydro-lH-isoindol-5-yl)oxy]methyl}piperidine-l-carboxylate Formula (XII-b) To an ice-cold solution of (-)-tert-butyl (trans, trans)-3-(hydroxymethyl)-4-[3-(2- m ethoxy ethoxy)phenyl]-2-methylpiperi dine- 1 -carboxylate Formula (X-a), 5.3 g, 14.0 mmol] in /c/7-butylmethylether (25 mL) was added trimethylamine (2.5 mL, 18.2 mmol, 1.3 eq) followed by methanesulfonyl chloride dropwise (1.4 mL, 18.2 mmol, 1.3 eq) to yield a thick white suspension. The ice bath was removed, and the reaction was stirred at rt for 2 hr. To the reaction was added 25 mL ice water, and the mixture stirred vigorously for 45 minutes, and then for an additional 15 minutes in an ice bath. The mixture was filtered and washed 3X 20 mL water and dried under vacuum in the filter funnel, then in a rt vacuum oven for 24 hours to yield 5.5 g of the mesylate of Formula (Xl-a) as a white solid. The white solid was transferred to a 250 mL 2-neck flask that was oven-dried and brought to rt under vacuum, and purged with nitrogen. Cesium carbonate (7.8 g, 24.0 mmol, 2.0 eq) and 6-hy droxy-2, 3 -dihydro- IH-isoindol- 1-one (2.2 g, 15.0 mmol, 1.25 eq) were added to the flask, followed by isopropyl alcohol (previously dried over 3 angstrom molecular sieves, 75 mL). The resulting mixture was stirred with an overhead mechanical stirrer under nitrogen for 2.5 hr, and then the mesylate was added (5.5 g, 12.0 mmol). The mixture was heated to and strirred at 70 °C overnight. The reaction was then cooled to rt, filtered of inorganics, and concentrated. The crude product was purified by normal phase chromatography (120 g Biotage Zip Sphere column; 8% - 70% acetone/hexanes) to yield 3.7 g (60%) of the compound of Formula (XII-b) as a white solid. LC-MS (ES, m/z, M- tBu): 455.3.

Preparation of (-)-6-{[(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidin-3- yl]methoxy}-2,3-dihydro-lH-isoindol-l-one Formula (XII-a) in hydrochoride salt form

To a solution of (-)-tert-butyl (trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-3- {[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)oxy]methyl}piperidine-l -carboxylate Formula (XII-b), 6.2 g, 12.1 mmol] in methanol (20 mL) was added IN HCl/EtOAc (61 mL, 61 mmol, 5 eq) and the resulting solution was stirred at rt overnight. The reaction was concentrated to a white foam, which was triturated with diethyl ether, then dried under high vacuum overnight to yield 5.8 g (quant.) of the compound of Formula (XIII-a) in hydrochloride salt form as a white solid. LCMS (ES, m/z, MH+): 411.2. ¹H N R (400 MHz, DMSO) 8 8.93 (d, J= 20.5, 2H), 8.54 (s, 1H), 7.44 (d, = 8.3, 1H), 7.21 (t, J= 7.9, 1H), 7.10 (dd, J= 8.3, 2.3, 1H), 7.02 (d, J = 2.2, 1H), 6.79 (dd, J= 8.2, 2.1, 1H), 6.75 (d, J= 7.6, 1H), 6.69 (s, 1H), 4.26 (s, 2H), 4.07 - 3.92 (m, 2H), 3.91 - 3.79 (m, 1H), 3.56 (t, J= 4.5, 2H), 3.50 (d, J= 7.8, 1H), 3.25 (s, 3H), 3.18 - 2.93 (m, 2H), 2.18 (t, J= 10.9, 1H), 2.06 (ddd, J= 16.0, 13.3, 3.4, 1H), 1.92 (d, J= 12.3, 1H), 1.37 (d, J= 6.4, 3H).

Preparation of (-)-6-{[(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-l-[2-(lH- pyrrol-l-yl)ethyl]piperidin-3-yl]methoxy}-2,3-dihydro-lH-isoindol-l-one Formula (XlV-d) and hydrochoride salt thereof

To a solution of (-)-6-{ [(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidin- 3-yl]methoxy}-2,3-dihydro-lH-isoindol-l-one, the compound of Formula (XIII-a), in hydrochloride salt form, 5.10 g, 12.42 mmol] in anhydrous acetonitrile (25 mL) was added potassium carbonate (3.43 g, 24.85 mmol, 2.0 eq) and 1 -pyrroleethylbromide (4.32 g, 24.85 mmol, 2.0 eq) and the reaction heated at 50°C for 168 hr. The reaction was cooled to rt, filtered of inorganics, and concentrated. The crude product was purified by reverse phase chromatography (Phenomenex Luna 5p C18 column, 30% - 50% MeCN/water/0.1% TFA. The product fractions were concentrated, and the residue dissolved in 25 mL DCM and washed with IN NaOH (ensuring aqueous basic by pH paper). The layers were separated, and the aqueous extracted 3X 10 mL DCM. The combined organics were washed with brine, filtered through cotton and concentrated to yield 6.4 g (84%) of the compound of Formula (XlV-d) as a white solid. The hydrochloride salt may be formed by dissolving the free base in MeCN/water, adding 1.05 eq. IN HC1, and lyophilizing to yield a white powder. LCMS (M+H) 504.3; HC1 salt ’H NMR (400 MHz, DMSO) 5 11.15 - 10.65 (m, 1H), 8.55 (s, 1H), 7.48 - 7.42 (m, 1H), 7.25 - 7.08 (m, 2H), 7.07 - 6.96 (m, 3H), 6.95 - 6.67 (m, 3H), 6.10 - 6.05 (m, 2H), 4.55 - 4.31 (m, 2H), 4.27 (s, 2H), 4.09 (d, J= 8.7, 1H), 4.03 - 3.82 (m, 3H), 3.76 - 3.62 (m, 1H), 3.61 - 3.48 (m, 5H), 3.27 - 3.23 (m, 3H), 3.22 - 2.96 (m, 2H), 2.46 - 2.12 (m, 2H), 1.95 - 1.71 (m, 1H), 1.48 - 1.37 (m, 3H).

Example 3. Liquid Chromatography-Mass Spectrometry (LC-MS) Compounds as described and provided herein as well as the reactions mixtures thereof described herein such as the compounds and reaction mixtures of Example 1-1 were analyzed with LC-MS for their purities and the reaction conversion rates and yields. The general experimental conditions for LC-MS are as follows: HPLC parameters

HPLC Gradient Table:

MSD parameters

The present examples demonstrate a surprising an unexpected ability to synthesize compounds provided for herein utilizing an enzyme catalyzed reaction. These reactions enable these compounds to be made at a larger scale and/or in a more efficient method, which could not have been predicted.

Example 4. Scale-Up Preparation of the Compound of Formula (XlV-d) in the Crystalline Free Base (FB) Form

A scale-up preparation of the compound of Formula (XlV-d) in the crystalline FB form was achieved, which demonstrates the ability to make the compound in significant quantities suitable for the manufacture of a medicament or pharmaceutical (Scheme 5). Advantageously, the scale-up preparation produced the compound of Formula (XlV-d) of high chemical purity and high enantiomeric purity. The amounts and purities of the starting material, intermediates, and the product and the yields of each step are shown in Scheme 6. Remarkably and surprisingly, the compound of Formula (XlV-d) made by the process produced a compound with a purity of about 99.7% w/w and an enantiomeric excess of about 99.9% (see Table 12 below for characterizations). Scheme 5

Scheme 6

Step (A): Preparation of the Compound of Formula (Xl-a)

The reaction of Step (A) is demonstrated in Scheme 7. The detailed procedure includes 22 steps as shown below with the corresponding materials listed in Table 8.

Scheme 7

Table 8.

Detailed Procedure:

1. Precondition a 100-gallon reactor and supporting equipment with MTBE (-100 L) at reflux (-55 °C), then cool down under N2 blanket and drain the solvent. Maintain N2 blanket.

2. Set the reactor jacket to 50 °C and charge the compound of Formula (X-a) (1.0 eq, SM) pre-warmed in a water bath (60 °C temperature setting) and initiate agitation.

3. Charge MTBE (5 vol) while maintaining the mixture at NLT 35 °C.

4. Cool the resulting solution to 15 to 30 °C (target 20 °C). 5. Pull a sample of the MTBE solution in the reactor for moisture control.

6. Charge more MTBE (5 vol).

7. Cool the mixture (solution) to 0 ± 5 °C under N2 blanket. 8. Charge TEA (1.5 eq) in one portion.

9. Charge MsCl (1.2 eq) over NLT 30 min while maintaining the reaction mixture at -5 to

10 °C (target 0 °C).

10. Stir the reaction mixture at -5 to 10 °C (target 0 °C) for NLT 4 hrs.

11. Pull a sample of the stirred reaction mixture (slurry) by HPLC. The HPLC results (FIG.

10) showed 0.2% (area) for the compound of Formula (X-a) and 99.8% (area) for the compound of Formula (XI-a).

12. Charge water (5 vol) over NLT 1 hr while maintaining the reaction mixture at 0 ± 5 °C.

13. Charge n-Heptane (10 vol) over NLT 1 hr while maintaining the reaction mixture at 0 ± 5 °C.

14. Stir the slurry at 0 ± 5 °C for NLT 1 h.

15. Collect the solids by filtration.

16. Rinse the parent reactor with n-Heptane (3 vol) and use the rinse to wash the filter cake.

17. Rinse the parent reactor with water (10 vol) and use the rinse to wash the filter cake.

18. Rinse the parent reactor with water (10 vol) and use the rinse to wash the filter cake.

19. Rinse the parent reactor with n-Heptane (5 vol) and use the rinse to wash the filter cake.

20. Rinse the parent reactor with n-Heptane (5 vol) and use the rinse to wash the filter cake.

21. Pull the solids dry on the filter to deliquor the cake.

22. Dry the solids under house vacuum at 45 °C (jacket set point) for NLT 24 hrs (to constant weight for tray drying) and pull a sample of solids for dry completion IPC by KF. KF results showed 0.005% (w/w) of water.

Characterization of Step (A) Product (Compound of Formula (XI-a)):

1) Yield: 9.7 kg (purity 84%)

2) Appearance by visual: white solid

3) Appearance by Munsell color: white solid

4) Purity by HPLC: 99.5% (area). See HPLC results in FIG. 11. 5) Stability studies were performed for the resultant compound of Formula (Xl-a) solids during vacuum oven drying stressed to 60 °C for 160 h. No visual change in appearance was observed and no degradation by HPLC was detected. Step (B): Preparation of the Compound of Formula (XII-b)

The reaction of Step (B) is demonstrated in Scheme 8. The detailed procedure includes 50 steps as shown below with the corresponding materials listed in Table 9.

Scheme 8

Table 9.

Detailed Procedure:

1. Charge the compound of Formula (Xl-a) (1 eq, SM) to a clean and dry 50-gallon reactor.

2. Charge the compound of Formula (XI-z) (1.2 eq). 3. Charge n-Bu₄N⁺HSO₄- (0.05 eq).

4. Charge K₂CO₃ (2 eq).

5. Charge ACN (8 vol). Initiate agitation.

6. Charge water(5 eq).

7. Heat the reaction mixture to 75 ± 5 °C using a jacket temperature mode or at approximately 40 °C/hr rate.

8. Stir the reaction mixture at 75 ± 5 °C for 72 to 84 hrs.

9. Cool the reaction mixture to 15 °C to 30 °C (target 20 °C).

10. Pull a sample of the stirred reaction mixture (slurry) by HPLC. The HPLC result (FIG. 12) showed 0.03% (area) for the compound of Formula (Xl-a) and 99.97% for the compound of Formula (Xll-b).

11. Concentrate the reaction mixture under reduced pressure at NMT 40 °C (jacket set point) to 2

- 3 vol (target 2.5 vol) residue volume.

12. Set jacket to 20 °C and charge MTBE (6 vol) to the concentrated reaction mixture.

13. Charge water (8 vol). 14. Stir the mixture for NLT 10 min.

15. Filter the mixture through an in-line filter (in a kilo-lab a plate filter lined with a double layer of GF-filter may be used) and collect the filtrate into a 100-gallon receiver reactor to remove minor insolubles.

16. Rinse the parent reactor and the lines with MTBE (2 vol).

17. Allow the layers in the combined filtrate to separate fora minimum of 30 min.

18. Separate bottom aqueous layer (pH ~ 9) from top organic.

19. Charge a solution of K₂CO₃ (1 eq) in water(8 vol) to the organic layer.

20. Stir the mixture fora minimum of 15 min and allow the layers to separate fora minimum of 2 h.

21. Separate bottom aqueous layer (pH ~ 11) from top organic.

22. Charge a solution of K₂CO₃ (1 eq) in water(8 vol) to the organic layer.

23. Stir the mixture fora minimum of 5 min and allow the layers to separate for a minimum of 1 h.

24. Separate bottom aqueous layer(pH ~ 11) from top organic.

25. Charge Na2SO4 (0.5 kg/kg SM).

26. Stir the mixture for NLT 2 hrs.

27. Filter off the spent drying agent through a filter lined with polypropylene filter cloth. Collect the filtrate in a clean, dry 50-gallon reactor.

28. Rinse the parent reactor with MTBE (3 vol) and use the rinse to wash the filter cake.

29. Concentrate the filtrate under reduced pressure at NMT 30 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

30. Transfer the residue to a clean, dry 100-gallon reactor.

31. Rinse the parent reactor with MTBE (3 vol) and combine the rinse with the material in the 100- gallon reactor.

32. Concentrate the resulting mixture under reduced pressure at NMT 30 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

33. Rinse the parent reactor with MTBE (3 vol) and combine the rinse with the material in the 100- gallon reactor. 34. Concentrate the resulting mixture under reduced pressure at NMT 30 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

35. Pull a sample of the concentrated residue for residual ACN content IPC by GC-HS, which observed 1% (v/v%) of ACN (NMT 2% (v/v%) of ACN).

36. Charge IP A (1 vol).

37. Set jacket to 25 °C and stir the resulting mixture for NLT 5 min until a clear solution forms.

38. Charge n-Heptane (2 vol).

39. Cool the mixture to 0 ± 5 °C.

40. Charge the compound of Formula (Xll-b) Seed Crystals (0.005 g/g SM) as a slurry in n- Heptane, followed by a rinse with n-Heptane.

41. Stir the resulting mixture at 0 ± 5 °C for NLT 2 hrs.

42. Charge n-Heptane (1 vol) over NLT 1 hr while maintaining the mixture at 0±5 °C.

43. Stir the resulting mixture at 0 ± 5 °C for NLT 2 hrs until formation of a thick slurry is observed.

44. Charge n-Heptane (10 vol) over NLT 2 hrs while maintaining the slurry at 0±5 °C.

45. Stir the slurry for NLT 2 hrs at 0 ± 5 °C.

46. Collect the solids by filtration.

47. Set the jacket of the parent reactor to 0 °C. Rinse the parent reactor with n-Heptane (3 vol) and use the rinse to wash the filter cake.

48. Rinse the parent reactor with n-Heptane (3 vol) and use the rinse to wash the filter cake.

49. Pull the solids dry on the filter to deliquor the cake.

50. Tray dry the solids under house vacuum at 35 °C (jacket set point) for NLT 12 hrs to yield constant weight.

Characterization of Step (B) Product (Compound of Formula (XILb)):

1) Yield: 10.3 kg (95% purity)

2) Appearance by visual: Off-white solid

3) Appearance by Munsell color: Off-white solid

4) Purity by HPLC: 99.6% (area). See HPLC results in FIG. 13a and FIG. 13b. Step (C): Preparation of the Compound of Formula (XIII-a)

The reaction of Step (C) is demonstrated in Scheme 9. The detailed procedure includes 24 steps as shown below with the corresponding materials listed in Table 10.

Scheme 9

Table 10.

Detailed Procedure:

1. Charge the compound of Formula (Xll-b) (1 eq, SM) solids to a clean and dry, 100-gallon reactor. 2. Charge IPA (5 vol) and initiate agitation.

3. Stir the mixture with a jacket temperature set point of 20 °C for NLT 10 min until a clear solution is formed.

4. Charge water (3 vol).

5. Charge cone. HC1 (3 eq). 6. Heat the reaction mixture to 50 ± 5 °C over NLT 1 hr.

7. Stir the reaction mixture at 50 ± 5 °C for 16 to 24 hrs.

8. Cool the reaction mixture to 15 °C to 30 °C (target 20 °C).

9. Pull a sample of the stirred reaction mixture (clear solution) for reaction completion IPC. add a kicker charge of cone. HC1 (0.5 eq), re-heat the reaction mixture to 50 ± 5 °C over NLT 1 hr and stir at 50±5 °C for 12 to 24 hrs, then cool down and repeat the IPC by HPLC. Reaction went to completion after the kicker charge addition. 0.4% (area) of SM (CML-468) The HPLC result (FIG. 14) showed 0.4% (area) of SM for the compound of Formula (Xll-b) and 99.6% (area) for the compound of Intermediate Formula (Xlll-a).

10. Charge MTBE (8 vol).

11. Charge a solution of K₂CO₃ (4 eq) in water (2 vol) over NLT 30 min while maintaining the mixture at 20 ± 5°C.

12. Stir the resulting biphasic mixture at 20 ± 5 °C for NLT 1 hr.

13. Pull a sample of the stirred reaction mixture (biphasic mixture) fora pH check: pH is 8 in aqueous (bottom) layer.

14. Allow the layers to separate for NLT 10 min.

15. Separate bottom aqueous layer (pH 8-9) from top organic. Collect the aqueous layer in a 50-gallon reactor.

16. Charge MTBE (2 vol) to the aqueous layer.

17. Stir the mixture for NLT 5 min and allow the layers to separate for NLT 10 min.

18. Separate bottom aqueous layer (pH 8-9) from top organic.

19. Concentrate the combined organic layers under reduced pressure at NMT 50 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

20. Charge ACN (5 vol) to the concentrated residue and concentrate the resulting mixture under reduced pressure at NMT 50 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

21. Charge ACN (5 vol) to the concentrated residue and concentrate the resulting mixture under reduced pressure at NMT 50 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

22. Charge ACN (5 vol) to the concentrated residue and concentrate the resulting mixture under reduced pressure at NMT 50 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

23. Cool the concentrated residue to 15 °C to 30 °C (target 20 °C).

24. Pull a sample of the concentrated residue for water content by KF, which observed 8.4%.

Step (D): Preparation of the Compound of Formula (XlV-d)

The reaction of Step (D) is demonstrated in Scheme 10. The detailed procedure (which continued after Step (C) above) includes 73 additional steps as below with the corresponding materials listed in Table 11.

Scheme 10

Table 11.

Detailed Procedure (continued from Detailed Procedure in Step (C)):

25. Charge K₂CO₃ powder, 325 mesh (2 eq) to the reactor containing the intermediate compound of Formula (Xlll-a) in ACN, concentrated to 2-3 vol.

26. Charge ACN (3 vol).

27. Charge the compound of Formula (XIII-z) (2 eq) and initiate agitation.

28. Heat the reaction mixture to 55±5 °C using the Jacket Set Point heating mode.

29. Stir the reaction mixture at 55±5 °C for 84 to 96 hrs. 30. Cool the reaction mixture to 15 °C to 30 °C (target 20 °C).

31. Pull a sample of the stirred reaction mixture (mobile slurry) for reaction completion IPC. Re-heat the reaction mixture to 55 ± 5 °C and stir at 55 ± 5 °C for 12 to 24 hrs, then cool down and repeat the IPC by HPLC. Reaction ultimately went to completion after additional stirring at 55 ± 5 °C for a total of 69 hrs: The HPLC result (FIG. 15) showed 0.4% (area) for the compound of Intermediate Formula (Xlll-a) and 99.6 % (area) for the compound of Formula (XlV-d)

32. Concentrate the reaction mixture under reduced pressure at NMT 40 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

33. Cool the concentrated reaction mixture (slurry) to 25 ± 5°C.

34. Charge i-PrOAc (8 vol) to the concentrated reaction mixture.

35. Charge water (8 vol).

36. Set the jacket to 25°C and stir the mixture for NLT 5 min.

37. Allow the layers to separate for NLT 60 min.

38. Separate bottom aqueous layer (pH 8-9) from top organic.

39. Charge a solution of NaCl (0.5 g/g SM) in water (8 vol) to the organic layer.

40. Stir the mixture for a minimum of 5 min and allow the layers to separate for a minimum of 60 min.

41. Separate bottom aqueous layer (pH 7-8) from top organic.

42. Charge IPA (1.25 vol) to the organic layer.

43. Charge water (9 vol) to the organic layer.

44. Charge cone. HC1 (1 eq) over NLT 15 min while maintaining the mixture at 20 ± 5°C.

45. Stir the resulting mixture at 20 ± 5 °C for NLT 5 min.

46. Pull a sample of the stirred mixture (biphasic mixture) for a pH check: pH < 4 in aqueous (bottom) layer using pH indicator strips.

47. Check the pulled above sample for absence of product oiling out (HC1 salt of the compound of Formula (XlV-d) oil on the bottom). If the triphasic mixture is observed, add water in 1 vol increments to the bulk mixture in the reactor, stir for NLT 5 min, pull a sample for visual check. Repeat as needed until all oil phase is dissolved and a normal biphasic aqueous/organic mixture was observed.

48. Allow the layers to separate for NLT 10 min.

49. Separate the product containing bottom aqueous (product containing) layer (pH < 4) from top organic. Transfer the aqueous layer into a clean, dry 50-gallon reactor. 50. Charge water (2 vol) to the organic layer in the 100-gallon reactor.

51. Stir the mixture for NLT 5 min at a jacket temperature set point of 25 °C and allow the layers to separate for NLT 30 min.

52. Separate bottom aqueous (product containing) layer from top organic. Combine aqueous layers in the 50- gallon reactor.

53. Charge water (2 vol) to the organic layer in the 100-gallon reactor.

54. Stir the mixture for NLT 5 min at a jacket temperature set point of 25 °C and allow the layers to separate for NLT 30 min.

55. Separate bottom aqueous (product containing) layer from top organic. Combine aqueous layers in the 50- gallon reactor.

56. Charge n-Heptane (4 vol) to the combined aqueous layers.

57. Stir the mixture for NLT 5 min at a jacket temperature set point of 25 °C and allow the layers to separate for NLT 10 min.

58. Separate bottom aqueous (product containing) layer from top organic. Transfer aqueous layers into an HDPE drum.

59. Charge water (2 vol) to the empty 50-gallon reactor as a rinse and combine with the organic layer in the 100-gallon reactor.

60. Stir the mixture for NLT 5 min at a jacket temperature set point of 25 °C and allow the layers to separate for NLT 10 min.

61. Separate bottom aqueous (product containing) layer from top organic. Combine aqueous layers in the HDPE drum.

62. Transfer the combined aqueous layers (product containing) from the HDPE drum to a clean 100-gallon reactor. Rinse the drum with water (1 vol).

63. Charge i-PrOAc (8 vol) to the combined aqueous layers.

64. Charge a solution of K₂CO₃ (2 eq) in water (1 vol) over NLT 10 min while maintaining the mixture at 25 ± 5 °C.

65. Stir the mixture for NLT 5 min at 25 ± 5 °C and allow the layers to separate for NLT 10 mm. 66. Separate bottom aqueous (pH 8-9) layer from top organic (product containing).

67. Partially transfer the organic layer to a clean, dry 50-gallon reactor.

68. Concentrate the organic layer under reduced pressure at NMT 45 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

69. Rinse the parent reactor with i-PrOAc (3 vol) and combine the rinse with the material in the 50-gallon reactor.

70. Concentrate the resulting mixture under reduced pressure at NMT 45 °C (jacket set point) to 2 - 3 vol (target 2.5 vol) residue volume.

71. Cool the concentrated residue to 25 ± 5 °C.

72. Pull a sample of the concentrated residue for water content by KF which observed NMT 0.03%.

73. Charge i-PrOAc (13 vol) to the concentrated residue.

74. Heat the mixture to 30 ± 5 °C.

75. Stir the mixture at 30 ± 5 °C for NLT 15 min to form a clear solution.

76. Perform filtration through carbon (Norit CGP Super) cartridge (0.05 - 0.2 kg/kg SM loading) at 30 ± 5 °C targeting 2 hrs of the filtration time. Collect the filtrate in a clean, dry 100- gallon reactor.

77. Charge i-PrOAc (5 vol) to the parent reactor. Heat the solvent to 30 ± 5 °C prior passing through the filter cartridge as a rinse.

78. Concentrate the filtered solution of crude compound of Formula (XlV-d) Free Base in i- PrOAc under reduced pressure at NMT 45 °C (jacket set point) to 4.5 - 5.5 vol (target 5.0 vol) residue volume.

79. Cool the residue (clear solution is expected) to 10 ± 5°C.

80. Stir the mixture at 10 ± 5°C for NLT 30 min until product precipitation is confirmed. Do not proceed to the next step before confirmation of the start of product precipitation.

81. Stir the resulting slurry at 10 ± 5°C for NLT 12 h.

82. Charge MTBE (5 vol) over NLT 2 h while maintaining the slurry at 10 ± 5°C.

83. Heat the slurry to 25 ± 5°C. 84. Charge n-Heptane (5 vol) over NLT 2 h while maintaining the slurry at 25 ± 5°C.

85. Heat the slurry to 40 ± 5°C.

86. Charge n-Heptane (5 vol) over NLT 2 h while maintaining the slurry at 25 ± 5°C.

87. Cool the slurry to 0 ± 5°C over NLT 4 h.

88. Stir the slurry at 0 ± 5°C for NLT 2 h.

89. Collect the solids by filtration.

90. Charge MTBE (2 vol) to the emptied parent reactor.

91. Charge n-Heptane (2 vol) to the parent reactor and initiate agitation. Use the prepared 1 : 1 (v/v) MTBE/ n-Heptane mixture to wash the filter cake.

92. Wash the filter cake with 1 : 1 (v/v) MTBE/ n-Heptane mixture prepared in the parent reactor above.

93. Charge MTBE (2 vol) to the emptied parent reactor.

94. Charge n-Heptane (2vol) to the parent reactor and initiate agitation. Use the prepared 1 : 1 (v/v) MTBE/ n-Heptane mixture to wash the filter cake.

95. Wash the filter cake with 1 : 1 (v/v) MTBE/ n-Heptane mixture prepared in the parent reactor above.

96. Pull the solids dry on the filter to deliquor the cake.

97. Dry the solids under house vacuum at 35 °C (jacket set point) for NLT 12 hrs (to constant weight for tray drying) and pull a sample of solids for drying completion by GC-HS with the results of i-PrOAc at NMT 2175 ppm, n-Heptane at 788 ppm, and MTBE at 562 ppm.

Characterization of Step (D) product (compound of Formula (XIV-d)) is shown in Table 12. A 72% yield was achieved to make 7.3 kg compound of Formula (XIV-d). The purity measured by HPLC is 99.7% (area, w/w). See HPLC results in FIG. 16a and FIG. 16b. The compound of Formula (XIV-d) made by the process has an enantiomeric excess of about 99.9% w/w. Table 12.

Example 5. Stability Studies of the Compound of Formula (XlV-d) in the Free Base (FB) Form The compound of Formula (XlV-d) in the crystalline FB form was made according to the procedure described in Example 4. Stability Studies of the compound of Formula (XlV-d) in the crystalline FB form are shown in Table 13. At 5°C or 25°C, the chemical purity of the compound of Formula (XlV-d) remains at about 99 ,7%-99.9% from 0 month to 3 months and the enantiomeric purity remains at or above about 99.9% from 0 month to 3 months. Remarkably, the compound of Formula (XlV-d) stayed stable with high chemical purity and high enantiomeric purity for at least 3 months.

Table 13.

Example 6. Stability Studies of the Compound of Formula (XlV-d) in the HC1 Salt Form

The compound of Formula (XlV-d) in the HC1 salt form was tested with the initial impurities characterized in Table 14 (unit: % purity (w/w)) and the impurities in 1 month, 2 months, and 6 months characterized in Table 15 (unit: % purity (w/w)). The water content was characterized in Table 16 for up to 36 months.

Table 14.

Table 15.

Table 16.

There wasn’t much change in terms of impurity profile from Initial to 1-month to 3- month, but there was variability in the water content likely due, at least in part, to the amorphous nature of the HC1 salt. There was a relatively large change in the impurity profile from 3 -month to 6-month.

In a different batch of the compound of Formula (XlV-d) in the HC1 salt form, the impurities in 1 month, 2 months, and 6 months were characterized in Table 17 (unit: % purity (w/w)), with a relatively large change in the impurity profile from 1 month to 3 months.

Table 17.

Abbreviations and Acronyms Used in the Examples

Claims

What Is Claimed Is:

1. A process of preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: contacting a racemic compound having formulae of

Formula (Il-a) and

Formula (Il-b) with an activation

agent in the presence of an esterase enzyme and, optionally in a solvent, under suitable conditions to produce a compound having the formula of

Formula (I) in a substantially enantiopure form, wherein: R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl; and n is 0-6. The process of claim 1, wherein the esterase enzyme is a lipase. The process of claim 2, wherein the lipase is an immobilized lipase. The process of claim 3, wherein the immobilized lipase is Novozym 435. The process of claim 1, wherein the ratio of the esterase enzyme to the racemic compound is in a range of about 0.01 : 1 w/w to about 1 : 1 w/w. The process of claim 1, wherein the ratio of the esterase enzyme to the racemic compound is in a range of about 0.1 : 1 w/w to about 1 : 1 w/w. The process of claim 1, wherein the ratio of the esterase enzyme to the racemic compound is in a range of about 0.2: 1 w/w.

8. The process of any one of claims 1-7, wherein the activation agent is an ester or an anhydride.

9. The process of claim 8, wherein the ester is a vinyl alcohol ester.

10. The process of claim 9, wherein the vinyl alcohol ester is vinyl propionate or vinyl acetate.

11. The process of claim 9, wherein the vinyl alcohol ester is vinyl propionate.

12. The process of claim 9, wherein the vinyl alcohol ester is vinyl acetate.

13. The process of claim 8, wherein the anhydride is propionic anhydride.

14. The process of any one of claims 1-13, wherein the molar ratio of the activation agent to the racemic compound is in a range of about 0.5 : 1 to about 20: 1.

15. The process of any one of claims 1-13, wherein the molar ratio of the activation agent to the racemic compound is in a range of about 0.55: 1 to about 8: 1.

16. The process of any one of claims 1-13, wherein the molar ratio of the activation agent to the racemic compound is about 1 : 1.

17. The process of any one of claims 1-13, wherein the molar ratio of the activation agent to the racemic compound is about 8: 1.

18. The process of any one of claims 1-13, wherein the volume ratio of the activation agent to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v.

19. The process of any one of claims 1-13, wherein the volume ratio of the activation agent to the racemic compound is in a range of about 2: 1 v/v to about 5: 1 v/v.

20. The process of any one of claims 1-13, wherein the volume ratio of the activation agent to the racemic compound is about 2: 1 v/v.

21. The process of any one of claims 1-13, wherein the volume ratio of the activation agent to the racemic compound is about 5: 1 v/v.

22. The process of any one of claims 1-21, wherein the solvent is an organic solvent.

23. The process of claim 22, wherein the organic solvent is a non-protic organic solvent.

24. The process of claim 23, wherein the solvent is the non-protic organic solvent is acetonitrile, acetone, toluene, or tetrahydrofuran, or a combination thereof.

25. The process of any one of claims 22-24, wherein the volume ratio of the solvent to the racemic compound is in a range of about 1 : 1 v/v to about 20: 1 v/v.

26. The process of any one of claims 22-24, wherein the volume ratio of the solvent to the racemic compound is about 5: 1 v/v.

27. The process of any one of claims 22-26, wherein the process produces a suspension.

28. The process of claim 27, wherein the suspension is heated to a temperature of about 20 to about 55 °C.

29. The process of claim 27, wherein the suspension is heated to a temperature of about 25 to about 30 °C.

30. The process according to claims 28 or 29, wherein the suspension is heated under an inert gas.

31. The process of claim 30, wherein the inert gas is nitrogen.

32. The process of any one of claims 28-31, wherein the suspension is stirred at the temperature for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours.

33. The process of any one of claims 28-31, wherein the suspension is stirred at the temperature for about 16 hours.

34. The process of any one of claims 28-32, wherein the heated suspension is filtered to produce a filtrate comprising the compound of Formula (I) and the compound of Formula (Il-b). 35. The process of claim 34, the process further comprising isolating the compound of Formula

(I) from the filtrate.

36. The process of claim 35, wherein the isolation of the compound of Formula (I) from the filtrate comprises isolating the compound Formula (I) with a High-performance liquid chromatography (HPLC) or silica gel flash chromatography. 37. The process of claim 35, wherein the isolation of the compound of Formula (I) comprises contacting the filtrate with a cyclic anhydride and optionally an anhydride activating reagent to form a mixture.

38. The process of claim 37, wherein the cyclic anhydride is an aryl containing cyclic anhydride, a saturated cyclic anhydride, or an unsaturated cyclic anhydride, or a combination thereof.

The process of claim 37, wherein the cyclic anhydride has a formula of

Formula

(XV-c), wherein R₁₂, R₁₃, R₁₄, R₁₅, R₁₂ , R₁₃ , R₁₄ , and R₁₅’ are each independently D, H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; optionally, R₁₂ and R₁₂’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₃ and R₁₃’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₄ and R₁₄’ together with the carbon atom to which they are both attached form a optionally substituted C_3-7 spirocyclic ring; optionally, R₁₂ and R₁₃ together with the carbon atom to which they are both attached form a optionally substituted carbocycle; m is 0-6; and p is 0-6.

40. The process of claim 39, wherein the cyclic anhydride together with the compound of

Formula (Il-b) forms an acid having a formula of

Formula (XVI-c). 41. The process according to claims 39 or 40, wherein m is 0.

42. The process of any one of claims 39-41, wherein p is 0.

43. The process of any one of claim 39-42, wherein R₁₂ is H.

44. The process of any one of claim 39-43, wherein R₁₂’ is H

45. The process of any one of claim 39-44, wherein R₁₃ is H.

46. The process of any one of claim 39-45, wherein RB’ is H.

47. The process of claim 39, wherein the cyclic anhydride has a formula of

48. The process of claim 40, wherein the acid has a formula of

Formula (XVII), and the variables are as defined in claim 1. 49. The process of any one of claims 37-48, wherein the molar ratio of the anhydride activating reagent to the racemic compound is in a range of about 0.01 : 1 to about 1 : 1.

50. The process of any one of claims 37-48, wherein the molar ratio of the anhydride activating reagent to the racemic compound is about 0.1 : 1.

51. The process of any one of claims 37-50, wherein the anhydride activating reagent is 4-dimethylaminopyridine (DMAP).

52. The process of any one of claims 37-51, further comprising heating the mixture to a temperature in a range of about 30 °C to about 80 °C.

53. The process of claim 52, wherein the suspension is heated to a temperature of about 65 to about 70 °C. 54. The process according to claims 52 or 53, wherein the mixture is stirred at the temperature for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours.

55. The process according to claims 52 or 53, wherein the mixture is stirred at the temperature for about 6 hours.

56. The process according to claims 54 or 55, wherein the mixture is further concentrated under vacuum to form a residue comprising the compound of Formula (I) and the acid.

57. The process of claim 56, the process further comprising removing the acid from the residue to produce the compound of Formula (I).

58. The process of claim 57, the process further comprising stirring the residue with a first basic solution to form a mixture.

59. The process of claim 58, wherein the first basic solution is a K₂CO₃ aqueous solution.

60. The process of claim 58, wherein the first basic solution is a 5% K₂CO₃ aqueous solution.

61. The process of claim 60, wherein the volume ratio of the first basic solution to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v.

62. The process of claim 60, wherein the volume ratio of the first basic solution to the racemic compound is about 8: 1 v/v.

63. The process of any one of claims 58-62, wherein the mixture is stirred for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours.

64. The process of any one of claims 58-62, wherein the mixture is stirred for about 1 hour.

65. The process of any one of claims 58-64, the process further comprising adding a non- protonic organic solvent to the mixture to form a biphasic mixture comprising an organic phase and an aqueous phase.

66. The process of claim 65, wherein the volume ratio of the non-protic organic solvent to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v.

67. The process of claim 65, wherein the volume ratio of the non-protic organic solvent to the racemic compound is about 5: 1 v/v.

68. The process of any one of claims 65-67, wherein the non-protic organic solvent is 2-methyl tetrahydrofuran or tetrahydrofuran.

69. The process of any one of claims 65-67, wherein the non-protic organic solvent is 2-methyl tetrahydrofuran.

70. The process of any one of claims 65-69, the process further comprising separating and washing the organic phase with the first basic solution.

71. The process of claim 70, wherein the volume ratio of the first basic solution to the racemic compound is about 1 : 1 v/v to about 10: 1 v/v.

72. The process of claim 70, wherein the volume ratio of the first basic solution to the racemic compound is about 8: 1 v/v.

73. The process of any one of claims 70-72, wherein the organic phase is washed with the first basic solution for at least once.

74. The process of any one of claims 70-72, wherein the organic phase is washed with the first basic solution for three times.

75. The process of any one of claims 70-74, the process further comprising concentrating the washed organic phase to form the compound of Formula (I).

76. The process of claim 75, wherein the washed organic phase is concentrated under vacuum below about 50 °C to produce the compound of Formula (I).

77. The process of any one of claims 57-76, wherein the compound of Formula (I) is produced in a substantially enantiopure form.

78. The process of claim 77, wherein the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 90%.

79. The process of claim 77, wherein the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 95%. 80. The process of claim 77, wherein the substantially enantiopure form of the compound of

Formula (I) has an enantiomeric excess of at least 98%.

81. The process of claim 77, wherein the substantially enantiopure form of the compound of Formula (I) has an enantiomeric excess of at least 99%.

82. A process of preparing a compound of Formula (Il-a), the process comprising hydrolyzing the compound of Formula (I) to form the compound of

Formula (Il-a) in a substantially enantiopure form, wherein the variables are as defined in claim 1.

83. The process of claim 82, wherein the hydrolysis condition is a suitable condition for removing

of Formula (I) to form the compound of Formula (Il-a).

84. The process of claim 83, wherein the suitable condition comprises adding a second basic solution to the compound of Formula (I) to form a mixture.

85. The process of claim 84, wherein the second basic solution comprises sodium hydroxide and water.

86. The process of claim 85, wherein the molar ratio of the sodium hydroxide to the racemic compound is in a range of about 10: 1 to about 1 : 1.

87. The process of claim 85, wherein the molar ratio of the sodium hydroxide to the racemic compound is about 3.5: 1.

88. The process of any one of claims 84-87, wherein the volume ratio of the water to the racemic compound is about 5 : 1 to about 1 : 1.

89. The process of any one of claims 84-87, wherein the volume ratio of the water to the racemic compound is about 2: 1.

90. The process of any one of claims 84-89, wherein the mixture is further heated to a temperature in a range of about 30 °C to about 80 °C.

91. The process of any one of claims 84-89, wherein the mixture is further heated to a temperature of about 60 °C to about 65 °C.

92. The process according to claims 90 or 91, wherein the heated mixture is stirred for about 0.1, 0.25, 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.

93. The process according to claims 90 or 91, wherein the mixture is stirred for about 18 hours.

94. The process according to claims 92 or 93, wherein the mixture is cooled to a temperature in a range of about 20 °C to about 30 °C.

95. The process of claim 94, the process further comprising adding a non-protonic organic solvent to the cooled mixture to form a biphasic mixture comprising an organic phase and an aqueous phase.

96. The process of claim 95, wherein the volume ratio of the non-protic organic solvent to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v.

97. The process of claim 95, wherein the volume ratio of the non-protic organic solvent to the racemic compound is about 5: 1 v/v.

98. The process of any one of claims 95-97, wherein the organic phase is separated and washed with water for at least once.

99. The process of any one of claims 95-97, wherein the organic phase is separated and washed with water for three times.

100. The process according to claims 98 or 99, wherein the volume ratio of the water to the racemic compound is in a range of about 1 : 1 v/v to about 10: 1 v/v.

101. The process according to claims 98 or 99, wherein the volume ratio of the water to the racemic compound is about 5: 1 v/v.

102. The process of any one of claims 97-101, the process further comprising concentrated the washed organic phase to produce the compound of Formula (Il-a) in a substantially enantiopure form.

103. The process of claim 102, wherein the substantially enantiopure form of the compound of Formula (Il-a) has an enantiomeric excess (ee) of at least 90%.

104. The process of claim 102, wherein the substantially enantiopure form of the compound of Formula (Il-a) has an enantiomeric excess (ee) of at least 95%.

105. The process of claim 102, wherein the substantially enantiopure form of the compound of Formula (Il-a) has an enantiomeric excess (ee) of at least 98%.

106. The process of claim 102, wherein the substantially enantiopure form of the compound of Formula (Il-a) has an enantiomeric excess (ee) of at least 99%.

107. The process of any one of claims 1-106, wherein R₁₀ is C₁-C₆ alkyl.

108. The process of claim 107, wherein R₁₀ is CH3.

109. The process of any one of claims 1-108, wherein R₃ is H.

110. The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (III), wherein the variables are as defined in claim 1. 111. The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (IV), wherein the variables are as defined in claim 1.

112. The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (V), wherein the variables are as defined in claim 1.

. The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (VI), wherein R? isH or optionally substituted branched or unbranched C₁-C₆ alkyl and the rest variables are as defined in claim 1. . The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (VII), wherein the variables are as defined in claim

1. . The process of claim 109, wherein the compound of Formula (I) has a formula of

Formula (VIII), wherein the variables are as defined in claim

116. The process of claim 109, wherein the compound of Formula (I) has a formula of

117. The process of any one of claims 82-106, wherein the compound of Formula (Il-a) in a substantially enantiopure form has a formula of Formula (X-a).

118. A process of preparing a compound of Formula (XI) comprising contacting the compound of Formula (Il-a) with a suitable substance to form a compound having a formula

Formula (XI), wherein:

R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl;

R11 is I, Br, Cl, OMs, and OTf; and n is 0-6. . The process of claim 118, further comprising contacting the compound of Formula (XI) with 6-hydroxy-2,3-dihydro-lH-isoindol-l-one to form a compound having a formula of

Formula (XII), wherein the variables are as defined in claim 118.

. The process of claim 119, wherein the compound of Formula (XII) has a formula of

Formula (Xll-a), wherein the variables are as defined in claim

118. . The process of claim 120, the process further comprising contacting the compound of Formula (Xll-a) with a deprotection agent to form a compound having a formula of

Formula (XIII).

. The process of claim 121, wherein the deprotection agent is an acid. . The process of claim 121, wherein the acid is hydrochloride acid. . The process of any one of claims 121-123, the process further comprising contacting the compound of Formula (XIII) with 1 -(2 -bromomethyl)- IH-pyrrole under a suitable condition to form a compound having a formula of Formula (XIV), or a

pharmaceutically acceptable salt.

. The process of any one of claims 121-124, wherein R₁₀ is C₁-C₆ alkyl. . The process of claim 125, wherein R₁₀ is CH3. . The process of any one of claims 121-126, wherein R₃ is H. . The process of claim 127, wherein the compound of Formula (XIV) has a formula of

Formula (XlV-a), wherein R₂ is as defined in claim 118. . The process of claim 127, wherein the compound of Formula (XIV) has a formula of

Formula (XlV-b), wherein R₆ is as defined in claim 118. . The process of claim 127, wherein the compound of Formula (XIV) has a formula of

Formula (XIV-c), wherein R? isH or optionally substituted branched or unbranched C₁-C₆ alkyl.

. The process of claim 127, wherein the compound of Formula (XIV) has a formula of

Formula (XlV-d).

. A process of preparing a compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, the process comprising: a) contacting a racemic compound having formulae of Formula

Formula (Xll-b); f) contacting the compound of Formula (Xll-b) with an acid under a suitable condition to produce a compound of Formula (Xlll-a); and

g) contacting the compound of Formula (Xlll-a) with 1 -(2 -bromomethyl)- IH-pyrrole and a fourth base to form a compound having a formula of

Formula (XlV-d). . The process of claim 132, wherein the activation agent is vinyl acetate. . The process according to claims 132 or 133, wherein the esterase enzyme is Novozym 435. . The process of any one of claims 132-134, wherein the solvent is acetonitrile. . The process of any one of claims 132-135, wherein the isolating the compound of

Formula (IX) comprises: i) filtering the suspension of step a) to form a filtrate comprising the compound of Formula (IX) and the compound of Formula (X-b); ii) contacting the filtrate of step i) with a cyclic anhydride having a formula of

and 4-dimethylaminopyridine to form a mixture comprising a compound of

Formula (XVII-a) and the compound of Formula (IX); iii) concentrating the mixture of step ii) to form a residue comprising the compound of Formula (XVII-a) and the compound of Formula (IX); iv) dissolving the residue of step iii) in 2-Me-tetrahydrofuran to from a solution and washing the solution with 5% K₂CO₃ aqueous solution at least once to remove the compound of Formula (XVII-a) from the mixture; and v) concentrating the washed solution of step iv) to produce the compound of Formula (IX).

137. The process of any one of claims 132-136, wherein the first base of step c) is sodium hydroxide.

138. The process of any one of claims 132-137, wherein the first base of step c) is a sodium hydroxide aqueous solution.

139. The process of any one of claims 132-138, wherein the acid of step f) is hydrochloride acid.

140. The process of any one of claims 132-139, wherein the second base of step d) is triethylamine.

141. The process of any one of claims 132-140, wherein the third base of step e) is K₂CO₃.

. The process of any one of claims 132-141, wherein the fourth base of step g) is K₂CO₃. . A process of preparing a compound of Formula (XlV-d), or a pharmaceutically acceptable salt thereof, the process comprising: a) contacting a racemic compound having formulae of Formula

(X-a) and

Formula (X-b) with vinyl acetate in the presence of

Novozym 435 in acetonitrile under suitable conditions to produce a suspension comprising a compound having the formula of

Formula (IX) and

Formula (X-b);

b) isolating the compound of Formula (IX) from the suspension of step a) comprising: i) filtering the suspension of step a) to form a filtrate comprising compound of Formula (IX) and the compound of Formula (X-b); ii) contacting the filtrate of step i) with a cyclic anhydride having a formula of

and 4-dimethylaminopyridine to form a mixture comprising a compound of

Formula (XVII-a) and the compound of Formula (IX); iii) concentrating the mixture of step ii) to form a residue comprising the compound of Formula (XVII-a) and the compound of Formula (IX); iv) dissolving the residue of step iii) in 2-Me-tetrahydrofuran to from a solution and washing the solution with K₂CO₃ aqueous solution at least once to remove the compound of Formula (XVII-a) from the mixture; and v) concentrating the washed solution of step iv) to produce the compound of Formula (IX); c) hydrolyzing the compound of Formula (IX) isolated from step b) with a sodium hydroxide solution under a suitable condition to form the compound of

Formula (X-a) in a substantially enantiopure form;

d) contacting the compound of Formula (X-a) of step c) with methanesulfonyl chloride and triethylamine under a suitable condition to form a compound of

Formula (Xll-b);

f) contacting the compound of Formula (Xll-b) with hydrochloride acid under a suitable condition to produce a compound of Formula (Xlll-a);

and g) contacting the compound of Formula (Xlll-a) with 1 -(2 -bromomethyl)- IH-pyrrole and K₂CO₃ to form a compound having a formula of Formula

(XlV-d).

. A compound having the formula of

Formula (I),

wherein: R₁ is a protecting group, C(=O)OR₅, C(=O)R₅, H, optionally substituted aryl, optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ haloalkenyl -(CH2)nR₈, optionally substituted heterocycle, optionally substituted C₁-C₆ ester, optionally substituted cycloalkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C₃-C₆ cyclic ether, or optionally substituted piperidyl; and R₂ and R₃ are each independently H, halo, optionally substituted C₁-C₆ haloalkyl, -SO₂C1- C₆alkyl, -OCF₃, optionally substituted C₁-C₆ alkyl, or -OR₆; wherein R₆ is H or optionally substituted C₁-C₆ alkyl; R₄ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₅ is H or optionally substituted branched or unbranched C₁-C₆ alkyl; R₈ is H, -C(=O)R₉, optionally substituted C₁-C₆ haloalkyl, optionally substituted nitrogen, optionally substituted C₁-C₆ branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; R₉ is phenyl or C₁-C₆ branched or unbranched alkyl; R₁₀ is H or C₁-C₆ branched or unbranched alkyl; and n is 0-6.

145. The compound of claim 144, wherein R₁₀ is C₁-C₆ alkyl.

146. The compound of claim 145, wherein R₁₀ is CH3. 147. The compound according to claims 144 or 145, wherein R₃ is H.

148. The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (III), wherein the variables are as defined in claim 144.

149. The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (IV), wherein the variables are as defined in claim 144.

150. The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (V), wherein the variables are as defined in claim 144.

. The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (VI), wherein R? is H or optionally substituted branched or unbranched C₁-C₆ alkyl and the rest variables are as defined in claim 144. . The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (VII), wherein the variables are as defined in claim

144. . The compound of claim 144, wherein the compound of Formula (I) has a formula of

Formula (VIII), wherein R₁is as defined in claim 144.

. The compound of claim 144, wherein the compound of Formula (I) has a formula of Formula (IX).

. A pharmaceutical composition comprising a compound of Formula (XIV) prepared according to a process of any one of claims 124-131 or a pharmaceutically acceptable salt thereof. . A pharmaceutical composition comprising a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143 or a pharmaceutically acceptable salt thereof. . A method of treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof comprising administering to a patient in need thereof, a compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . A method of treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson’s disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, PTSD, or related disorders and conditions or any combination thereof comprising administering to a patient in need thereof, a compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutical composition according to claims 155 or 156. . A method of treating hyperalgesia in a subject comprising administering to the subject comprising administering to a patient in need thereof, the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . The method of claim 159, wherein the hyperalgesia is opioid-induced hyperalgesia. . The method of claim 160, wherein the opioid-induced hyperalgesia is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin-induced hyperalgesia. . The method of claim 161, wherein the subject has been administered an opioid prior to being administered the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . A method of decreasing nociceptive sensitization in a subject comprising administering to a patient in need thereof, the compound of Formula (XIV) prepared a compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . The method of claim 163, wherein the subject has opioid-induced nociceptive sensitization.

. A method of treating pain in a subject comprising administering an opioid agonist to the subject until the opioid increases nociceptive sensitization in the subject and administering to a patient in need thereof, the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . The method of claim 165, wherein the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or a pharmaceutically acceptable salt thereof. . A method of treating pain in an opioid exposed subject comprising: a) administering an opioid agonist to the subject; b) administering to the subject of step a), in the absence of the opioid administered in step a), the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156. . The method of claim 167, wherein the opioid is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or a pharmaceutically acceptable salt thereof. . A method of treating medication overuse headache in a subject comprising administering to a patient in need thereof, the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156.

170. The method of claim 169, wherein the medication overuse headache is caused by acetaminophen, aspirin, a mu-opioid agonist, a non-steroidal anti-inflammatory drug (NS AID), or a triptan.

171. The method of claim 170, wherein the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan, or donitriptan, or a pharmaceutically acceptable salt thereof.

172. The method of claim 170, wherein the mu-opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, or heroin, or a pharmaceutically acceptable salt thereof.

173. A method of treating a migraine in a subject, the method comprising: administering a triptan to a subject; and administering to a patient in need thereof, the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XIV- d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 155 or 156.

174. The method of claim 173, wherein the compound or a pharmaceutical composition thereof is administered in the absence of the triptan.

175. The method of claim 174, wherein the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan, or donitriptan, or a pharmaceutically acceptable salt thereof.

176. The method of claim 173, wherein the subject develops medication overuse headache prior to being administered the compound of Formula (XIV) prepared according to a process of any one of claim 124-131, or a compound of Formula (XlV-d) prepared according to a process of any one of claims 132-143, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claims 155 or 156.