Process for the preparation of ethyl (2S)-2-{2-fluoro-6-methyl-4-[(3R)-3-(trifluoromethyl)morpholin-4-yl]benzamido]-3 -[(8M)-8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin -5-yl]propanoate

Abstract

The present disclosure relates generally to processes for preparing ethyl (2S)-2-{2-fluoro-6-methyl-4-[(3R)-3-(trifluoromethyl) morpholin-4-yl]benzamido]-3-[(8M)-8-(l-methyl-2,4-dioxo-l,4- dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl]propanoate (compound I) or a salt thereof, comprising: coupling Compound II or a salt thereof with Compound III or a salt thereof in the presence of a coupling agent to form Compound I and to processes for preparing the intermediates II and III, and other intermediates of said processes. Compound I is an inhibitor for α4β7 integrin for use in the treatment of e.g. autoimmune and inflammatory diseases, such as e.g. inflammatory bowel disease (Crohn's disease and ulcerative colitis).

Description

Attorney Docket No.: 1583-US-NP / WO-PCT PROCESSES FOR PREPARING AN ALPHA4BETA7 INHIBITORCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Number 63 / 764,865, filed on February 28, 2025, the content of which is hereby incorporated herein in its entirety.FIELD

[0002] The present disclosure relates generally to processes for preparing a compound that is an inhibitor for a4f>7 integrin and the synthetic intermediates prepared thereby.BACKGROUND

[0003] Ethyl (2S)-2-{2-fhioro-6-methyl-4-[(3 / ?)-3-(trifhioromethyl)morpholin-4-yl]benzamido}-3-[(8M)-8-(l-methyl-2,4-dioxo-l,4-dihydropyrido[3,4-d]pyrimidin-3(2 / 7)-yl)quinolin-5-yl]propanoate (Compound I):is an inhibitor for a4p7 integrin.

[0004] Integrins are heterodimeric cell surface proteins involved in numerous cellular processes including cell-cell and cell-extracellular matrix interactions. Upon binding of an extracellular ligand, integrins mediate signal transduction to the cell interior resulting in lymphocyte cell capture, adhesion, and infiltration into the tissue. Integrins are heterodimeric proteins consisting of an alpha and a beta subunit. There are 18 known alpha subunits and 8 known beta subunits. The «4f>7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing cell adhesion molecule- 1 (MAdCAM-1). «4f>7 integrin governs lymphocyte trafficking to and retention in gut tissues through its interaction with MAdCAM-1, which is expressed on venules in the intestinal mucosa and high endothelial venules (HEY) in the gut associated lymphoid tissues (GALT). Inhibiting the interactions of integrins with their respective ligands has been proposed as an effective method of treating a variety of autoimmune and inflammatory diseases, and blocking the a4p7-MAdCAM-l interaction has shown therapeutic benefit in inflammatory bowel disease (Crohn’s disease and ulcerative colitis).

[0005] Accordingly, there is a continued need to improve synthetic processes for preparing a4p7 inhibitors such as ethyl (2S)-2-{2-fluoro-6-methyl-4-[(3 / ?)-3-(trifluoromethyl)morpholin-4-Attorney Docket No.: 1583-US-NP / WO-PCT yl]benzamido}-3-[(8A / )-8-(l-methyl-2,4-dioxo-l,4-dihydropyrido[3,4-6?]pyrimidin-3(2 / 7)-yl)quinolin-5-yl]propanoate (Compound I) and structurally related compounds, for example, to improve yields, purity, and scaling.SUMMARY

[0006] Provided are processes for preparing Compound I and the synthetic intermediates prepared thereby.

[0007] In some embodiments, the present disclosure provides a process for preparing Compound Ior a salt thereof, comprising:coupling Compound IIor a salt thereof with Compound IIIor a salt thereof in the presence of a coupling agent to form Compound I or a salt thereof.

[0008] In some embodiments, the present disclosure provides a process for preparing Compound IIIor a salt thereof, comprising:(a) contacting Compound III- laAttorney Docket No.: 1583-US-NP / WO-PCT / Bocor a salt thereof with ethanol in the presence of an acid to form Compound IllaIllaor a salt thereof; and(b) crystallizing Compound Illa from a solvent to provide Compound III as a single atropisomer.

[0009] In some embodiments, the present disclosure provides a process for preparing Compound III- la / Bocor a salt thereof, comprising:(a) contacting a compound of Formula IV- 1Bocor a salt thereof with zinc; and(b) contacting a product from step (a) with a compound of Formula Vawherein X is Br or I,or a salt thereof in the presence of a catalytic system to form Compound III-2a / BocAttorney Docket No.: 1583-US-NP / WO-PCT or a salt thereof.

[0010] In some embodiments, the present disclosure provides a process for preparing a compound of Formula Vawherein X is Br or I,or a salt thereof, comprising:(a) contacting Compound VIor a salt thereof with a compound of Formula VIIwherein X is Br or I,or a salt thereof in the presence of an azide source or a deoxo-fluor to form a compound of Formula V-3wherein X is Br or I,or a salt thereof;(b) subjecting the compound of Formula V-3 or a salt thereof into a cyclization condi lion to provide a compound of Formula V-lwherein X is Br or I,or a salt thereof; and(c) contacting the compound of Formula V-l or a salt thereof with a methylation agent to form Compound Va or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0011] Also provided is a process for preparing Compound IIIor a salt thereof, comprising:(a) contacting Compound IV-3Bocor a salt thereof with zinc;(b) contacting a product from step (a) with Compound V-Ior a salt thereof in the presence of a catalytic system to form Compound III-3Bocor a salt thereof; and(c) subjecting Compound III-3 or a salt thereof to a deprotection condition to form Compound III or a salt thereof.

[0012] Also provided is a process for preparing Compound III-3Bocor a salt thereof, comprising:(a) contacting Compound IV-5Attorney Docket No.: 1583-US-NP / WO-PCT Bociv-5or a salt thereof with a benzoxazolium salt acli valor;(bl) contacting a product from step (a) with Compound V-l-Bror a salt thereof in the presence of a pholosensilizer to provide Compound III-4 / Bocor a salt thereof; or(b2) contacting the product from step (a) with Compound V-Bror a salt thereof in the presence of a pholosensilizer to provide Compound III-3Bocor a salt thereof; and(c) when step (bl) occurs, contacting Compound III -4 or a salt thereof with a methylation agent to form Compound III-3 or a salt thereof.

[0013] Also provided is a process for preparing a compound of Formula V-lawherein X is Br or I,Attorney Docket No.: 1583-US-NP / WO-PCT or a salt thereof, comprising:subjecting a compound of Formula V-2wherein R is a C1-3 alkyl and X is Br or I,or a salt thereof into a cyclization condition to form a compound of Formula V- la or a salt thereof.

[0014] Also provided is a process for preparing Compound III-4Bocor a salt thereof, comprising:(a) subjecting Compound III-5Bocor a salt thereof into a cyclization condition to form Compound III -4 or a salt thereof.

[0015] Also provided is a process for preparing Compound IIor a salt thereof, comprising:(a) contacting Compound VIIIAttorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof with Compound IXor a salt thereof in the presence of a catalytic system to provide Compound II-2or a salt thereof; and(b) subjecting Compound II-2 or a salt thereof into a hydrolysis condition to form Compound II or a salt thereof.

[0016] Also provided is a process for preparing Compound IXor a salt thereof, comprising:(a) contacting a compound of Formula IX- 1or a salt thereof with a trifluoromethylation agent to form a compound of Formula IX-2or a salt thereof;Attorney Docket No.: 1583-US-NP / WO-PCT (b) subjecting the compound of Formula IX-2 or a salt thereof to an asymmetric hydrogenation condition to form a compound of Formula IX-30.N CF3PG IX-3or a salt thereof; and(c) subjecting the compound of formula IX-3 or a salt thereof to a deprotection condi lion to form Compound IX or a salt thereof, wherein the deprotection condition in step (c) comprises a chiral acid.

[0017] Also provided is a process for preparing Compound II,or a salt thereof, comprising:(a) contacting Compound VIIIor a salt thereof with morpholin-3-one in the presence of a catalytic system to form Compound II-3or a salt thereof;(b) contacting Compound II-3 with a tri lluoromelhylalion agent;(c) subjecting a product from step (b) into an elimination condition to form Compound II-4or a salt thereof;(d) subjecting Compound II-4 into an asymmetric hydrogenation condition to form Compound II-2Attorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof.

[0018] Also provided is a process for preparing Compound Xor a salt thereof, comprising:contacting quinolin- 8 -amine with an ammonia source and a pyruvate source to form Compound X or a salt thereof.

[0019] Also provided is a process for preparing Compound X-3Bocor a salt thereof, comprising:(a) contacting Compound IV-4Bociv-4or a salt thereof with Compound VII-2or a salt thereof in the presence of a catalytic system to provide Compound X-4BocAttorney Docket No.: 1583-US-NP / WO-PCT or a salt thereof; and(b) subjecting Compound X-4 or a salt thereof to a reductive condition to provide Compound X-3 or a salt thereof.DESCRIPTIONDefinitions

[0020] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0021] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, reference to “the compound” includes a plurality of such compounds.

[0022] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 2.5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”.

[0023] Recitation of numeric ranges of values throughout the disclosure is intended to serve as a shorthand notation of referring individually to each separate value falling within the range inclusive of the values defining the range, and each separate value is incorporated in the specification as it were individually recited herein.

[0024] As used herein, the term “contacting” refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0025] The term “reaction conditions” is intended to refer to the physical and / or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid or catalyst, radiation, etc. Reaction condilions may be named after the particular chemical reaction in which the condilions are employed, such as, coupling conditions, hydrogenation conditions, acylal ion conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformationsAttorney Docket No.: 1583-US-NP / WO-PCT provided herein can be found throughout, and in particular, the examples below. It is also contemplated that the reaction conditions can include reagents in addition to those listed in the specific reaction.

[0026] “Catalyst” refers to a chemical reactant that increases the rate of a reaction without itself being consumed. Similarly, “cocatalyst” or “co-catalyst” refers to a substance that works with another as a catalyst.

[0027] A “ligand” as used herein refers to an ion or molecule that binds to a metal atom to form a coordination complex. Denticity of a ligand refers to the number of times a ligand bonds to a metal through noncontiguous donor sites. Ligands may be monodentate (i.e., they possess one binding site) or bidentate (i.e., they possess two binding sites).

[0028] “Hydrolysis” as used herein refers to the cleavage by water of a carboxylic ester into a carboxylic acid and an alcohol.

[0029] As used herein, the term “salt” refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion. In general, a salt is defined as a compound that is formed by the combination of positively and negatively charged ions, where the charges of the ions result in a neutral compound. Salts can be either inorganic or organic. As used herein, the term “salt” includes partially or fully ionized salt forms. In some embodiments, the salt is fully ionized.

[0030] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March ’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0031] The term “alkyl” as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms. The term “Ci-Ce-alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci-Cg-alkyl” means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, Ao-propyl, n-butyl, .vcc-bulyl, Ao-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, and n-decyl.Attorney Docket No.: 1583-US-NP / WO-PCT

[0032] The term “aromatic” refers to the ring moieties which satisfy the Hiickel 4n+2 rule for aromaticity, and includes both aryl (i.e., carbocyclic) and heteroaryl (also called hclcroaroinalic) structures.

[0033] The term “aryl” as used herein, refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group. Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups. Representative examples of bicyclic aryls include, but are not limited to, naphthyl. Representative examples of tricyclic aryls include, but are not limited to, anthracenyl. The monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted.

[0034] The term “halogen” or “halo” as used herein, means Cl, Br, I, or F.

[0035] The term “amine” or “amine base” as used herein generally refers to a primary, secondary, or tertiary amine, such as a alkyl amine, dialkyl amine, trialkyl amine, or nitrogen-containing heterocycle, wherein each of which is optionally substituted, e.g., by alkyl.

[0036] The term “nitrogen-containing heterocyclic” base as used herein, refers to a saturated or partially unsaturated cyclic alkyl group, with at least one ring nitrogen atom, and optionally one or more additional ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclic” includes heterocycloalkenyl rings (i.e., a heterocyclic ring having at least one double bond), bridged-heterocyclic rings, fused-heterocyclic rings, and spiro-heterocyclic rings. A heterocycle may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., one to three or one or two) oxo (=0) or N-oxide (-O ) moieties. Any nonaromatic ring containing at least one nitrogen atom capable of accepting a proton is considered a nitrogen-containing heterocyclic base. Further, the term heterocyclic is intended to encompass any nonaromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl or heteroaryl ring, regardless of the position of the heteroatom. As used herein, a nitrogen-containing heterocyclic has 2 to 20 ring carbon atoms (i.e., C2-20 heterocycle), 2 to 12 ring carbon atoms (i.e., C2-12 heterocycle), 2 to 10 ring carbon atoms (i.e., C2-10 heterocycle), 2 to 8 ring carbon atoms (i.e., C2-8 heterocycle), 3 to 12 ring carbon atoms (i.e., C3-12 heterocycle), 3 to 8 ring carbon atoms (i.e., C3-8 heterocycle), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocycle); having at least 1 nitrogen atom capable of accepting a proton, and optionally an additional 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.Attorney Docket No.: 1583-US-NP / WO-PCT

[0037] The term “nitrogen-containing heteroaryl” base refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with at least one nitrogen atom capable of accepting a proton, and optionally one or more additional ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, nitrogen-containing heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and having at least 1 nitrogen atom, and optionally an additional 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.

[0038] The term “basic aroinalic compound” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with at least one atom capable of accepting a proton. In some embodiments, the atom capable of accepting a proton is a nitrogen atom. In some embodiments, the basic aroinalic compound is a nitrogen-containing heteroaryl base.

[0039] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0040] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0041] Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms unless specified otherwise. In particular, compounds of any formula given herein may have asymmetric centers or axial chirality and therefore exist in different stereoisomers. All optical isomers and stereoisomers of the compounds of a formula, and mixtures thereof, are considered within the scope of the present disclosure. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers) or as tautomers. All geometric isomers and tautomers of the compounds of a formula, and mixtures thereof, are considered within the scope of the present disclosure.

[0042] The compound disclosed herein may be depicted by a structure comprising a wedged bold and / or a dashed bond. It can be appreciated that the wedged bold or dashed bond is used to indicate absoluteAttorney Docket No.: 1583-US-NP / WO-PCT stereochemistry. Where the composition is identified as stereochemically enriched, it is intended that the composition comprises more than 50% of a single stereoisomer, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% of a single stereoisomer.

[0043] For example, a compound according to the following structure:have asymmetric centers and therefore may exist in different stereoisomers, such asAttorney Docket No.: 1583-US-NP / WO-PCT

[0044] As used herein, “Compound I” is intended to represent a stereochemically enriched compound as shown in the following structure:

[0045] It is to be understood that all ophcal isomers and stereoisomers of Compound I (e.g., the stereoisomers shown above), and mixtures thereof, are considered within the scope of the present disclosure.

[0046] Additionally or alternatively, a compound according to the following structure:have asymmetric centers and therefore may exist in different stereoisomers, such asAttorney Docket No.: 1583-US-NP / WO-PCT

[0047] As used herein, “Compound III” is intended to represent a stereochemically enriched compound as shown in the following structure:

[0048] It is to be understood that all optical isomers and stereoisomers of Compound III (e.g., the stereoisomers shown above), and mixtures (including racemic mixtures) thereof, are considered within the scope of the present disclosure.

[0049] Further, it is to be understood that processes used for the preparation of a stereochemically enriched compound as described herein may be used for preparing a stereoisomer thereof or a mixture of stereoisomers (including racemic mixtures). For example, processes used for the preparation of Compound I (which is stereochemically enriched) may be used for preparing a stereoisomer thereof or a mixture of stereoisomers. Likewise, processes used for the preparation of Compound III (which is stereochemically enriched) may be used for preparing a stereoisomer thereof or a mixture of stereoisomers. For instance, processes used for the preparation of Compound III (which is stereochemically enriched) may be used for preparing Compound Illa:Illa

[0050] Additionally or alternatively, processes used for the preparation of a mixture of stereoisomers (including a racemic mixture) as described herein may be used for preparing a stereochemically enriched compound. For example, processes used for the preparation of Compound Illa may be used for preparing Compound III.

[0051] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment.Conversely, various features of the disclosure, which are, for brevity, described in the context of a singleAttorney Docket No.: 1583-US-NP / WO-PCT embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the disclosure are embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (i.e., compounds that can be made, isolated, characterized, and tested for biological act i vity). In addition, all sub-combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing such variables) are also embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.Processes

[0052] The processes described herein provide Compound I or a salt thereof, as well as the corresponding synthetic intermediates or a salt thereof.

[0053] In certain embodiments, the processes disclosed herein can take place concurrently, in a sequential order as described herein, or in any possible order thereof.

[0054] It can be appreciated that the wedged bolded or dashed bond is used to indicate absolute stereochemistry. Where the composition is identified as stereochemically enriched, it is intended that the composition comprises more than 50% of a single stereoisomer, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% of a single stereoisomer.

[0055] As noted above, it is to be understood that processes used for the preparation of a stereochemically enriched compound as described herein may be used for preparing a mixture of stereoisomers (including a racemic mixture). Additionally or alternatively, processes used for the preparation of a mixture of stereoisomers (including a racemic mixture) as described herein may be used for preparing a stereochemically enriched compound.

[0056] Ethyl (2S)-2-{2-fhioro-6-methyl-4-[(37?)-3-(trifhioromethyl)morpholin-4-yl]benzamido}-3-[(8Af)-8-(l-methyl-2,4-dioxo-l,4-dihydropyrido[3,4-6?]pyrimidin-3(2 / 7)-yl)quinolin-5-yl]propanoate (Compound I) is an inhibitor for a4f>7 integrin and has the following structure:Attorney Docket No.: 1583-US-NP / WO-PCTCompound I is disclosed in International Publication No. WO 2020092375, which is incorporated herein by reference in its entirety.Synthesis of Compound I from Compound II and Compound III

[0057] Provided herein are processes for preparing Compound I or a salt thereof.

[0058] In some embodiments, provided is a process for preparing Compound Ior a salt thereof, comprising:coupling Compound IIor a salt thereof with Compound IIIor a salt thereof in the presence of a coupling agent to form Compound I.Attorney Docket No.: 1583-US-NP / WO-PCT

[0059] Suitable coupling agents (e.g., coupling agents used to provide Compound I from Compound II and Compound III) include, but are not limited to, acid halide forming agents (e.g., thionyl chloride, oxalyl chloride, phosgene, triphosgene, etc.), 1 , 1’ -carbonyldiimidazole (CDI), alkyl chloroformates (e.g., ethyl chloroformate, isobutyl chloroformate, etc.), carbodiimides (e.g., N'-dicyclohcxylcarbodiimidc (DCC), N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), etc.), propanephosphonic acid anhydride (T3P), and peplide coupling reagents (e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), 2-(3h-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-(6-chlorobenzotriazol-l-yl)-A,A,A’,A’-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), [[(Z)-(l-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium hexafluorophosphate (COMU), etc.).

[0060] In some embodiments, the coupling agent is an acid halide forming agent. In some embodiments, the coupling agent is thionyl chloride.

[0061] In some embodiments, the coupling agent is an acid halide forming agent (e.g., thionyl chloride), and Compound II is converted to Compound II- 1by the coupling agent prior to reacting with Compound III.

[0062] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs in the presence of a base. Suitable bases (e.g., bases used to provide Compound I from Compound II and Compound III) include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0063] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0064] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs in the presence of a solvent. Suitable solvents include, but are not limited to, esters (e.g.,Attorney Docket No.: 1583-US-NP / WO-PCT ethyl acetate, isopropyl acetate, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (e.g., benzene, toluene, n-heptane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and polar aprotic solvents (e.g., A mielhy I formamide, A miclhylacclamidc, A-methyl-2-pyrrolidone, etc.).

[0065] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile.

[0066] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs in the presence of a catalyst. Suitable catalysts include, but are not limited to, amide catalysts (e.g., dimethylacetamide, A-methyl-2-pyrrolidone, A mielhy I formamide, etc.), 4-(dimethylamino)pyridine, 1 -hydroxybenzotriazole (HOBt), and l-hydroxy-7-azabenzotriazole (HOAt).

[0067] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs in the absence of a catalyst.

[0068] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs at a temperature of about -15°C to about 80 °C. In some embodiments, the coupling occurs at a temperature of about 5 °C to about 25 °C. In some embodiments, the coupling occurs at a temperature of about 15 °C.

[0069] In some embodiments, the coupling of Compound II or a salt thereof and Compound III or a salt thereof occurs in the presence of a coupling agent such as an acid halide forming agent (e.g., thionyl chloride), a base such as an amine base (e.g., triethylamine), a solvent such as a nitrile solvent (e.g., acetonitrile), and at a suitable temperature such as a temperature of about 5 °C to about 25 °C (e.g., about 15°C).

[0070] The Compound I may form a complex (e.g., a salt of Compound I and / or a cocrystal of Compound I) with an acid. Alternatively or additionally, the Compound I may exist in crystalline form (e.g., Compound I Form I) or amorphous form (e.g., Compound I Amorphous). Accordingly, provided are processes for the corresponding transformations.

[0071] For example, in some embodiments, the process may comprise crystallizing Compound I from a solvent in the presence of an acid.

[0072] In some embodiments, the acid is malonic acid. In some embodiments, the process comprises crystallizing Compound I from a solvent in the presence of malonic acid to provide Compound I Mono-Malonate:Attorney Docket No.: 1583-US-NP / WO-PCT

[0073] Suitable solvents (e.g., solvents used to provide Compound I Mono-Malonate from Compound I) include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether, di-n-butyl ether, 1,4-dioxane, etc.), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, acetone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), nitriles (e.g., acetonitrile, propionitrile, butyronitrile, benzonitrile, etc.), water, and any combination thereof.

[0074] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of acetonitrile, tert-butyl methyl ether, and water.

[0075] In some embodiments, the crystallization (e.g., the crystallization of Compound I) occurs at a temperature of about 0°C to about 70 °C. In some embodiments, the temperature is about 40 °C to about 20 °C. In some embodiments, the crystallization comprises cooling a solution comprising Compound I and malonic acid from about 30-50 °C (e.g., about 40 °C) to about 10-30 °C (e.g., about 20 °C).

[0076] In some embodiments, the process comprises crystallizing Compound I from a solvent such as a mixed solvent (e.g., a mixture of acetonitrile, tert-butyl methyl ether, and water), by cooling a solution comprising Compound I and malonic acid from about 30-50 °C (e.g., about 40 °C) to about 10-30 °C (e.g., about 20 °C), to provide Compound I Mono-Malonate.

[0077] In some embodiments, the acid is genlisic acid. In some embodiments, the process comprises crystallizing Compound I from a solvent in the presence of gentisic acid to provide Compound I Gentisate:Attorney Docket No.: 1583-US-NP / WO-PCT

[0078] Suitable solvents (e.g., solvents used to provide Compound I Gentisatefrom Compound I) include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether, di-n-butyl ether, 1,4-dioxane, etc.), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, acetone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), nitriles (e.g., acetonitrile, propionitrile, butyronitrile, benzonitrile, etc.), water, and any combination thereof.

[0079] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile.

[0080] In some embodiments, the crystallization (e.g., the crystallization of Compound I) occurs at a temperature of about 0 °C to about 70 °C. In some embodiments, the temperature is about 40 °C to about 20 °C. In some embodiments, the crystallization comprises cooling a solution comprising Compound I and malonic acid from about 30-50 °C (e.g., about 40 °C) to about 10-30 °C (e.g., about 20 °C).

[0081] In some embodiments, the process comprises crystallizing Compound I from a solvent such as a nitrile solvent (e.g., acetonitrile), by cooling a solution comprising Compound I and gentisic acid from about 30-50 °C (e.g., about 40 °C) to about 10-30 °C (e.g., about 20 °C), to provide Compound I Gentisate.

[0082] Also provided are processes for providing Compound I Form I. For example, the process may comprise converting Compound I or a salt thereof to Compound I Form I.

[0083] In some embodiments, the process comprises crystallizing Compound I from a solvent to provide Compound I Form I. In some embodiments, the Compound I is amorphous (e.g., Compound I Amorphous), and the process comprises crystallizing Compound I Amorphous from a solvent to provide Compound I Form I. In some embodiments, the Compound I is obtained from a process described herein and is subject to the reaction without isolation and / or purification.

[0084] Suitable solvents (e.g., solvents used to provide Compound I Form I from Compound I) include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether, di-n-butyl ether, 1,4-dioxane, etc.), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, acetone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), nitriles (e.g., propionitrile, butyronitrile, benzonitrile, etc.), water, and any combination thereof.

[0085] In some embodiments, the solvent is an alcohol solvent. In some embodiments, the solvent is ethanol.

[0086] In some embodiments, the crystallization (e.g., the crystallization of Compound I) occurs at a temperature of about -10 °C to about 70 °C. In some embodiments, the temperature is about 50 °C to about 20 °C. In some embodiments, the crystallization comprises cooling a solution comprising Compound I from about 40-60 °C (e.g., about 50 °C) to about 10-30 °C (e.g., about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0087] In some embodiments, the process comprises crystallizing Compound I from a solvent such as an alcohol solvent (e.g., ethanol), by cooling a solution (e.g., an ethanol soludon) of Compound I from about 40-60 °C (e.g., about 50 °C) to about 10-30 °C (e.g., about 20 °C), to provide Compound I Form I.

[0088] Alternatively or additionally, a salt or a cocrystal of Compound I may be converted to Compound I Form I.

[0089] In some embodiments, the process comprises subjecting Compound I Mono-Malonate to a suitable condition to provide Compound I Form I.

[0090] In some embodiments, the condition (e.g., the condition for converting Compound I Mono-Malonate to Compound I Form I) comprises a solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether, di-n-butyl ether, 1,4-dioxane, etc.), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, acetone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), nitriles (e.g., propionitrile, butyronitrile, benzonitrile, etc.), water, and any combination thereof.

[0091] In some embodiments, the solvent is an alcohol solvent. In some embodiments, the solvent is ethanol.

[0092] In some embodiments, the condition (e.g., the condition for converting Compound I Mono-Malonate to Compound I Form I) comprises a temperature of about -10 °C to about 70 °C. In some embodiments, the temperature is about 50 °C to about 20 °C. In some embodiments, the temperature is about 20 °C.

[0093] In some embodiments, the process comprises subjecting Compound I Mono-Malonate to a solvent such as an alcohol solvent (e.g., ethanol), and at a suitable temperature such as a temperature of about 20 °C to about 50 °C (e.g., about 20 °C) to provide Compound I Form I.

[0094] Also provided are processes for providing Compound I Amorphous.

[0095] A salt or cocrystal of Compound I may be converted to Compound I Amorphous under suitable conditions.

[0096] In some embodiments, the process comprises subjecting Compound I Mono-Malonate to a suitable condition to provide Compound I Amorphous.

[0097] In some embodiments, the condition (e.g., the condition for converting Compound I Mono-Malonate to Compound I Amorphous) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), hydrocarbons (e.g., n-heptane, etc.), nitriles (e.g., acetonitrile, etc.), water, and any combination thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0098] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of ethyl acetate, n-heptane, and water.

[0099] In some embodiments, the condition (e.g., the condition for converting Compound I Mono-Malonate to Compound I Amorphous) comprises a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, A,A-diisopropylethylamine, tripropylamine, tributylamine, 1,4-diazabicylo[2.2.2] -octane, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.), phosphates (e.g., sodium phosphate, disodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, cesium phosphate, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), and hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.).

[0100] In some embodiments, the base is a phosphate base. In some embodiments, the base is dipotassium hydrogen phosphate.

[0101] In some embodiments, the condition (e.g., the condition for converting Compound I Mono-Malonate to Compound I Amorphous) comprises a temperature of about 0 °C to about 70 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0102] In some embodiments, the process comprises subjecting Compound I Mono-Malonate to a solvent such as mixture of ethyl acetate, n-heptane, and water in the presence of a base such as a phosphate base (e.g., dipotassium hydrogen phosphate), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C) to provide Compound I Amorphous.

[0103] The Compound I Amorphous may be further converted to Compound I Form I according to a process described anywhere herein.Synthesis of Compound III and Synthetic Intermediates

[0104] Also provided are processes for preparing Compound III or a salt thereof (or a precursor for preparing Compound III or a salt thereof). In some embodiments, the Compound III or a salt thereof (or a precursor for preparing Compound III or a salt thereof) prepared according to a process described herein may be used for preparing Compound I or a salt thereof.Compound Ill-la to Compound III

[0105] In some embodiments, provided herein is a process for preparing Compound IIIor a salt thereof, comprising:Attorney Docket No.: 1583-US-NP / WO-PCT (a) contacting Compound III- laBocor a salt thereof with ethanol in the presence of an acid to form Compound Illaor a salt thereof; and(b) crystallizing Compound Illa from a solvent to provide Compound III as a single atropisomer.

[0106] In some embodiments, the process comprises contacting Compound III- la or a salt thereof with ethanol in the presence of an acid. Suitable acids include, but are not limited to, sulfonic acids (e.g., methanesulfonic acid, p-toluenesul fonic acid, etc.), mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), and carboxylic acids (e.g., acetic acid, pivalic acid, trifluoroacetic acid, etc.).

[0107] In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is methanesulfonic acid.

[0108] In some embodiments, the reaction between Compound III- la or a salt thereof and ethanol (step (a)) occurs in the presence of a solvent. In some embodiments, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, di-n-butyl ether, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile), and a combination of any of the foregoing with ethanol. In some embodiments, the solvent is ethanol.

[0109] In some embodiments, the reaction between Compound III- la or a salt thereof and ethanol occurs in the presence of an activating agent. The activating agent may be an acid halide forming agent such as oxalyl chloride.

[0110] In some embodiments, the reaction between Compound III- la or a salt thereof and ethanol occurs in the absence of an activating agent.

[0111] In some embodiments, the reaction between Compound III- la or a salt thereof and ethanol occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 65 °C to about 85 °C. In some embodiments, the temperature is about 75 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0112] In some embodiments, the reaction between Compound III- la or a salt thereof and ethanol occurs in the presence of an acid such as a sulfonic acid (e.g., methanesulfonic acid), a solvent (e.g., ethanol), and a suitable temperature such as a temperature of about 65 °C to about 85 °C (e.g., about 75 °C).

[0113] In some embodiments, Compound III-6aor a salt thereof, is formed in step (a), which is subsequently converted to Compound Illa or a salt thereof.

[0114] In some embodiments, Compound III-3aBocor a salt thereof, is formed in step (a), which is subsequently converted to Compound Illa or a salt thereof.

[0115] In some embodiments, the process comprises crystallizing Compound Illa or a salt thereof from a solvent to provide Compound III or a salt thereof as a single atropisomer. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., acetone, 2-butanone, 4-metyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), hydrocarbons (e.g., benzene, toluene, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), nitriles (e.g., acetonitrile), and any combination thereof.

[0116] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile.

[0117] In some embodiments, the crystallization (e.g., crystallization of Compound Illa) occurs at a temperature of about 0 °C to about 120 °C. In some embodiments, the temperature is about 60 °C to about 10 °C. In some embodiments, the temperature is about 50 °C to about 20 °C. In some embodiments, the crystallization comprises cooling a solution comprising Compound Illa from about 50 °C to about 20 °C.

[0118] In some embodiments, the crystallization (e.g., crystallization of Compound Illa) occurs under a condition comprising a solvent such as a nitrile solvent (e.g., acetonitrile) and a suitable temperature such as a temperature of about 60 °C to about 10 °C (e.g., about 50°C to about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0119] In some embodiments, the process further comprises equilibrating Compound Illa or a salt thereof prior to crystallization. In accordance with any embodiments described herein, Compound Illa may represent a mixture of atropisomers including Compound III. The equilibration may be performed under an acidic or thermal condition.

[0120] In some embodiments, the equilibration is performed under an acidic condition (e.g., acidic equilibration).

[0121] In some embodiments, the acidic condition (e.g., the acidic condition for equilibrating Compound Illa) comprises an acid. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, carboxylic acids (e.g., acetic, pivalic, trifluoroacetic acid, etc.), phosphoric acid, and sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, etc.).

[0122] In some embodiments, the acid for acidic equilibration is a sulfonic acid. In some embodiments, the acid for acidic equilibration is methanesulfonic acid.

[0123] The acidic condition (e.g., the acidic condition for equilibrating Compound Illa) may comprise a solvent. In some embodiments, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, di-n-butyl ether, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile), and a combination of any of the foregoing with ethanol. In some embodiments, the solvent is ethanol.

[0124] In some embodiments, the acidic condition (e.g., the acidic condition for equilibrating Compound Illa) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 65 °C to about 85 °C. In some embodiments, the temperature is about 75 °C.

[0125] In some embodiments, the equilibration occurs under a condition comprising an acid such as a sulfonic acid (e.g., methanesulfonic acid), a solvent (e.g., ethanol), and a suitable temperature such as a temperature of about 65 °C to about 85 °C (e.g., about 75°C).

[0126] Alternatively or additionally, the equilibration may be performed under a thermal condition (e.g., thermal equilibration). In some embodiments, the thermal equilibration is performed in a continuous manner by using a flow reactor.

[0127] In some embodiments, the thermal condition (e.g., the thermal condition for equilibrating Compound Illa) comprises a solvent. Suitable solvents include, but are not limited to, nitriles (e.g., acetonitrile), alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc), ketones (e.g., acetone, 2-butanone, 4-metyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), hydrocarbons (e.g., benzene, toluene, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.).

[0128] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile.Attorney Docket No.: 1583-US-NP / WO-PCT

[0129] In some embodiments, the thermal condition (e.g., the thermal condition for equilibrating Compound Illa) comprises a temperature of about 80 °C to about 200 °C. In some embodiments, the temperature is about 140 °C to about 200 °C. In some embodiments, the temperature is about 150 °C to about 195 °C. In some embodiments, the temperature is about 170 °C to about 190 °C. In some embodiments, the temperature is about 180 °C. In some embodiments, the temperature is about 160 °C.

[0130] In some embodiments, the equilibration (e.g., equilibrating Compound Illa) occurs under a condition comprising a solvent such as a nitrile solvent (e.g., acetonitrile) and a suitable temperature such as a temperature of about 150 °C to about 195 °C (e.g., about 160°C).

[0131] In some embodiments, the equilibration (e.g., equilibrating Compound Illa) occurs under a condition comprising a solvent such as a nitrile solvent (e.g., acetonitrile) and a suitable temperature such as a temperature of about 170 °C to about 190 °C (e.g., about 180°C).

[0132] In some embodiments, the process comprises equilibrating Compound Illa under an acidic or thermal condition (e.g., an acidic or thermal condition as described herein), followed by crystallizing Compound Illa from a solvent to provide Compound III as a single atropisomer.Synthesis of Compound Ill-la

[0133] In some embodiments, provided is a process for preparing Compound III- laBocor a salt thereof, comprising:(a) contacting Compound IV- 1Bocor a salt thereof with zinc; and(b) contacting a product from step (a) with a compound of Formula Vawherein X is Br or I,or a salt thereof in the presence of a catalytic system to form Compound III-2aAttorney Docket No.: 1583-US-NP / WO-PCTBocor a salt thereof.

[0134] In some embodiments, the reaction between Compound IV- 1 or a salt thereof and zinc (step (a)) occurs in the presence of a solvent. Suitable solvents include, but are not limited to aromatic solvents (e.g., toluene, xylene, etc.), polar aprotic solvents (e.g., MA mielhy I formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and nitriles (e.g., acetonitrile, benzonitrile, etc.), and any combination thereof.

[0135] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of toluene and W-diinclhyllorinamidc.

[0136] In some embodiments, the reaction between Compound IV- 1 or a salt thereof and zinc (step (a)) occurs in the presence of an acli valor. Suitable acli valors include, but are not limited to methanesulfonic acid, iodine, 1 ,2-dibromoethane, and silyl chlorides (e.g., trimethylsilyl chloride, etc.).

[0137] In some embodiments, the acli valor is a silyl chloride. In some embodiments, the acli valor is trimethylsilyl chloride.

[0138] In some embodiments, the reaction between Compound IV- 1 or a salt thereof and zinc occurs at a temperature of about -20° C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0139] In some embodiments, the reaction between Compound IV-1 or a salt thereof and zinc occurs under a condition comprising a solvent (e.g. a mixture of toluene and N,N-Dimethylformamide), an ac ivator such as a silyl chloride (e.g., trimethylsilyl chloride), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0140] In some embodiments, the reaction between Compound IV-1 or a salt thereof and zinc provides Compound IV-2Bociv-2or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0141] In some embodiments, the process comprises contacting Compound IV-2 or a salt thereof with a compound of Formula Va or a salt thereof in the presence of a catalytic system to form Compound III-2a or a salt thereof.

[0142] The catalytic system (e.g., the calalylic system for providing Compound III-2a from Compound IV-2 and a compound of Formula Va) may comprise a catalyst. The catalyst may be a palladium catalyst or a nickel catalyst. The palladium catalyst can be a palladium(II) source (e.g., palladium(II) acetate, palladium(II) chloride, etc.) or a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.). The nickel catalyst can be a nickel(II) source (e.g., nickel(II) chloride, etc.) or a nickel(O) source (e.g., bis(cyclooctadiene)nickel(0)).

[0143] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) acetate.

[0144] The catalytic system (e.g., the calalylic system for providing Compound III-2a from Compound IV-2 and a compound of Formula Va) may further comprise a ligand. Suitable ligands include, but are not limited to, monodentate phosphine ligands (e.g., triphenylphosphine, 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, etc.), bidentate phosphine ligands (e.g., l,2-bis(diphenylphosphino)ethane, 2, 2’ -bis(diphenylphosphino)- 1,1’ -binaphthyl, l,l’-bis(diphenylphosphino)ferrocene, etc.), bipyridine ligands (e.g., 4,4’ -di -tert-butyl-2, 2’ -dipyridyl, 2,2’ -dipyridine), 1,10-phenanthroline, and terpyridine ligands.

[0145] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the ligand is 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl.

[0146] The catalytic system (e.g., the calalylic system for providing Compound III-2a from Compound IV-2 and a compound of Formula Va) may further comprise a solvent. Suitable solvents include, but are not limited to, aromatic solvents (e.g., toluene, xylene, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, V,V-dimethylacetamide, V-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and nitriles (e.g., acetonitrile, benzonitrile, etc.).

[0147] In some embodiments, the solvent is an aromatic solvent. In some embodiments, the solvent is toluene.

[0148] In some embodiments, the reaction between Compound IV-2 or a salt thereof and a compound of Formula Va or a salt thereof occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0149] In some embodiments, the reaction between Compound IV-2 or a salt thereof and a compound of Formula Va or a salt thereof occurs at a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C), and in the presence of a calalylic system comprising a catalyst such as aAttorney Docket No.: 1583-US-NP / WO-PCT palladium catalyst (e.g., palladium(II) acetate), a ligand such as a monodentate phosphine ligand (e.g., 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl), and a solvent (e.g., a mixture of toluene and N,N-dimethylformamide) .

[0150] In some embodiments, the process further comprises subjecting Compound III-2aBocor a salt thereof to a hydrolysis condition to form Compound III- laBocor a salt thereof.

[0151] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for proving Compound III- la from Compound III-2a) comprises a base. Suitable bases include, but are not limited to, hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc.), carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), and phosphates (e.g., potassium phosphate, sodium phosphate, etc.).

[0152] In some embodiments, the base is a hydroxide. In some embodiments, the base is sodium hydroxide (e.g., aqueous sodium hydroxide).

[0153] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for proving Compound III- la from Compound III-2a) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), nitriles (e.g., benzonitrile, etc.), alcohols (e.g., methanol, etc.), aromatic solvents (e.g., toluene, etc.), any combination thereof, and a combination of any of the foregoing with water.

[0154] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of toluene and 2-methyltetrahydrofuran.

[0155] In some embodiments, the hydrolysis of Compound III-2a or a salt thereof occurs at a temperature of about -10 °C to about 80 °C. In some embodiments, the temperature is about -10 °C to about 10 °C. In some embodiments, the temperature is about 0 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0156] In some embodiments, the hydrolysis of Compound III-2a occurs under a hydrolysis condition comprising a base such as a hydroxide (e.g., sodium hydroxide such as aqueous sodium hydroxide), a solvent such as a mixture of toluene and 2-methyltetrahydrofuran, and a suitable temperature such as a temperature of about -10 °C to about 10 °C (e.g., about 0 °C).

[0157] In some embodiments, Compound III-2a or a salt thereof is subject to hydrolysis without isolation and / or purification.

[0158] In some embodiments, the process further comprises converting Compound III- la or a salt thereof to Compound III or a salt thereof according to a process described anywhere herein.Synthesis of Compound III

[0159] In some embodiments, provided is a process for preparing Compound IIIor a salt thereof, comprising:(a) contacting Compound IV-3Bocor a salt thereof with zinc;(b) contacting a product from step (a) with Compound V-Ior a salt thereof in the presence of a catalytic system to form Compound III-3Bocor a salt thereof; and(c) subjecting Compound III-3 or a salt thereof to a deprotection condi lion to form Compound III or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0160] In some embodiments, the reaction between Compound IV-3 or a salt thereof and zinc occurs in the presence of an activator. Suitable activators include, but are not limited to, silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, etc.), methanesulfonic acid, iodine, and 1 ,2-dibromoethane.

[0161] In some embodiments, the acli valor is a silyl chloride. In some embodiments, the activator is trimethylsilyl chloride.

[0162] In some embodiments, the reaction between Compound IV-3 or a salt thereof and zinc occurs in the presence of a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents (e.g., V A i methyl formamide, W-diinclhylacclamidc, V-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), aromatic solvents (e.g., toluene, etc.), and any combination thereof.

[0163] In some embodiments, the solvent is a mixture of W-diinclhyllorinamidc and toluene.

[0164] In some embodiments, the reaction between Compound IV-3 or a salt thereof and zinc occurs at a temperature of about -10 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0165] In some embodiments, the reaction between Compound IV-3 or a salt thereof and zinc occurs in the presence of an activator (e.g., trimethylsilyl chloride), a solvent (e.g., a mixture of N,N-dimethylformamide and toluene), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0166] In some embodiments, the product from the reaction between Compound IV-3 or a salt thereof and zinc (step (a)) is Compound IV-4 or a salt thereof.Boc

[0167] In some embodiments, Compound IV-4 or a salt thereof (e.g., the product from step (a)) is subject to the next step without isolation and / or purification.

[0168] In some embodiments, the process comprises contacting Compound IV-4 or a salt thereof (e.g., the product from step (a)) with Compound V-I or a salt thereof in the presence of a catalytic system to form Compound III-3.

[0169] The catalytic system (e.g., the catalytic system for providing Compound III-3 from Compound IV-4 and Compound V-l) may comprises a catalyst. The catalyst may be a palladium catalyst or a nickel catalyst. The palladium catalyst can be a palladium(II) source (e.g., palladium(II) acetate, palladium(II) chloride, etc.) or a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.). The nickel catalyst can be a nickel(II) source (e.g., nickel(II) chloride, etc.) or a nickel(0) source (e.g., bis(cyclooctadiene)nickel(0)) .Attorney Docket No.: 1583-US-NP / WO-PCT

[0170] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) acetate.

[0171] The catalytic system (e.g., the calalylic system for providing Compound III-3 from Compound IV-4 and Compound V-I) may further comprise a ligand. Suitable ligands include, but are not limited to, monodentate phosphine ligands (e.g., triphenylphosphine, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, 2-dicyclohexylphosphino-2’ ,6’ -dimethoxybiphenyl, etc.), bidentate phosphine ligands (e.g., l,2-bis(diphenylphosphino)ethane, 2, 2’ -bis(diphenylphosphino)-l,T -binaphthyl, 1,1’-bis(diphenylphosphino)ferrocene, etc.), bipyridine ligands (e.g., 4,4’ -di -tert-butyl-2, 2’ -dipyridyl, 2,2’ -dipyridine), 1,10-phenanthroline, and terpyridine ligands.

[0172] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the ligand is 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl.

[0173] The catalytic system (e.g., the calalylic system for providing Compound III-3 from Compound IV-4 and Compound V-I) may further comprise a solvent. Suitable solvents include, but are not limited to, aromatic solvents (e.g., toluene, etc.), polar aprotic solvents (e.g., W-diinclhyllorinamidc, N,N-dimethylacetamide, V-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and any combination thereof.

[0174] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of toluene and W-diinclhyllorinamidc.

[0175] In some embodiments, the reaction between Compound IV-4 or a salt thereof and Compound V-I or a salt thereof occurs at a temperature of about 20°C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0176] In some embodiments, the reaction between Compound IV-4 or a salt thereof and Compound V-I or a salt thereof occurs at a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C), and in the presence of a catalytic system comprising a catalyst such as a palladium catalyst (e.g., palladium(II) acetate), a ligand such as a monodentate phosphine ligand (e.g., 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl), and a solvent (e.g., a mixture of toluene and N,N-dimethylformamide) .

[0177] In some embodiments, the process comprises subjecting Compound III-3 or a salt thereof to a deprotection condition to form Compound III or a salt thereof.

[0178] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound III from Compound III-3) comprises a deprotection reagent. Suitable deprotection reagents include, but are not limited to, mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (e.g., acetic acid, pivalic acid, irilluoroacelic acid, etc.), sulfonic acids (e.g., ptoluenesulfonic acid, etc.), Lewis acids (e.g., boron trifluoride diethyl etherate, boronAttorney Docket No.: 1583-US-NP / WO-PCT trifluoride THF complex, etc.), oxalyl chloride, and metal salts (e.g., iron(III) chloride, zinc(II) bromide, etc.).

[0179] In some embodiments, the deprotection reagent is an acid. In some embodiments, the deprotection reagent is phosphoric acid.

[0180] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound III from Compound III-3) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, tert-butyl methyl ether, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, A miclhylacclamide, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), halogenated solvents (e.g., dichloromethane), and a combination of any of the foregoing with ethanol.

[0181] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of ethanol and tetrahydrofuran.

[0182] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound III from Compound III-3) comprises a temperature of about 0°C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0183] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound III from Compound III-3) comprises a deprotection reagent such as an acid (e.g., phosphoric acid), a solvent (e.g., a mixture of ethanol and tetrahydrofuran), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Synthesis of Compound III-2a

[0184] In some embodiments, provided is a process for preparing Compound III-2aBocor a salt thereof, comprising:(a) contacting Compound IV-6Bociv-6or a salt thereof with Compound Va-BrAttorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof in the presence of a photosensitizer to provide Compound III-2a or a salt thereof.

[0185] Suitable photosensitizers (e.g., photosensitizers for providing Compound III-2a from Compound Va-Br and Compound IV-6) include, but are not limited to, iridium photocatalyst (e.g., Ir(dFCF3ppy)2(dtbbpy)PF6, Ir[ppy]2(dtbbpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFFppy)2(dtbbpy)PF6, Ir(dFCF3ppy)2(bpy)PFe, Ir(dFCF3ppy)2(dCF3bpy)PFe), and donor-acceptor fluorophores photocatalyst (e.g., l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-Tetrakis(9H-carbazol-9-yl) isophthalonitrile (4CzIPN, CAS 1416881-52-1), 2,4,6-tris(diphenylamino)-5-fhioroisophthalonitrile (3DPAIPN, CAS 2260543-73-3), 3,4,5,6-tetrakis(carbazol-9-yl)-l,2-dicyanobenzene (4CzPN, CAS 1416881-51-0), 2,3,5,6-tetrakis(carbazol-9-yl)-l,4-dicyanobenzene (4CzTPN, CAS 1416881-53-2), 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile (4DPAIPN, CAS 1846598-27-3), etc.).

[0186] In some embodiments, the pholosensilizer is an iridium photocatalyst. In some embodiments, the photosensitizer is Ir(dFCF3ppy)2(dtbbpy)PF6.

[0187] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a co-catalyst. In some embodiments, the co-catalyst is a nickel co-catalyst. Suitable nickel co-catalysts include, but are not limited to, nickel(II) bromide ethylene glycol dimethyl ether, nickel(II) chloride hexahydrate, nickel(II) chloride ethylene glycol dimethyl ether, nickel(II) tetrafluoroborate, nickel(II) acetate, nickel(II) bromide trihydrate, nickel(II) acetylacetonate, and nickel(II) stearate.

[0188] In some embodiments, the co-catalyst is nickel(II) bromide ethylene glycol dimethyl ether.

[0189] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a ligand. Suitable ligands include, but are not limited to, bipyridine ligands (e.g., 4,4'-di-tert-butyl-2,2'-dipyridyl, 2,2'-dipyridine, etc.) and 1,10-phenanthroline.

[0190] In some embodiments, the ligand is a bipyridine ligand. In some embodiments, the ligand is 4,4'-di -tert-butyl- 2, 2' -dipyridyl .

[0191] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a reductant. Suitable reductants include, but are not limited to, silanes (e.g., tris(trimethylsilyl)silane, triphenylsilane, triethylsilane, dimethyl(phenyl)silane, N-(tert-butyl)- 1,1,1 ,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-amine, N-isopropyl- 1 ,1 , 1 ,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-amine, N-butyl-l,l,l,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-Attorney Docket No.: 1583-US-NP / WO-PCT 2-amine, tris(trimethylsilyl)silanol, etc.), and amines (e.g., triethylamine, triethanolamine, N, N-diisopropylethylamine, tripropylamine, diethylpropylamine, etc.).

[0192] In some embodiments, the reductant is a silane. In some embodiments, the reductant is tris(trimethylsilyl)silane.

[0193] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a base. Suitable bases include, but are not limited to, cyclic aliphatic amines (e.g., 2,2,6,6-tetramethylpiperidine, 1 -methylpiperidine, pyrrolidine, piperidine, etc.), acetates (e.g., potassium acetate, lithium acetate, sodium acetate, ammonium acetate, cesium acetate, etc.), carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), quinuclidine-based bases (e.g., quinuclidine, l,4-diazabicyclo[2.2.2]octane (DABCO), hydroxyquinuclidine, 3-acetoxyquinuclidine, etc.), guanidine bases (e.g., 1,1,3,3-tetramethylguanidine, etc.), hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), heterocyclic aromatic bases (e.g., 2,6-lutidine, etc.), and phosphates (e.g., tripotassium phosphate, trilithium phosphate, etc.).

[0194] In some embodiments, the base is a carbonate base. In some embodiments, the base is sodium carbonate.

[0195] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the absence of an addili ve.

[0196] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of an additive. Suitable additives include, but are not limited to, phthalimide addili ves (e.g., phthalimide, 4-tert-butylphthalimide, 4-chloro- 1,3 -dioxo- 1,3-dihydroisoindole, methyl l,3-dioxoisoindoline-5-carboxylate, etc.) and succinimide additives (e.g., succinimide, 1,2,3,6-tetrahydrophthalimide, 2,2,3,3-tetramethylsuccinimide, (±)-a-methyl-a-phenylsuccinimide, bicyclo[2.2.1]heptane-2,3-dicarboximide, etc.).

[0197] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, etc.), nitriles (e.g., acetonitrile, etc.), polar aprotic solvents (e.g., dimethylacetamide, N, N'-dimethylpropyleneurea, l,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide, etc.), and alcohols (e.g., isopropyl alcohol, l,l,l,3,3,3-hexafhioro-2-propanol, etc.).

[0198] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is 1,2-dimethoxyethane.

[0199] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs at a temperature of about 0 °C to about 120 °C. In some embodiments, the temperature is about 15°C to about 35 °C. In some embodiments, the temperature is about 25°C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0200] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs under a light having a wavelength of about 330 nm to about 500 nm. In some embodiments, the wavelength is about 450 nm.

[0201] In some embodiments, the reaction between Compound IV-6 or a salt thereof and Compound Va-Br or a salt thereof occurs in the presence of a photosensitizer such as an iridium photocatalyst (e.g., Ir(dFCF3ppy)2(dtbbpy)PF6), a co-catalyst such as a nickel co-catalyst (e.g., nickel(II) bromide ethylene glycol dimethyl ether), a ligand such as a bipyridine ligand (e.g., 4,4’- di-tert-butyl-2, 2’ -bipyridine), a base such as a carbonate (e.g., sodium carbonate), a solvent such as an ether solvent (e.g., 1,2-dimethoxy ethane), at a suitable temperature such as a temperature of about 15°C to about 35 °C (e.g., about 25 °C), and under a light having a suitable wavelength such as a wavelength of about 330 nm to about 500 nm (e.g., about 450 nm).

[0202] In some embodiments, the process further comprises converting Compound III-2a or a salt thereof to Compound Illa or Compound III or a salt thereof according to a process described anywhere herein.Synthesis of Compound III-3a

[0203] In some embodiments, provided is a process for preparing Compound III-3aBocor a salt thereof, comprising:contacting Compound Va-Ior a salt thereof with Compound IV- 8BocCompound IV- 8under an electrochemical coupling condition to provide Compound III-3a or a salt thereof.

[0204] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a catalyst. In some embodiments, the catalyst is a nickel catalyst. Suitable nickel catalysts include, but are not limited to, nickel(II) chloride hexahydrate, nickel(II) chloride ethylene glycolAttorney Docket No.: 1583-US-NP / WO-PCT dimethyl ether, nickel(II) bromide ethylene glycol dimethyl ether, nickel(II) chloride, nickel(II) iodide, nickel(II) tetrafluoroborate, nickel(II) acetate, nickel(II) bromide trihydrate, nickel(II) acetylacetonate, and nickel(II) stearate.

[0205] In some embodiments, the catalyst is nickel(II) chloride hexahydrate.

[0206] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a ligand. Suitable ligands include, but are not limited to, bipyridine ligands (e.g., 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-dipyridyl, 4,4'-dimethyl-2,2'-dipyridine, etc.), 1,10-phenanthroline, picolinimidamide hydrochloride, 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine, and 2-(pyridin-2-yl)-4,5-dihydrooxazole.

[0207] In some embodiments, the ligand is a bipyridine ligand. In some embodiments, the ligand is 2,2'-bipyridine.

[0208] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises an additive. Suitable additives include, but are not limited to, silver salts (e.g., silver nitrate, etc.), acids (e.g., acetic acid, trifluoroacetic acid, etc.), and bases (e.g., sodium acetate, sodium bicarbonate, sodium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, etc.).

[0209] In some embodiments, the additive is a silver salt. In some embodiments, the additive is silver nitrate.

[0210] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a solvent. The solvent may be a polar aprotic solvent (e.g., V,V-dimethylacetamide, N,N'-dimethylpropyleneurea, l,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, V-methyl-2-pyrrolidone, VV-dimethylformamide, etc.).

[0211] In some embodiments, the solvent is V,V-dimethylacetamide.

[0212] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a temperature of about 0 °C to about 70 °C. In some embodiments, the temperature is about 15 °C to about 35 °C. In some embodiments, the temperature is about 25 °C.

[0213] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a current of about 2 F / mol to about 10 F / mol. In some embodiments, the current is about 3.2 F / mol.

[0214] The electrochemical coupling rection (e.g., the reaction between Compound Va-I and Compound IV-8) may occur by using suitable electrodes known in the art. For example, the electrochemical coupling rection may occur by using a magnesium anode combined with a reticulated vitreous carbon cathodeAttorney Docket No.: 1583-US-NP / WO-PCT (Mg(+) / RVC(-)), a zinc anode combined with a reticulated vitreous carbon cathode (Zn(+) / RVC(-)), an aluminum anode combined with a reticulated vitreous carbon cathode (Al(+) / RVC(-)), a magnesium anode combined with a carbon cathode (Mg(+) / C(-)), a zinc anode combined with a carbon cathode (Zn(+) / C(-)), or an aluminum anode combined with a carbon cathode (Al(+) / C(-)).

[0215] In some embodiments, the electrochemical coupling occurs by using a magnesium anode combined with a reliculaled vitreous carbon cathode (Mg(+) / RVC(-)).

[0216] In some embodiments, the electrochemical coupling condition (e.g., the electrochemical coupling condition for providing Compound III-3a from Compound Va-I and Compound IV-8) comprises a catalyst such as a nickel catalyst (e.g., nickel(II) chloride hexahydrate), a ligand such as a bipyridine ligand (e.g., 2,2'-bipyridine), an additive such as a silver salt (e.g., silver nitrate), a solvent such as a polar aprotic solvent (e.g., A,A-dimethylacetamide), a suitable temperature such as a temperature of about 15 °C to about 35 °C (e.g., about 25 °C), and under a suitable current such as a current of about 3.2 F / mol by using suitable electrodes such as a magnesium anode combined with a reticulated vitreous carbon cathode (Mg(+) / RVC(-)).

[0217] In some embodiments, the process further comprises converting Compound III-3a or a salt thereof to Compound Illa or Compound III or a salt thereof according to a process described anywhere herein.Synthesis of Compound III-3

[0218] In some embodiments, provided is a process for preparing Compound III-3or a salt thereof, comprising:(a) contacting Compound IV-5Bocor a salt thereof with a benzoxazolium salt acli valor;(bl) contacting a product from step (a) with Compound V-l-Bror a salt thereof in the presence of a pholosensilizer to provide Compound III-4Attorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof; or(b2) contacting the product from step (a) with Compound V-Bror a salt thereof in the presence of a photosensitizer to provide Compound III-3 or a salt thereof; and (c) when step (bl) occurs, contacting Compound III -4 or a salt thereof with a methylation agent to form Compound III-3 or a salt thereof.

[0219] In some embodiments, the process comprises contacting Compound IV-5 or a salt thereof with a benzoxazolium salt activator. Suitable benzoxazolium salt activators include, but are not limited to, 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate, 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium triflate, 5, 7-di-tert-butyl-3-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-3-ium tetrafluoroborate, 5, 7-di-tert-butyl-3-(4-chlorophenyl)benzo[d]oxazol-3-ium tetrafluoroborate, 5,7-di-tert-butyl-3-(4-methoxyphenyl)benzo[d]oxazol-3-ium tetrafluoroborate, and 5,7-di-tert-butyl-3-(4-(trifluoromethoxy)phenyl)benzo [d] oxazol-3 -ium tetrafluoroborate .

[0220] In some embodiments, the benzoxazolium salt activator is 5,7-di-tert-butyl-3-phenylbenzo [d] oxazol-3 -ium tetrafluoroborate.

[0221] In some embodiments, the reaction between Compound IV-5 or a salt thereof and the benzoxazolium salt activator occurs in the presence of a base. Suitable bases include, but are not limited to, pyridine bases (e.g., pyridine, 2,6-dimethylpyridine, etc.), and amine bases (e.g., tetramethylpiperidine, etc.).

[0222] In some embodiments, the base is a pyridine base. In some embodiments, the base is pyridine.

[0223] In some embodiments, the reaction between Compound IV-5 or a salt thereof and the benzoxazolium salt activator occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dibutyl ether, etc.), aromatic solvents (e.g., toluene, trifluorotoluene, etc.), and mixtures of (i) an aromatic solvent or an ether with (ii) a polar aprotic solvent (e.g., N,N-dimethylacetamide, V,V-dimethylformamide, V-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0224] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tertbutyl methyl ether.

[0225] In some embodiments, the reaction between Compound IV-5 or a salt thereof and the benzoxazolium salt activator occurs at a temperature of about -20 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0226] In some embodiments, the reaction between Compound IV-5 or a salt thereof and the benzoxazolium salt activator occurs in the presence of a benzoxazolium salt activator (e.g., 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate), a base such as a pyridine base (e.g., pyridine), a solvent such as an ether solvent (e.g., tert-butyl methyl ether), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0227] In some embodiments, the product from the reaction between Compound IV-5 or a salt thereof and the benzoxazolium salt acli valor (e.g., the product from step (a)) is Compound IV -7 or a salt thereof.BocCompound IV-7

[0228] In some embodiments, the process comprises contacting Compound IV-5 or a salt thereof with Compound V-l-Br or a salt thereof in the presence of a photosensitizer to provide Compound III-4 or a salt thereof.

[0229] In some embodiments, the process comprises contacting Compound IV-5 or a salt thereof with Compound V-Br or a salt thereof in the presence of a photosensitizer to provide Compound III-3 or a salt thereof.

[0230] Suitable photosensitizers (e.g., photosensitizers for providing Compound III-4 or Compound III-3) include, but are not limited to iridium photocatalyst (e.g., Ir[ppy]2(dtbbpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFFppy)2(dtbbpy)PF6, Ir(dFCF3ppy)2(dtbbpy)PF6, Ir(dFCF3ppy)2(dCF3bpy)PFe), and donor-acceptor fluorophores photocatalyst (e.g., 1, 2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-Tetrakis(9H-carbazol-9-yl) isophthalonitrile (4CzIPN, CAS 1416881-52-1), 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile (3DPAIPN, CAS 2260543-73-3), 3,4,5,6-tetrakis(carbazol-9-yl)-l,2-dicyanobenzene (4CzPN, CAS 1416881-51-0), 2,3,5,6-tetrakis(carbazol-9-yl)-l,4-dicyanobenzene (4CzTPN, CAS 1416881-53-2), 2, 4,5,6-tetrakis(diphenylamino)isophthalonitrile (4DPAIPN, CAS 1846598-27-3), etc.).

[0231] In some embodiments, the photosensitizer is a donor-acceptor fluorophores photocatalyst. In some embodiments, the photosensitizer is 4CzIPN (CAS 1416881-52-1).Attorney Docket No.: 1583-US-NP / WO-PCT

[0232] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of a co-catalyst. In some embodiments, the cocatalyst is a nickel co-catalyst. Suitable nickel co-catalysts include, but are not limited to, nickel(II) bromide ethylene glycol dimethyl ether, nickel(II) chloride hexahydrate, nickel(II) chloride ethylene glycol dimethyl ether, nickel(II) tetrafluoroborate, nickel(II) acetate, nickel(II) bromide trihydrate, nickel(II) acetylacetonate, and nickel(II) stearate.

[0233] In some embodiments, the co-catalyst is nickel(II) bromide ethylene glycol dimethyl ether.

[0234] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of a ligand. Suitable ligands include, but are not limited to, bipyridine ligands (e.g., 4,4’ -dimethyl-2, 2’ -bipyridine, 4,4'-di-tert-butyl-2,2'-dipyridyl, 2,2'-dipyridine, etc.) and 1,10-phenanthroline.

[0235] In some embodiments, the ligand is a bipyridine ligand. In some embodiments, the ligand is 4,4’ -dimethyl-2, 2’ -bipyridine.

[0236] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of a base. Suitable bases include, but are not limited to, cyclic aliphatic amines (e.g., 2,2,6,6-tetramethylpiperidine, 1 -methylpiperidine, pyrrolidine, piperidine, etc.), acetates (e.g., potassium acetate, lithium acetate, sodium acetate, ammonium acetate, cesium acetate, etc.), carbonates (e.g., cesium carbonate, potassium carbonate, cesium carbonate, etc.), quinuclidine-based bases (e.g., quinuclidine, l,4-diazabicyclo[2.2.2]octane (DABCO), hydroxyquinuclidine, 3-acetoxyquinuclidine, etc.), and guanidine bases (e.g., 1, 1,3,3-tetramethylguanidine, etc.).

[0237] In some embodiments, the base is a cyclic aliphatic amine. In some embodiments, the base is 2,2,6 , 6-tetramethylpiperidine .

[0238] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of an addilive. Suitable additives include, but are not limited to, phthalimide additives (e.g., phthalimide, 4-tert-butylphthalimide, 4-chloro-l,3-dioxo-l,3-dihydroisoindole, methyl l,3-dioxoisoindoline-5-carboxylate, etc.) and succinimide additives (e.g., succinimide, 1,2,3,6-tetrahydrophthalimide, 2,2,3,3-tetramethylsuccinimide, (±)-a-methyl-a-phenylsuccinimide, bicyclo[2.2.1]heptane-2,3-dicarboximide, etc.).

[0239] In some embodiments, the additive is a phthalimide additive. In some embodiments, the additive is phthalimide. In some embodiments, the addilive is succinimide.

[0240] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dibutyl ether, etc.), polar aprotic solvents (e.g., N,N-Attorney Docket No.: 1583-US-NP / WO-PCT dimethylacetamide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, l,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), ketones (e.g., acetone, etc.), aromatic solvents (e.g., toluene, etc.), nitriles (e.g., acetonitrile, etc.), and any combination thereof.

[0241] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of tert-butyl methyl ether and dimethyl sulfoxide.

[0242] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs at a temperature of about 0 °C to about 120 °C. In some embodiments, the temperature is about 15°C to about 35 °C. In some embodiments, the temperature is about 25 °C.

[0243] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs under a light having a wavelength of about 330 nm to about 500 nm. In some embodiments, the wavelength is about 450 nm.

[0244] In some embodiments, the reaction between Compound IV-5 or a salt thereof and Compound V-1-Br or V-Br or a salt thereof occurs in the presence of a photosensitizer such as a donor-acceptor fluorophores photocatalyst (e.g., 4CzIPN (CAS 1416881-52-1)), a co-catalyst such as a nickel co-catalyst (e.g., nickel(II) bromide ethylene glycol dimethyl ether), a ligand such as a bipyridine ligand (e.g., 4,4’-dimethyl-2, 2’ -bipyridine), a base such as a cyclic aliphatic amine base (e.g., 2, 2,6,6-tetramethylpiperidine), an additive such as phthalimide, a solvent such as a mixture of tert-butyl methyl ether and N,N-dimethylacetamide, at a suitable temperature such as a temperature of about 15°C to about 35 °C (e.g., about 25 °C), and under a light having a suitable wavelength such as a wavelength of about 330 nm to about 500 nm (e.g., about 450 nm).

[0245] In some embodiments, the reaction between Compound IV-5 and Compound V-l-Br (step (bl) occurs and provides Compound III-4 or a salt thereof.

[0246] In some embodiments, the reaction between Compound IV-5 and Compound V-Br (step (b2) occurs and provides Compound III-3 or a salt thereof.

[0247] In some embodiments, the reaction between Compound IV-5 and Compound V-l-Br (step (bl) occurs and provides Compound III-4 or a salt thereof, and the process further comprises contacting Compound III -4 or a salt thereof with a methylation agent to form Compound III-3 or a salt thereof.

[0248] Suitable methylation agents (e.g., the methylation agent used to provide Compound III-3 from Compound III -4) include, but are not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, and dimethyl carbonate.

[0249] In some embodiments, the inelhylalion agent is methyl iodide.

[0250] In some embodiments, the methylation reaction (e.g., the methylation reaction of Compound III-4) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., N,N-Attorney Docket No.: 1583-US-NP / WO-PCT diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0251] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate.

[0252] In some embodiments, the methylation reaction (e.g., the methylation reaction of Compound III-4) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., A imclhy I formamide, A imclhylacclamide, dimethyl sulfoxide, A-methyl-2-pyrrolidone, etc.), nitriles (e.g., acetonitrile, etc.), and halogenated solvents (e.g., dichloromethane, etc.).

[0253] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is A-methyl-2-pyrrolidone.

[0254] In some embodiments, the melhylalion reaction (e.g., the methylation reaction of Compound III-4) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0255] In some embodiments, the methylation reaction (e.g., the methylation reaction of Compound III-4 with a methylation agent such as methyl iodide ) occurs in the presence of a base such as a carbonate (e.g., potassium carbonate), a solvent such as an polar aprotic solvent (e.g., A-methyl-2-pyrrolidone), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0256] In some embodiments, the process further comprises converting Compound III-3 or a salt thereof to Compound III or a salt thereof according to a process described anywhere herein.Synthesis of Compound III via asymmetric cyclization (Synthesis of Compound III-4)

[0257] Also provided is the synthesis of Compound III or a salt thereof via asymmetric cyclization.

[0258] For example, Compound III-4Bocor a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) contacting Compound IV-4Attorney Docket No.: 1583-US-NP / WO-PCT Bocompound VII- 1or a salt thereof to form Compound X-2Bocor a salt thereof;(b) subjecting Compound X-2 or a salt thereof to a deprotection condition to form Compound X-3or a salt thereof;(c) contacting Compound X-3 or a salt thereof with Compound VIor a salt thereof to form Compound III-5Bocor a salt thereof; and(d) subjecting Compound III-5 or a salt thereof to a cyclization condition to form Compound III-4 or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0259] In some embodiments, provided is a process for preparing Compound III-4Bocor a salt thereof, comprising:subjecting Compound III-5or a salt thereof into a cyclization condition to form Compound III -4 or a salt thereof.

[0260] In some embodiments, Compound X-3 or a salt thereof is prepared according to a process described anywhere herein, and Compound III-4 is prepared by a process comprising: (c) contacting Compound X-3 or a salt thereof with Compound VI or a salt thereof to form Compound III-5 or a salt thereof; and (d) subjecting Compound III-5 or a salt thereof to a cyclization condition to form Compound III-4 or a salt thereof.

[0261] In some embodiments, the process further comprises converting Compound III-4 or a salt thereof to Compound III-3 or a salt thereof according to a process described anywhere herein.

[0262] In some embodiments, the process further comprises converting Compound III-4 or a salt thereof to Compound III or a salt thereof according to a process described anywhere herein.

[0263] In some embodiments, the process comprises contacting Compound IV-4 or a salt thereof with Compound VII- 1 or a salt thereof to form Compound X-2 or a salt thereof.

[0264] In some embodiments, the reaction (e.g., the reaction between Compound IV-4 and Compound VII- 1) occurs in the presence of a catalyst. The catalyst may be a palladium catalyst or a nickel catalyst. The palladium catalyst can be a palladium(II) source (e.g., palladium(II) chloride, etc.) or a palladium(O) source (e.g., tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), etc.). The nickel catalyst can be a nickel(II) source (e.g., nickel(II) chloride, etc.) or a nickel(0) source (e.g., bis(cyclooctadiene)nickel(0)) .

[0265] In some embodiments, the catalyst is a palladium(O) source. In some embodiments, the catalyst is tris(dihenzylideneacetone)dipalladium(0).

[0266] In some embodiments, the reaction (e.g., the reaction between Compound IV-4 and Compound VII- 1) occurs in the presence of a ligand. Suitable ligands include, but are not limited to, monodentateAttorney Docket No.: 1583-US-NP / WO-PCT phosphine ligands (e.g., triphenylphosphine, 2-dicyclohexylphosphino-2’, 4’, 6’ -triisopropylbiphenyl, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, etc.), bidentate phosphine ligands (e.g., 1,2-bis(diphenylphosphino)ethane, 2,2’ -bis(diphenylphosphino)- 1,1’ -binaphthyl, 1,1’-bis(diphenylphosphino)ferrocene, etc.), bipyridine ligands (e.g., 4,4’ -di -tert-butyl-2, 2’ -dipyridyl, 2,2’ -dipyridine), 1,10-phenanthroline, and terpyridine ligands.

[0267] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the ligand is 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl.

[0268] In some embodiments, the reaction (e.g., the reaction between Compound IV-4 and Compound VII- 1) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and nitriles (e.g., acetonitrile, benzonitrile, etc.).

[0269] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0270] In some embodiments, the reaction (e.g., the reaction between Compound IV-4 and Compound VII-1) occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 45 °C to about 65 °C. In some embodiments, the temperature is about 55 °C.

[0271] In some embodiments, the reaction (e.g., the reaction between Compound IV-4 and Compound VII-1) occurs in the presence of a catalyst such as a palladium(O) source (e.g., tris(dibenzylideneacetone)dipalladium(0)), a ligand such as a monodentate phosphine ligand (e.g., 2-dicyclohexylphosphino-2’, 6’ -dimethoxybiphenyl), a solvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide), and at a suitable temperature such as a temperature of about 45 °C to about 65 °C (e.g., about 55 °C).

[0272] In some embodiments, the process comprises subjecting Compound X-2 or a salt thereof to a deprotection condition to form Compound X-3 or a salt thereof.

[0273] In some embodiments, the deprotection condition (e.g., the condition for providing Compound X-3 from Compound X-2) comprises a catalyst. Suitable catalysts include, but are not limited to, solid-supported transition metals (e.g., platinum on carbon, palladium on carbon), Raney Nickel, transition metal catalysts (e.g., (S -4)-(r|2,r|2-cycloocta-l,5-diene)(pyridine)(tricyclohexylphosphine)iridium(l-i-) hexafluoridophosphate(l-), (SP-4)-chloridotris(triphenylphosphene)rhodium, etc.), a palladium(II) source (e.g., palladium(II) chloride, etc.), a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.), a nickel(II) source (e.g., nickel(II) chloride, etc.), and a nickel(0) source (e.g., bis(cyclooctadiene)nickel(0), etc.).

[0274] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) chloride.Attorney Docket No.: 1583-US-NP / WO-PCT

[0275] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a ligand. Suitable ligands include, but are not limited to, monodentate phosphine ligands (e.g., triphenylphosphine, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, etc.), bidentate phosphine ligands (e.g., l,2-bis(diphenylphosphino)ethane, 2,2’-bis(diphenylphosphino)-l,l’ -binaphthyl, l,l’-bis(diphenylphosphino)ferrocene, etc.), bipyridine ligands (e.g., 4,4’ -di -tert-butyl-2, 2’ -dipyridyl, 2,2’ -dipyridine), 1,10-phenanthroline, and terpyridine ligands.

[0276] In some embodiments, the deprotection condition (e.g., the deprolcclion condition for providing Compound X-3 from Compound X-2) does not comprise a ligand.

[0277] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a hydrogen source such as hydrogen gas, an organosilane (e.g., triethylsilane, etc.), formic acid, or a formate (e.g., sodium formate, tetrabutylammonium formate, etc).

[0278] In some embodiments, the hydrogen source is an organosilane. In some embodiments, the hydrogen source is triethylsilane.

[0279] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a base such as an amine base such as triethylamine, tripropylamine, and tributylamine. In some embodiments, the base is triethylamine.

[0280] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a solvent. Suitable solvents include, but are not limited to, alcohols (e.., methanol, etc.), halogenated solvents (e.g., dichloromethane, etc.), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and nitriles (e.g., acetonitrile, benzonitrile, etc.), and any combination thereof.

[0281] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of methanol and dichloromethane.

[0282] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0283] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound X-3 from Compound X-2) comprises a catalyst such as a palladium(II) source (e.g., palladium(II) chloride), a hydrogen source such as an organosilane (e.g., triethylsilane), a base such as an amine base (e.g., triethylamine), a solvent such as a mixture of methanol and dichloromethane, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0284] In some embodiments, the process comprises contacting Compound X-3 or a salt thereof with Compound VI or a salt thereof to form Compound III-5 or a salt thereof.

[0285] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,4-diazabicylo[2.2.2] -octane, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.) and basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.).

[0286] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0287] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs in the presence of an azide source (e.g., diphenylphosphoryl azide (DPP A), trimethylsilyl azide, sodium azide, lithium azide, 4-carboxybenzenesulfonazide, 4-acetamidobenenesulfonyl azide, etc.) or deoxo-fluor.

[0288] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs in the presence of an azide source. In some embodiments, the azide source is diphenylphosphoryl azide (DPP A).

[0289] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, toluene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.).

[0290] In some embodiments, the solvent is an aromatic solvent. In some embodiments, the solvent is toluene.

[0291] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs at a temperature of about -10 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0292] In some embodiments, the reaction (e.g., the reaction between Compound X-3 and Compound VI) occurs in the presence of a base such as an amine base (e.g., triethylamine), an azide source such as diphenylphosphoryl azide (DPP A), a solvent such as an aromatic solvent (e.g., toluene), and at a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).

[0293] In some embodiments, the process comprises subjecting Compound III-5 or a salt thereof to a cyclizalion condition to form Compound III-4 or a salt thereof.

[0294] In some embodiments, the process comprises subjecting Compound III-5 or a salt thereof to a cyclizalion condition to form Compound III-4 or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0295] In some embodiments, the cyclization condition (e.g., the cyclizalion condition for providing Compound III -4 from Compound III-5) comprises an organocatalyst. Suitable organocatalysts include, but are not limited to, squaramides (e.g., 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[(8a,9s)-cinchonan-9-ylamino] -3 -cyclobutene- 1,2-dione (CAS 1256245-86-9), 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(8a,9S)-6’-methoxycinchonan-9-yl]amino]-3-cyclobutene-l,2-dione (CAS 1256245-84-7), 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[[(8a,9S)-10,ll-dihydrocinchonan9-yl]amino]-3-cyclobutene- 1,2-dione (CAS 1407166-62-4), 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((lS,2S)-l,2-diphenyl-2-(piperidin-l-yl)ethyl)amino)cyclobut-3-ene-1, 2-dione (CAS 1943732-17-9), 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[[(lS,2S)-2-(l-piperidinyl)cyclohexyl]amino]-3-Cyclobutene- 1,2-dione (CAS 1312991-15-3), etc.), chiral guanidines (e.g., (2R,6R)-2,6-di-tert-butyl-2,3,5,6-tetrahydro-lH-imidazo[l,2-a]imidazole (CAS 1502026-83-6), etc.), and chiral phase transfer catalysts.

[0296] In some embodiments, the organocatalyst is a squaramide organocatalyst. In some embodiments, the organocatalyst is CAS 1256245-86-9.

[0297] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound III -4 from Compound III-5) comprises a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo(5.4.0)undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0298] In some embodiments, the base is a carbonate. In some embodiments, the base is cesium carbonate.

[0299] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound III -4 from Compound III-5) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), and halogenated solvents (e.g., dichloromethane).

[0300] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0301] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound III -4 from Compound III-5) comprises a temperature of about 0 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0302] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing Compound III -4 from Compound III-5) comprises an organocatalyst such as a squaramide organocatalyst (e.g., CAS 1256245-86-9), a base such as a carbonate (e.g., cesium carbonate), a solvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide), and a suitable temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Synthesis of Compound III via Erlenmeyer reaction

[0303] Also provided is the synthesis of Compound III or a salt thereof via Erlenmeyer reaction.

[0304] For example, Compound Illaor a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) subjecting Compound Va-Ior a salt thereof to a reductive carbonylation condi lion to form Compound V-4aor a salt thereof;(b) contacting Compound V-4a or a salt thereof with N-acetylglycine to form Compound III-7aor a salt thereof;(c) subjecting Compound III-7a or a salt thereof to a ring opening condi lion to form a compound of Formula III-8aAttorney Docket No.: 1583-US-NP / WO-PCTwherein R is a C1-4 alkyl,or a salt thereof;(d) subjecting a compound of Formula III-8a or a salt thereof to an asymmetric hydrogenation condilion to form a compound of Formula III-9awherein R is a C1-4 alkyl,or a salt thereof; and(e) converting a compound of Formula III-9a or a salt thereof to Compound Illa or a salt thereof.In some embodiments, R is methyl or ethyl. In some embodiments, R is ethyl.

[0305] In some embodiments, the process further comprises: (f) converting Compound Illaor a salt thereof to Compound IIIor a salt thereof according to a process described anywhere herein.

[0306] In some embodiments, the process comprises subjecting Compound Va-I or a salt thereof to a reductive carbonylal ion condition to form Compound V-4a or a salt thereof.

[0307] In some embodiments, R is a C1-4 alkyl. In some embodiments, R is methyl or ethyl.

[0308] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing form Compound V-4a from Compound Va-I) comprises a carbonylation source (e.g., carbon monoxide, molybdenum hexacarbonyl, etc.) and a hydride source (e.g., hydrogen gas, triethylsilane, sodium formate, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0309] In some embodiments, syngas (a mixture of carbon monoxide and hydrogen gas) serves as both carbonylation source and hydride source.

[0310] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing form Compound V-4a from Compound Va-I) comprises a base, such as an amine base (e.g., VM V) V'-Tclramclhylclhylcncdiaminc (TMEDA), triethylamine, N,N-diisopropylethylamine, tributylamine, tripropylamine, etc.).

[0311] In some embodiments, the base is A,A,A’,A’-Tetramethylethylenediamine (TMEDA).

[0312] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing Compound V-4a from Compound Va-I) comprises a catalyst such as a palladium catalyst. For example, the catalyst may be a palladium(II) source (e.g., palladium(II) acetate, palladium(II) chloride, etc.) or a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.).

[0313] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) acetate.

[0314] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing Compound V-4a from Compound Va-I) comprises a ligand, such as a monodentate or bidentate phosphine ligand. Suitable ligands include, but are not limited to, di(l-adamantyl)-n-butylphosphine (cataCXium A), l,l’-binaphthyl-2,2’-diphemyl phosphine (rac-BINAP), dicyclohexyl (2’,6’-dimethoxy [1,1’ -biphenyl] -2-yl)phosphine (SPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 2- (dicyclohexylphosphino)-3,6-dimethoxy-2’-4’-6’-tri-i-propyl-l,r-biphenyl (BrettPhos), 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)-biphenyl (DavePhos), P'Bm, and JosiPhos ligands.

[0315] In some embodiments, the ligand is di(l-adamantyl)-n-butylphosphine (cataCXium A).

[0316] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing Compound V-4a from Compound Va-I) comprises a drying agent such as a molecular sieve (e.g., 3 A molecular sieves).

[0317] In some embodiments, the reductive carbonylation condilion (e.g., the carbonylation condilion for providing Compound V-4a from Compound Va-I) comprises a solvent. Suitable solvents include, but are not limited to, aromatic solvents (e.g., toluene, xylene, etc.), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (acetonitrile, benzonitrile, etc.), and any combination thereof.

[0318] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of toluene and N,N-dimethylacetamide.Attorney Docket No.: 1583-US-NP / WO-PCT

[0319] In some embodiments, the reductive carbonylation condition (e.g., the carbonylation condition for providing Compound V-4a from Compound Va-I) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 75 °C to about 95 °C. In some embodiments, the temperature is about 85 °C.

[0320] In some embodiments, the reductive carbonylation condition (e.g., the carbonylation condition for providing Compound V-4a from Compound Va-I) comprises an elevated pressure. In some embodiments, the pressure is about 15 psig to about 200 psig. In some embodiments, the pressure is about 140 psig to about 160 psig. In some embodiments, the pressure is about 150 psig.

[0321] In some embodiments, the reductive carbonylation condition (e.g., the carbonylation condition for providing Compound V-4a from Compound Va-I) comprises a carbonylation source and a hydride source such as syngas, a catalyst such as a palladium (II) source (e.g., palladium(II) acetate), a ligand such as a monodentate or bidentate phosphine ligand (e.g., di(l-adamantyl)-n-butylphosphine (cataCXium A)), a drying agent such as a 3 A molecular sieve, a solvent such as a mixture of toluene and N,N-dimethylacetamide, a suitable temperature such as a temperature of about 75 °C to about 95 °C (e.g., about 85 °C), and an elevated pressure such as a pressure of about 140 psig to about 160 psig (e.g., about 150 psig).

[0322] In some embodiments, the process comprises contacting Compound V-4a or a salt thereof with N-acetylglycine to form Compound III-7a or a salt thereof.

[0323] In some embodiments, the reaction (e.g., the reaction for proving Compound III-7a from Compound V-4a) occurs in the presence of a base. Suitable base include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, etc.), phosphates (e.g., tripotassium phosphate, dipotassium phosphate, trisodium phosphate, trilithium phosphate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, etc.), and amines (e.g., triethylamine, N,N-diisopropylethylamine, tributylamine, tripropylamine, etc.).

[0324] In some embodiments, the base is a phosphate base. In some embodiments, the base is tripotassium phosphate.

[0325] In some embodiments, the reaction (e.g., the reaction for proving Compound III-7a from Compound V-4a) occurs in the presence of a solvent. The solvent may be acetic anhydride or a mixture of acetic anhydride and another solvent such as an ether (e.g., cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dibutyl ether, tert-butyl, methyl ether, tetrahydrofuran etc.), a nitrile (e.g., acetonitrile, etc.), apolar aprotic solvent (e.g., dimethylacetamide, N, N'-dimethylpropyleneurea, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide, etc.), or an aromatic solvent (e.g., toluene, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0326] In some embodiments, the solvent is acetic anhydride.

[0327] In some embodiments, the reaction (e.g., the reaction for proving Compound III-7a from Compound V-4a) occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 75 °C to about 95 °C. In some embodiments, the temperature is about 85 °C.

[0328] In some embodiments, the reaction (e.g., the reaction for proving Compound III-7a from Compound V-4a) occurs in the presence of a base such as a phosphate base (e.g., tripotassium phosphate), a solvent such as acelic anhydride, and at a suitable temperature such as a temperature of about 75 °C to about 95 °C (e.g., about 85 °C).

[0329] In some embodiments, the process comprises subjecting Compound III-7a or a salt thereof to a ring opening condition to form a compound of Formula III-8a.

[0330] In some embodiments, the ring opening condition (e.g., the condition for converting Compound III-7a to a compound of Formula III-8a) comprises a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, etc.), phosphates (e.g., tripotassium phosphate, trisodium phosphate, trilithium phosphate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), and acetates (e.g., sodium acetate, potassium acetate, lithium acetate, tetrabutylammonium acetate, etc.).

[0331] In some embodiments, the base is an acetate base. In some embodiments, the base is sodium acetate.

[0332] In some embodiments, the ring opening condition (e.g., the condition for converting Compound III-7a to a compound of Formula III-8a) comprises a solvent. The solvent may be ethanol or methanol. Additionally or alternatively, the solvent may be a mixture of (i) ethanol or methanol and (ii) another solvent such as an ether (e.g., cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dibutyl ether, tertbutyl methyl ether, tetrahydrofuran, etc.), a nitrile (e.g., acetonitrile, etc.), a polar aprotic solvent (e.g., dimethylacetamide, N, N'-dimethylpropyleneurea, l,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide, etc.), an aromatic solvent (e.g., toluene, etc.).

[0333] In some embodiments, the solvent is ethanol or methanol.

[0334] In some embodiments, the ring opening condition (e.g., the condition for converting Compound III-7a to a compound of Formula III-8a) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0335] In some embodiments, the ring opening condition (e.g., the condition for converting Compound III-7a to a compound of Formula III-8a) comprises a base such as an acetate base (e.g., sodium acetate), a solvent such as ethanol or methanol, and a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).

[0336] In some embodiments, the process comprises subjecting a compound of Formula III-8a or a salt thereof to an asymmetric hydrogenation condilion to form a compound of Formula III-9a or a salt thereof.

[0337] In some embodiments, the asymmetric hydrogenation condition (e.g., the condilion for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a catalyst.Suitable catalysts include, but are not limited to, rhodium(I) sources (e.g., bis( 1 ,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, bis( 1 ,5-cyclooctadiene)rhodium(I) tetrafluoroborate, tris(triphenylphosphine)rhodium(I) chloride, etc.), ruthenium(II) sources (e.g., bis(2-methylallyl) (l,5-cyclooctadiene)ruthenium(II), etc.), and nickel(II) sources (e.g., nickel(II) acetate tetrahydrate, etc.).

[0338] In some embodiments, the catalyst is a rhodium(I) source. In some embodiments, the catalyst is bis( 1 ,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate.

[0339] In some embodiments, the asymmetric hydrogenalion condition (e.g., the condilion for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a ligand, such as a chiral phosphine ligand. Suitable phosphine ligand ligands include, but are not limited to, (1R)-1-(diphenylphosphino)2-[(lR)-l-[(diphenylphosphino)methylamino]ethyl]ferrocene, 2,2’ -bis(diphenylphosphino)- 1 , 1 ’ -binaphthyl, and 1 ,2-bis[2,5-dimethylphospholano]benzene, 2,2’ -di-tert-butyl-2,3 ,2’ ,3 ’ -tetrahydro- 1 H, 1’ H-( 1 , 1’ jbiisophosphindolyl.

[0340] In some embodiments, the ligand is (lR)-l-(diphenylphosphino)2-[(lR)-l-[(diphenylphosphino)methylamino]ethyl]ferrocene.

[0341] In some embodiments, the asymmetric hydrogenalion condition (e.g., the condilion for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a hydrogen source. Suitable hydrogen sources include, but are not limited to, hydrogen gas, formic acid, sodium formate, and tetrabutylammonium formate.

[0342] In some embodiments, the hydrogen source is hydrogen gas.

[0343] In some embodiments, the asymmetric hydrogenalion condition (e.g., the condilion for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a solvent.Suitable solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), aromatic solvents (e.g., toluene, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and nitriles (e.g., acetonitrile, benzonitrile, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0344] In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol.

[0345] In some embodiments, the asymmetric hydrogenation condition (e.g., the condition for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 40 °C to about 60 °C. In some embodiments, the temperature is about 50 °C.

[0346] In some embodiments, the asymmetric hydrogenation condition (e.g., the condition for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a pressure of about 10 psig to about 100 psig. In some embodiments, the pressure is about 40 psig.

[0347] In some embodiments, the asymmetric hydrogenation condition (e.g., the condition for converting a Compound of Formula III-8a to a compound of Formula III-9a) comprises a catalyst such as a rhodium(I) source (e.g., bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate), a ligand such as a chiral phosphine ligand (e.g., (lR)-l-(diphenylphosphino)2-[(lR)-l-[(diphenylphosphino)methylamino]ethyl]ferrocene), a hydrogen source such as hydrogen gas, a solvent such as an alcohol solvent (e.g., methanol), a suitable temperature such as a temperature of about 40 °C to about 60 °C (e.g., about 50 °C), and a suitable pressure such as a pressure of about 40 psig.

[0348] In some embodiments, the process comprises converting a compound of Formula III-9a or a salt thereof to Compound Illa or a salt thereof.

[0349] In some embodiments, the reaction (e.g., the reaction for providing Compound Illa from a compound of Formula III-9a) occurs in the presence of an acid. Suitable acids include, but are not limited to, sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, etc.), mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), and carboxylic acids (e.g., acetic acid, pivalic acid, trifluoroacetic acid, etc.).

[0350] In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is methanesulfonic acid.

[0351] In some embodiments, the reaction (e.g., the reaction for providing Compound Illa from a compound of Formula III-9a) occurs in the presence of a solvent. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), and a combination of any of the foregoing with ethanol.

[0352] In some embodiments, the solvent is ethanol.

[0353] In some embodiments, the reaction (e.g., the reaction for providing Compound Illa from a compound of Formula III-9a) occurs at a temperature of about 30 °C to about 120 °C. In someAttorney Docket No.: 1583-US-NP / WO-PCT embodiments, the temperature is about 65 °C to about 85 °C. In some embodiments, the temperature is about 75 °C.

[0354] In some embodiments, the reaction (e.g., the reaction for providing Compound Illa from a compound of Formula III-9a) occurs in the presence of an acid such as a sulfonic acid (e.g., methanesulfonic acid), a solvent such as ethanol, and at a suitable temperature such as a temperature of about 65 °C to about 85 °C (e.g., about 75 °C).Synthesis of Compound HI via Heck reaction

[0355] Also provided is the synthesis of Compound III or a salt thereof via Heck reaction.

[0356] For example, Compound III-8awherein R is a Ci-4 alkyl, In some embodiments, R is methyl or ethyl. In some embodiments, R is ethyl. or a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) subjecting an alkyl serinate:wherein R is a Ci-4 alkyl,or a salt thereof to an acylation condition to form a compound of Formula IV-9wherein R is a Ci-4 alkyl,or a salt thereof;(b) subjecting a compound of Formula IV-9 or a salt thereof to a dehydration condi lion to form a compound of Formula IV- 10Attorney Docket No.: 1583-US-NP / WO-PCTwherein R is a C1-4 alkyl,or a salt thereof; and(c) contacting a compound of Formula IV-10 or a salt thereof with Compound Va-Ior a salt thereof to form Compound III-8a or a salt thereof.

[0357] In some embodiments, the process further comprises: (d) converting III-8awherein R is a C1-4 alkyl,or a salt thereof to Compound Illaor a salt thereof according to a process described anywhere herein.

[0358] In some embodiments, the process further comprises: (e) converting Compound Illaor a salt thereof to Compound IIIor a salt thereof according to a process described anywhere herein.Attorney Docket No.: 1583-US-NP / WO-PCT

[0359] In some embodiments, R is a C1-4 alkyl. In some embodiments, R is methyl or ethyl.

[0360] In some embodiments, the process comprises subjecting an alkyl serinate (e.g., methyl serinate) or a salt thereof to an acylation condition to form a compound of Formula IV-9 or a salt thereof.

[0361] In some embodiments, the acylalion condition (e.g., the condilion for providing a compound of Formula IV-9 from alkyl serinate) comprises an acyl source (e.g., an acetyl source) and an oplional coupling reagent. The acyl source may be acelic anhydride, acetyl chloride, or acelic acid; and the coupling reagent, when present, may be 1,1’ -carbonyldiimidazole.

[0362] In some embodiments, the acyl source is acetic anhydride.

[0363] In some embodiments, the acylalion condition (e.g., the condilion for providing a compound of Formula IV-9 from alkyl serinate) comprises a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0364] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0365] In some embodiments, the acylalion condition (e.g., the condilion for providing a compound of Formula IV-9 from alkyl serinate) comprises a catalyst. The catalyst can be a nucleophilic compound, such as a N-containing heterocycle. Suitable catalysts include, but are not limited to, 4-(dimethylamino)pyridine, 1 -methylimidazole, pyridine, and 4-methylpyridine.

[0366] In some embodiments, the catalyst is 4-(dimethylamino)pyridine.

[0367] In some embodiments, the acylation condition (e.g., the condition for providing a compound of Formula IV-9 from alkyl serinate) comprises a solvent. Suitable solvents include, but are not limited to, esters (e.g., ethyl acetate, isopropyl acetate, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (e.g., benzene, toluene, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.).

[0368] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane .

[0369] In some embodiments, the acylation condition (e.g., the condition for providing a compound of Formula IV-9 from alkyl serinate) comprises a temperature of about -20 °C to about 50 °C. In some embodiments, the temperature is about -5 °C to about 15 °C. In some embodiments, the temperature is about 5 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0370] In some embodiments, the acylation condition (e.g., the condition for providing a compound of Formula IV-9 from alkyl serinate) comprises an acyl source (e.g., an acetyl source) such as acetic anhydride, a base such as an amine base (e.g., triethylamine), a catalyst such as a N-containing heterocycle (4-(dimethylamino)pyridine), a solvent such as a halogenated solvent (e.g., dichloromethane), and a suitable temperature such a temperature of about -5 °C to about 15 °C (e.g., about 5 °C).

[0371] In some embodiments, the process comprises subjecting a compound of Formula IV-9 or a salt thereof to a dehydration condi lion to form compound of Formula IV- 10 or a salt thereof.

[0372] In some embodiments, the dehydration condition (e.g., the condition for providing a compound of Formula IV-10 from a compound of Formula IV-9) comprises a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, etc.), heterocyclic bases (e.g., pyridine), carbonates (e.g., sodium carbonate, lithium carbonate, potassium carbonate), acetates (e.g., lithium acetate, sodium acetate, potassium acetate, tetrabutylammonium acetate, etc.), phosphates such as phosphate tribasic (e.g., potassium phosphate tribasic, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), lithium bis(trimethylsilyl)amide, and hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.).

[0373] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0374] In some embodiments, the dehydration condition (e.g., the condition for providing a compound of Formula IV-10 from a compound of Formula IV-9) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), hydrocarbons (e.g., toluene, etc.), halogenated solvents (e.g., 1,2-dichloroethane, chlorobenzene, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), hydrocarbons (e.g., benzene, toluene, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.).

[0375] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0376] In some embodiments, the dehydration condition (e.g., the condition for providing a compound of Formula IV-10 from a compound of Formula IV-9) comprises a temperature of about -30 °C to about 120 °C. In some embodiments, the temperature is about 80 °C to about 100 °C. In some embodiments, the temperature is about 90 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0377] In some embodiments, the dehydration condition (e.g., the condition for providing a compound of Formula IV-10 from a compound of Formula IV-9) comprises a base such as an amine base (e.g., triethylamine), a solvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide), a suitable temperature such as a temperature of about 80 °C to about 100 °C (e.g., about 90 °C).

[0378] In some embodiments, the compound of Formula IV-10 or a salt thereof obtained from step (b) is subject to the next step (e.g., step (c)) without isolation and / or purification.

[0379] In some embodiments, the process comprises contacting a compound of Formula IV-10 or a salt thereof with Compound Va-I or a salt thereof to form a compound of Formula III-8a or a salt thereof.

[0380] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a catalyst such as a palladium catalyst. The palladium catalyst can be a palladium(II) source (e.g., palladium(II) acetate, palladium(II) chloride, etc.) or a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.).

[0381] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) acetate.

[0382] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a ligand. Suitable ligands include, but are not limited to, phosphine ligands (e.g., 2,2'-bis(diphenylphosphino)-l,T-binaphthyl, etc.) and N-heterocyclic carbene ligands (e.g., l,3-bis(l-adamantyl)imidazolium tetrafluoroborate, etc.).

[0383] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the absence of a ligand.

[0384] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., sodium carbonate, lithium carbonate, potassium carbonate, etc.), acetates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, tetrabutylammonium carbonate, etc.), phosphates such as phosphate tribasic (e.g., potassium phosphate tribasic, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), lithium bis(trimethylsilyl)amide, hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.), and amines (e.g., triethylamine, N,N-diisopropylethylamine, tributylamine, etc.).

[0385] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0386] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of an additive such as tetrabutylammonium salts (e.g., tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, etc.) or lithium salts (e.g., lithium iodide, lithium bromide, lithium chloride, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0387] In some embodiments, the additive is a tetrabutylammonium salt. In some embodiments, the additive is tetrabutylammonium chloride.

[0388] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), hydrocarbons (e.g., benzene, toluene, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, 2-butanol, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.).

[0389] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0390] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 80 °C to about 100 °C. In some embodiments, the temperature is about 90 °C.

[0391] In some embodiments, the reaction (e.g., the reaction between a compound of Formula IV-10 and Compound Va-I) occurs in the presence of a catalyst such as a palladium(II) source (e.g., palladium(II) acetate), a base such as an amine base (e.g., triethylamine), an additive such as a tetrabutylammonium salt (e.g., tetrabutylammonium chloride), a solvent such as apolar aprotic solvent (e.g., N,N-dimethylformamide), and a suitable temperature such as a temperature of about 80 °C to about 100 °C (e.g., about 90 °C).Synthesis of Compound III via asymmetric cyclization

[0392] Also provided is the synthesis of Compound III or a salt thereof via asymmetric cyclization.

[0393] For example, Compound IIIor a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) subjecting a compound of Formula X-lAttorney Docket No.: 1583-US-NP / WO-PCT wherein R is a C1-4 alkyl,or a salt thereof to an isocyanation condition to form a compound of Formula X-2wherein R is a C1-4 alkyl,or a salt thereof;(b) contacting a compound of Formula X-2 or a salt thereof with Compound VI- 1vi-1or a salt thereof to form a compound of Formula III- 10or a salt thereof;(c) subjecting Compound III- 10 or a salt thereof to a cyclization condition to form a compound of BocFormulawherein R is a C1-4 alkyl,or a salt thereof.

[0394] In some embodiments, R is a C1-4 alkyl. In some embodiments, R is methyl or ethyl.

[0395] In some embodiments, R is methyl and a compound of Formula III- 11 is Compound III-2BocI-2.Attorney Docket No.: 1583-US-NP / WO-PCT

[0396] In some embodiments, R is ethyl and a compound of Formula III- 11 is Compound III-3Boc

[0397] In some embodiments, the process further comprises: (d) converting Compound III-2Bocor a salt thereof to Compound IIIsalt thereof.

[0398] In some embodiments, the reaction (e.g., the reaction for providing Compound III from III-2) occurs in the presence of an acid. In some embodiments, the acid is a sulfonic acid (e.g., methanesulfonic acid).

[0399] In some embodiments, the reaction (e.g., the reaction for providing Compound III from III-2) occurs in the presence of a solvent. In some embodiments, the solvent is an alcohol (e.g., ethanol).

[0400] In some embodiments, the process comprises subjecting a compound of Formula X-l or a salt thereof to an isocyanation condition to form a compound of Formula X-2 or a salt thereof.

[0401] In some embodiments, the isocyanalion condition (e.g., the condilion for providing a compound of Formula X-2 from a compound of Formula X-l) comprises an isocyanation reagent, such as 1,1’-carbonyldiimidazole, phosgene, triphosgene, or carbon monoxide.

[0402] In some embodiments, the isocyanalion reagent is 1,1’ -carbonyldiimidazole.

[0403] In some embodiments, the isocyanalion condition (e.g., the condilion for providing a compound of Formula X-2 from a compound of Formula X-l) comprises a base. Suitable bases include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, triethylamine, tributylamine, 4-methylmorpholine, etc.), carbonates (e.g., sodium carbonate, lithium carbonate, potassium carbonate, etc.), acetates (e.g., lithium acetate, sodium acetate, potassium acetate, tetrabutylammonium acetate, etc.), phosphates such as phosphate tribasic (e.g., potassium phosphate tribasic, etc.), alkoxides (e.g., sodium methoxide, sodiumAttorney Docket No.: 1583-US-NP / WO-PCT tert-butoxide, potassium tert-butoxide, etc.), lithium bis(trimethylsilyl)amide, and hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.).

[0404] In some embodiments, the base is an amine base. In some embodiments, the base is N,N-diisopropylethylamine .

[0405] In some embodiments, the isocyanalion condition (e.g., the condilion for providing a compound of Formula X-2 from a compound of Formula X-l) comprises a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), hydrocarbons (e.g., benzene, toluene, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.).

[0406] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane.

[0407] In some embodiments, the isocyanalion condition (e.g., the condilion for providing a compound of Formula X-2 from a compound of Formula X-l) comprises a temperature of about -20 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0408] In some embodiments, the isocyanalion condition (e.g., the condilion for providing a compound of Formula X-2 from a compound of Formula X-l) comprises an isocyanalion reagent such as 1,1’-carbonyldiimidazole, a base such as an amine base (e.g., N,N-diisopropylethylamine), a solvent such as a halogenated solvent (e.g., dichloromethane), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0409] In some embodiments, the process comprises contacting a compound of Formula X-2 or a salt thereof with Compound VI- 1 or a salt thereof to form a compound of Formula III- 10 or a salt thereof.

[0410] In some embodiments, the reaction (e.g., the reaction between a compound of Formula X-2 and Compound VI-1) occurs in the presence of a base. Suitable bases include, but are not limited to, basic aromatic compounds (e.g., pyridine, etc.), amines (e.g., triethylamine, tributylamine, 4-methylmorpholine, etc.), carbonates (e.g., sodium carbonate, lithium carbonate, potassium carbonate, etc.), acetates (e.g., lithium acetate, sodium acetate, potassium acetate, tetrabutylammonium acetate, etc.), phosphates such as phosphate tribasic (e.g., potassium phosphate tribasic, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), lithium bis(trimethylsilyl)amide, and hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.).

[0411] In some embodiments, the base is a basic aromatic compound. In some embodiments, the base is pyridine.Attorney Docket No.: 1583-US-NP / WO-PCT

[0412] In some embodiments, the reaction (e.g., the reaction between a compound of Formula X-2 and Compound VI-1) occurs in the presence of a solvent. The solvent may be a polar aprotic solvent (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), an ether solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), a nitrile solvent (e.g., acetonitrile, benzonitrile, etc.), or a hydrocarbon solvent (e.g., benzene, toluene, etc.). In some embodiments, pyridine (e.g., the pyridine base) is used as a solvent.

[0413] In some embodiments, the reaction (e.g., the reaction between a compound of Formula X-2 and Compound VI- 1) occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 90 °C to about 110 °C. In some embodiments, the temperature is about 100 °C.

[0414] In some embodiments, the reaction (e.g., the reaction between a compound of Formula X-2 and Compound VI-1) occurs in the presence of a base such as a basic aromatic compound (e.g., pyridine), a solvent (e.g., pyridine), and at a suitable temperature such as a temperature of about 90 °C to about 110 °C (e.g., about 100 °C).

[0415] In some embodiments, the process comprises subjecting a compound of Formula III- 10 or a salt thereof to a cyclization condi lion to form a compound of Formula III- 11 or a salt thereof.

[0416] In some embodiments, the cyclization condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a catalyst such as a palladium catalyst. The palladium catalyst can be a palladium(II) source (e.g., allyl(cyclopentadienyl)palladium(II), palladium(II) chloride, etc.) or a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.).

[0417] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is allyl (cyclopentadienyl)palladium(II) .

[0418] In some embodiments, the cyclization condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a ligand. Suitable ligands include, but are not limited to, chiral phosphine ligands such as Josiphos ligands or 2,2’-p-tolylphosphino-l,r-binaphthyl.

[0419] In some embodiments, the ligand is Josiphos ligand. In some embodiments, the ligand is Josiphos ligand SL-J013-1 (CAS 187733-50-2).

[0420] In some embodiments, the cyclization condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a base. Suitable bases include, but are not limited to, amines (e.g., diisopropylethylamine, triethylamine, tripropylamine, tributylamine, etc.), carbonates (e.g., sodium carbonate, lithium carbonate, potassium carbonate, etc.), phosphates such as phosphate tribasic (e.g., potassium phosphate tribasic, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), lithium bis(trimethylsilyl)amide, and hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0421] In some embodiments, the base is an amine base. In some embodiments, the base is diisopropylethylamine .

[0422] In some embodiments, the cyclizalion condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a carbonyl source such as carbon monoxide.

[0423] In some embodiments, the cyclizalion condition (e.g., the condition for providing a compound of Formula III-ll from a compound of Formula III-10) comprises a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and hydrocarbons (e.g., benzene, toluene, etc.).

[0424] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0425] In some embodiments, the cyclizalion condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 60 °C to about 80 °C. In some embodiments, the temperature is about 70 °C.

[0426] In some embodiments, the cyclizalion condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a pressure of about 15 psig to about 500 psig. In some embodiments, the pressure is about 450 psig.

[0427] In some embodiments, the cyclizalion condition (e.g., the condition for providing a compound of Formula III- 11 from a compound of Formula III- 10) comprises a catalyst such as a palladium(II) source (e.g., allyl(cyclopentadienyl)palladium(II)), a ligand such as a Josiphos ligand (e.g., Josiphos ligand SL-J013-1), a base such as an amine base (e.g., diisopropylethylamine), a solvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide), a suitable temperature such as a temperature of about 60 °C to about 80 °C (e.g., about 70 °C), and a suitable pressure such as about 450 psig.Synthesis of a compound of Formula V or VaSynthesis of a compound of Formula VaCyclization Route A

[0428] A compound of Formula Va or a salt thereof may be prepared via a cyclization reaction.

[0429] In some embodiments, provided is a process for preparing a compound of Formula VaAttorney Docket No.: 1583-US-NP / WO-PCTwherein X is Br or I,or a salt thereof, comprising:(a a) contacting Compound VICO2MeCO2H yjor a salt thereof with a compound of Formula VIIwherein X is Br or I,or a salt thereof in the presence of an azide source or a deoxo-fluor to form a compound of Formula V-3wherein X is Br or I,or a salt thereof;(b) subjecting the compound of Formula V-3 or a salt thereof into a cyclization condi lion to provide a compound of Formula V-lwherein X is Br or I,or a salt thereof; and(c) contacting the compound of Formula V-l or a salt thereof with a methylation agent to form the compound of Formula Va.

[0430] In some embodiments, the process comprises contacting Compound VI or a salt thereof with a compound of Formula VII or a salt thereof in the presence of an azide source or a deoxo-fluor to form a compound of Formula V-3 or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0431] In some embodiments, the reaction between Compound VI or a salt thereof and a compound of Formula VII or a salt thereof occurs in the presence of an azide source. Suitable azide source include, but are not limited to, diphenylphosphoryl azide (DPP A), trimethylsilyl azide, sodium azide, lithium azide, carboxybenzenesulfonazide, and acetamidobenenesulfonyl.

[0432] In some embodiments, the azide source is diphenylphosphoryl azide (DPP A).

[0433] In some embodiments, the reaction between Compound VI or a salt thereof and a compound of Formula VII or a salt thereof occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., A,A-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,4-diazabicylo[2.2.2]-octane, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,64utidine, imidazole, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0434] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0435] In some embodiments, the reaction between Compound VI or a salt thereof and a compound of Formula VII or a salt thereof occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, toluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, trifluorotoluene, etc.).

[0436] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is trifluorotoluene.

[0437] In some embodiments, the reaction between Compound VI or a salt thereof and a compound of Formula VII or a salt thereof occurs at a temperature of about -10 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0438] In some embodiments, the reaction between Compound VI or a salt thereof and a compound of Formula VII or a salt thereof occurs in the presence of an azide source (e.g., diphenylphosphoryl azide (DPP A)), a base such as an amine base (e.g., triethylamine), a solvent such as a halogenated solvent (e.g., trifluorotoluene), and at a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).

[0439] In some embodiments, the process comprises subjecting the compound of Formula V-3 or a salt thereof into a cyclization condition to provide a compound of Formula V-l or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0440] In some embodiments, the cyclization condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-3) comprise a base. Suitable bases include, but are not limited to, amines (e.g., MA iisopmpylclhylaininc, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0441] In some embodiments, the base is an amine base. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0442] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-3) comprise a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., V,V-dimethylformamide, W-diinclliylacclamidc, dimethyl sulfoxide, V-inclhyl-2-pyrrolidone, etc.), nitriles (e.g., acetonitrile, etc.), and halogenated solvents (e.g., dichloromethane, etc.).

[0443] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is V-methyl-2-pyrrolidone.

[0444] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-3) comprises a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0445] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-3) comprises a base such as an amine base (e.g., l,8-diazabicyclo[5.4.0]undec-7-ene), a solvent such as a polar aprotic solvent (e.g., V-inclhyl-2-pyrrolidone), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0446] In some embodiments, the methylation agent (e.g., the methylation agent used to provide a compound of Formula Va from a compound of Formula V-l) includes, but is not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, and dimethyl carbonate.

[0447] In some embodiments, the methylation agent is methyl iodide.

[0448] In some embodiments, the methylation reaction (e.g., the methylation reaction of a compound of Formula V-l) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., VV-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-Attorney Docket No.: 1583-US-NP / WO-PCT diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0449] In some embodiments, the base is an amine base. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0450] In some embodiments, the methylation reaction (e.g., the methylation reaction of a compound of Formula V-l) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, A miclhylacclamide, dimethyl sulfoxide, iV-methyl-2-pyrrolidone, etc.), nitriles (e.g., acetonitrile, etc.), and halogenated solvents (e.g., dichloromethane, etc.).

[0451] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is iV-methyl-2-pyrrolidone.

[0452] In some embodiments, the melhylalion reaction (e.g., the methylation reaction of a compound of Formula V-l) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0453] In some embodiments, the melhylalion reaction (e.g., the methylation reaction of a compound of Formula V-l with a methylation agent such as methyl iodide ) occurs in the presence of a base such as an amine base (e.g., l,8-diazabicyclo[5.4.0]undec-7-ene), a solvent such as an polar aprotic solvent (e.g., N-methyl-2-pyrrolidone), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0454] In some embodiments, the compound of Formula V-l (e.g., the product obtained from step (b)) or a salt thereof is subject to the methylation reaction (step (c)) without isolation.

[0455] In some embodiments, X is Br. In some embodiments, X is I.

[0456] In some embodiments, Compound VI or a salt thereof is prepared from pyridine-3,4-dicarboxylic acid through an anhydride intermediate that is furo[3,4-c]pyridine-l, 3-dione.[0 a457] In some embodiments, provided is a process for preparing Compound VICO2MeCO2H yjor a salt thereof, comprising(a) convening pyridine-3,4-dicarboxylic acid into an anhydride intermediate that is furo[3,4-c]pyridine-1, 3-dione; andAttorney Docket No.: 1583-US-NP / WO-PCT (b) subjecting the anhydride intermediate into a ring opening condition to form Compound VI or a salt thereof.

[0458] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the presence of an anhydride forming reagent. Suitable anhydride forming reagents include, but are not limited to acetic anhydride, di -tert-butyl dicarbonate, oxalyl chloride, 1,1’-carbonyldiimidazole, oxalyl chloride, phosgene, triphosgene, alkyl chloroformates (e.g., ethyl chloroformate, isobutyl chloroformate, etc.), carbodiimides (e.g., dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide), propanephosphonic acid anhydride (T3P), and peptide coupling reagents (e.g., HATU, HBTU, TATU, TBTU, HCTU, BOP, PyBOP, COMU, etc.).

[0459] In some embodiments, the anhydride forming reagent is acetic anhydride.

[0460] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the presence of a catalyst. Suitable catalysts include but are not limited to magnesium salts (e.g., magnesium iodide, magnesium bromide, magnesium chloride, etc.).

[0461] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the absence of a catalyst.

[0462] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the presence of a solvent. Suitable solvents include, but are not limited to, halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, chloroform, etc.), and ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.).

[0463] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the absence of a solvent.

[0464] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 95 °C to about 115 °C. In some embodiments, the temperature is about 105 °C.

[0465] In some embodiments, the conversion of pyridine-3,4-dicarboxylic acid to the anhydride intermediate occurs in the presence of a suitable reagent such as acetic anhydride, and at a suitable temperature such as a temperature of about 95 °C to about 115 °C (e.g., about 105 °C).

[0466] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) comprises a ring opening reagent. Suitable ring opening reagents include, but are not limited to, acetyl chloride, reagents capable of generating acids in situ (chlorosilanes such as trimethylsilyl chloride and methanol), and acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0467] In some embodiments, the ring opening reagent is acetyl chloride.

[0468] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) comprises a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), and amines (e.g., triethylamine, V,V-diisopropylethylamine, etc.).

[0469] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) does not comprise a base.

[0470] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) comprises a solvent. Suitable solvents include, but are not limited to, water, methanol, and a combi nal ion thereof.

[0471] In some embodiments, the solvent is methanol.

[0472] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) comprises a temperature of about -10 °C to about 80 °C. In some embodiments, the temperature is about 0 °C to about 20 °C. In some embodiments, the temperature is about 10 °C.

[0473] In some embodiments, the ring opening condition (e.g., the ring opening condition for proving a salt of Compound VI) comprises a ring opening reagent (e.g., acetyl chloride), a solvent (e.g., methanol), and a suitable temperature such as a temperature of about 0 °C to about 20 °C (e.g., about 10 °C).

[0474] In some embodiments, the ring opening reaction (step (b)) provides a salt of Compound VI. In some embodiments, the ring opening reaction (step (b)) provides Compound VI HC1 salt.

[0475] In some embodiments, the process further comprises free basing the salt of Compound VI (e.g., the salt of Compound VI obtained from the ring opening reaction (step (b)). In some embodiments, the salt of Compound VI (e.g., the salt of Compound VI obtained from the ring opening reaction (step (b)) is Compound VI HC1 salt.

[0476] In some embodiments, the free basing step (e.g., free basing the salt of Compound VI) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, l,4-diazabicylo[2.2.2]-octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.), phosphates (e.g., sodium phosphate, dipotassium hydrogen phosphate, disodium phosphate, potassium phosphate, cesium phosphate, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), and hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.).Attorney Docket No.: 1583-US-NP / WO-PCT

[0477] In some embodiments, the base is a phosphate. In some embodiments, the base is dipotassium hydrogen phosphate.

[0478] In some embodiments, the free basing step (e.g., free basing the salt of Compound VI) occurs in the presence of a solvent. In some embodiments, the solvent is water. In some embodiments, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), nitriles (e.g., acetonitrile), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and a combination of any of the foregoing with water.

[0479] In some embodiments, the solvent is water.

[0480] In some embodiments, the free basing step (e.g., free basing the salt of Compound VI) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0481] In some embodiments, the free basing step (e.g., free basing the salt of Compound VI) occurs in the presence of a base such as a phosphate (e.g., dipotassium hydrogen phosphate), a solvent such as water, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0482] In some embodiments, the compound of Formula VII can be prepared by contacting quinolin- 8-amine with an iodi nalion agent or a bromination agent.

[0483] In some embodiments, X is iodo, and the compound of Formula VII is Compound VII-I

[0484] In some embodiments, provided is a process for preparing Compound VII-Ior a salt thereof, comprising contacting quinolin- 8 -amine with an iodination agent to form Compound VII-I or a salt thereof.

[0485] Suitable iodination agents (e.g., iodi nalion agents for proving Compound VII-I) include, but are not limited to, iodide, N-iodosuccinimide, iodine monochloride, and l,3-diiodo-5,5-dimethylhydantoin.

[0486] In some embodiments, the iodination agent is iodine.

[0487] In some embodiments, the reaction between quinolin-8-amine with an iodination agent occurs in the presence of an additive such as tert-butyl hydroperoxide in water.Attorney Docket No.: 1583-US-NP / WO-PCT

[0488] In some embodiments, the reaction between quinolin-8-amine with an iodination agent occurs in the presence of a solvent. Suitable solvents include, but are not limited to, pyridine, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, etc.), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), and nitriles (e.g., acetonitrile, etc.), and any combination thereof.

[0489] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and pyridine.

[0490] In some embodiments, the reaction between quinolin-8-amine and an iodination agent occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 15 °C to about 35 °C. In some embodiments, the temperature is about 25 °C.

[0491] In some embodiments, the reaction between quinolin- 8 -amine with an iodination agent (e.g., iodine) occurs in the presence of an additive (e.g., tert-butyl hydroperoxide in water), a solvent (e.g., a mixture of isopropyl acetate and pyridine), and at a suitable temperature such as a temperature of about 15 °C to about 35 °C (e.g., about 25 °C).Cyclization Route B

[0492] Additionally or alternatively, Compound Va-Bror a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) coupling isonicotinic acid or a salt thereof with Compound VII-Bror a salt thereof in the presence of a coupling agent to form Compound XIor a salt thereof;(b) converting Compound XI or a salt thereof to Compound V-la-BrAttorney Docket No.: 1583-US-NP / WO-PCTla-Bror a salt thereof;(c) contacting Compound V-la-Br or a salt thereof with a methylation agent to form Compound Va-Br or a salt thereof.

[0493] In some embodiments, the process comprises coupling isonicotinic acid or a salt thereof with Compound VII-Br or a salt thereof in the presence of a coupling agent to form Compound XI or a salt thereof.

[0494] In some embodiments, the coupling agent (e.g., coupling agents used to provide Compound XI from isonicotinic acid and Compound VII-Br) include, but are not limited to, acid halide forming agents (e.g., thionyl chloride, oxalyl chloride, phosgene, triphosgene, etc.), 1,1’ -carbonyldiimidazole (CDI), alkyl chloroformates (e.g., ethyl chloroformate, isobutyl chloroformate, etc.), carbodiimides (e.g., N,N’-dicyclohexylcarbodiimide (DCC), V,V’-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), etc.), propanephosphonic acid anhydride (T3P), and peptide coupling reagents (e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), 2-(3h-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(lH-benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-ifi-Chlorobcnzolriazol- 1 -yl)-WN', V-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), [[(Z)-(l-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium hexafluorophosphate (COMU), etc.).

[0495] In some embodiments, the coupling agent is an acid halide forming agent. In some embodiments, the coupling agent is oxalyl chloride.

[0496] In some embodiments, the coupling agent is an acid halide forming agent (e.g., oxalyl chloride), and isonicolinic acid is converted to isonicotinoyl chloride by the coupling agent prior to reacting with Compound VII-Br.

[0497] In some embodiments, the reaction (e.g., the reaction for providing Compound XI from isonicotinic acid and Compound VII-Br) occurs in the presence of a catalyst. Suitable catalysts include, but are not limited to, amides (e.g., N,N-dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, etc.), 4-(dimethylamino)pyridine, 1 -hydroxybenzotriazole (HOBt), and l-hydroxy-7-azabenzotriazole (HO At).Attorney Docket No.: 1583-US-NP / WO-PCT

[0498] In some embodiments, the catalyst is an amine catalyst. In some embodiments, the catalyst is N,N-dimethylformamide.

[0499] In some embodiments, the reaction (e.g., the reaction for providing Compound XI from isonicotinic acid and Compound VII-Br) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, triethylamine, tripropylamine, Iribulylamine, 4-methylmorpholine, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0500] In some embodiments, the base is an amine base. In some embodiments, the base is N,N-diisopropylethylamine .

[0501] In some embodiments, the reaction (e.g., the reaction for providing Compound XI from isonicotinic acid and Compound VII-Br) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, esters (e.g. ethyl acetate, isopropyl acetate, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (e.g., benzene, toluene, n-heptane, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.).

[0502] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane.

[0503] In some embodiments, the reaction (e.g., the reaction for providing Compound XI from isonicotinic acid and Compound VII-Br) occurs at a temperature of about -15 °C to about 80 °C. In some embodiments, the temperature is about 5 °C to about 25 °C. In some embodiments, the temperature is about 15 °C.

[0504] In some embodiments, the reaction (e.g., the reaction for providing Compound XI from isonicotinic acid and Compound VII-Br) occurs in the presence of a coupling agent such as an acid halide forming agent (e.g., oxalyl chloride), a catalyst such as an amine catalyst (e.g., N,N-dimethylformamide), a base such as an amine base (N,N-diisopropylethylamine), a solvent such as a halogenated solvent (e.g., dichloromethane), and at a suitable temperature such as a temperature of about 5 °C to about 25 °C (e.g., about 15 °C).

[0505] In some embodiments, the reaction provides Compound XI. In some embodiments, the reaction provides a salt of Compound XI (e.g., a HC1 salt of Compound XI).

[0506] In some embodiments, the process comprises converting Compound XI or a salt thereof to Compound V-la-Br or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0507] The reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) may occur in the presence of a catalyst. The catalyst may be a copper catalyst such as copper(II) acetate (e.g., copper(II) acetate monohydrate, anhydrous copper(II) acetate, etc.), copper(II) chloride, or copper(II) bromide.

[0508] In some embodiments, the catalyst is copper(II) acetate monohydrate.

[0509] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs in the presence of a cyanate. The cyanate may be sodium cyanate, potassium cyanate, or silver cyanate.

[0510] In some embodiments, the cyanate is potassium cyanate.

[0511] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., potassium carbonate, sodium carbonate, lithium carbonate, etc.), acetates (e.g., potassium acetate, sodium acetate, lithium acetate, etc.), and propionates (e.g., potassium propionate, lithium propionate, etc.).

[0512] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs in the absence of a base.

[0513] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs in the presence of a solvent. The solvent may be a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide.

[0514] In some embodiments, the solvent is N,N-dimethylformamide.

[0515] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 70 °C to about 90 °C. In some embodiments, the temperature is about 80 °C.

[0516] In some embodiments, the reaction (e.g., the reaction for proving Compound V-la-Br from Compound XI) occurs in the presence of a catalyst such as a copper catalyst (e.g., copper(II) acetate monohydrate), a cyanate such as potassium cyanate, a solvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide), and at a suitable temperature such as a temperature of about 70 °C to about 90 °C (e.g., about 80 °C).

[0517] In some embodiments, the process comprises contacting Compound V-la-Br or a salt thereof with a methylation agent to form Compound Va-Br or a salt thereof.

[0518] Suitable methylation agents (e.g., methylation agents for providing Compound Va-Br from Compound V-la-Br) include, but are not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, and dimethyl carbonate.Attorney Docket No.: 1583-US-NP / WO-PCT

[0519] In some embodiments, the methylation agent is methyl iodide.

[0520] In some embodiments, the reaction (e.g., the reaction for providing Compound Va-Br from Compound V-la-Br) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0521] In some embodiments, the base is an amine base. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0522] In some embodiments, the reaction (e.g., the reaction for providing Compound Va-Br from Compound V-la-Br) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), and halogenated solvents (e.g., dichloromethane, etc.).

[0523] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0524] In some embodiments, the reaction (e.g., the reaction for providing Compound Va-Br from Compound V-la-Br) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0525] In some embodiments, the reaction (e.g., the reaction for providing Compound Va-Br from Compound V-la-Br) occurs in the presence of a methylation agent such as methyl iodide, a base such as an amine base (e.g., l,8-diazabicyclo[5.4.0]undec-7-ene), a solvent such as a polar aprotic solvent (e.g., N-methyl-2-pyrrolidone), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0526] The process may further comprise free basing a salt of Compound XI (e.g., a HC1 salt of Compound XI) prior to subjecting to the next step (e.g., prior to converting to Compound V-la-Br).

[0527] The free basing step (e.g., free basing a salt such as a HC1 salt of Compound XI) can be performed in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, l,4-diazabicylo[2.2.2]-octane, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.), phosphates (e.g., sodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, cesium phosphate, etc.), basicAttorney Docket No.: 1583-US-NP / WO-PCT aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), and hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.).

[0528] In some embodiments, the base is a bicarbonate. In some embodiments, the base is potassium bicarbonate.

[0529] In some embodiments, the free basing step (e.g., free basing a salt such as a HC1 salt of Compound XI) is performed in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., 1,2-dichloroethane, chlorobenzene, etc.) or a combinate of any of the foregoing with water.

[0530] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of dichloromethane and water.

[0531] In some embodiments, the free basing step (e.g., free basing a salt such as a HC1 salt of Compound XI) is performed at a temperature of about 0 °C to about 120 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0532] In some embodiments, the free basing step (e.g., free basing a salt such as a HC1 salt of Compound XI) is performed in the presence of a base such as a bicarbonate (e.g., potassium bicarbonate), a solvent such as a mixture of dichloromethane and water, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Synthesis of a compound of Formula V

[0533] Also provided is the synthesis of a compound of Formula V (including Compound V-I and Compound V-Br) or a salt thereof.

[0534] A compound of Formula V-l or a salt thereof may be prepared via an asymmetric cyclization reaction.Asymmetric Cyclization Route A

[0535] For example, in some embodiments, provided is a process for preparing a compound of Formula V-lwherein R is a C1-3 alkyl and X is Br or I,or a salt thereof, comprising:Attorney Docket No.: 1583-US-NP / WO-PCT subjecting a compound of Formula V-2wherein R is a C1-3 alkyl and X is Br or I,or a salt thereof into a cyclization condition to form a compound of Formula V-l or a salt thereof.

[0536] In some embodiments, R is methyl, ethyl, or isopropyl. In some embodiments, X is Br or I.

[0537] In some embodiments, R is methyl and X is I.

[0538] In some embodiments, R is methyl and X is Br.

[0539] In some embodiments, R is ethyl and X is I.

[0540] In some embodiments, R is ethyl and X is Br.

[0541] In some embodiments, R is isopropyl and X is I.

[0542] In some embodiments, R is isopropyl and X is Br.

[0543] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-2) comprises an organocatalyst. Suitable organocatalysts include, but are not limited to, squaramides (e.g., 3-[ [3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(8a,9S)-6’-methoxycinchonan-9-yl]amino]-3-cyclobutene-l,2-dione (CAS 1256245-84-7), 3-[[3,5-bis(trifhioroMethyl)phenyl]amino]-4-[(8a,9S)-cinchonan-9-ylamino]-3-cyclobutene- 1,2-dione (CAS 1256245-86-9), 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[[(8a, 9S)-10,ll-dihydrocinchonan9-yl]amino]-3-cyclobutene-l, 2-dione (CAS 1407166-62-4), 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((lS,2S)-l,2-diphenyl-2-(piperidin-l-yl)ethyl)amino)cyclobut-3-ene-1, 2-dione (CAS 1943732-17-9), 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[[(lS,2S)-2-(l-piperidinyl)cyclohexyl]amino]-3-cyclobutene- 1,2-dione (CAS 1312991-15-3), etc.), chiral guanidines (e.g., (2R,6R)-2,6-di-tert-butyl-2,3,5,6-tetrahydro-lH-imidazo[l,2-a]imidazole (CAS 1502026-83-6), etc.), and chiral phase transfer catalysts.

[0544] In some embodiments, the organocatalyst is a squaramide organocatalyst. In some embodiments, the organocatalyst is CAS 1256245-84-7.

[0545] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-2) comprises a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-Attorney Docket No.: 1583-US-NP / WO-PCT diazabicyclo(5.4.0)undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0546] In some embodiments, the base is a carbonate or an amine base. In some embodiments, the base is potassium carbonate or l,8-diazabicyclo(5.4.0)undec-7-ene.

[0547] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-2) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), and halogenated solvents (e.g., dichloromethane).

[0548] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0549] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-2) comprises a temperature of about 0 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0550] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l from a compound of Formula V-2) comprises an organocatalyst such as a squaramide organocatalyst (e.g., CAS 1256245-84-7), a base such as a carbonate (e.g., cesium carbonate) or an amine base (e.g., l,8-diazabicyclo(5.4.0)undec-7-ene), a solvent such as a polar aprotic solvent (e.g., N-methyl-2-pyrrolidone), and a suitable temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0551] Additionally or alternatively, a compound of Formula V-l-Br may be prepared by a process comprising one or more or all of the following steps:(a) subjecting a compound of Formula V-2-Brwherein R is (+)-menthyl or (-)-l -phenylethyl,or a salt thereof into a cyclization condition to form Compound V-l-BrAttorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof.

[0552] In some embodiments, R is (+)-menthyl. In some embodiments, R is (-)-l -phenylethyl.

[0553] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) comprises an organocatalyst. Suitable organocatalysts include, but are not limited to, squaramides (e.g., 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(8a,9S)-6’-methoxycinchonan-9-yl]amino]- 3 -cyclobutene- 1,2-dione (CAS 1256245-84-7), 3-[[3,5-bis(trifhioromethyl)phenyl]amino]-4-[[(8a,9S)-10,ll-dihydrocinchonan9-yl] amino] -3 -cyclobutene- 1,2-dione (CAS 1407166-62-4), 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((lS,2S)-l,2-diphenyl-2-(piperidin-l-yl)ethyl)amino)cyclobut-3-ene-1, 2-dione (CAS 1943732-17-9), 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(lS,2S)-2-(l-piperidinyl)cyclohexyl]amino]-3-cyclobutene-l, 2-dione (CAS 1312991-15-3), etc.), chiral guanidines (e.g., (2R,6R)-2,6-di-tert-butyl-2,3,5,6-tetrahydro-lH-imidazo[l,2-a]imidazole (CAS 1502026-83-6), etc.), and chiral phase transfer catalysts.

[0554] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) does not comprise an organocatalyst.

[0555] In some embodiments, the cyclization condition (e.g., the cyclizalion condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) comprises abase. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0556] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate.

[0557] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide,Attorney Docket No.: 1583-US-NP / WO-PCT dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, etc.), aromatics (e.g., benzene, toluene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.).

[0558] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0559] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) comprises a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0560] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula V-l-Br from a compound of Formula V-2-Br) comprises a base such as a carbonate (e.g., potassium carbonate), a solvent such as a polar aprotic solvents (e.g., N-methyl-2-pyrrolidone), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0561] In some embodiments, the process further comprises converting a compound of Formula V-l or a salt thereof to a compound of Formula V or a salt thereof according to a process described anywhere herein.

[0562] For example, the process may comprise contacting a compound of Formula V-lwherein X is Br or I,or a salt thereof with a methylation agent to form a compound of Formula Vwherein X is Br or I,or a salt thereof.

[0563] In some embodiments, X is Br. In some embodiments, X is I.

[0564] Suitable methylation agents (e.g., the methylation agent for providing a compound of Formula V from a compound of Formula V-l) include, but are not limited to, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, and dimethyl carbonate.

[0565] In some embodiments, the melhylalion agent is methyl iodide.Attorney Docket No.: 1583-US-NP / WO-PCT

[0566] In some embodiments, the reaction (e.g., the reaction for proving a compound of Formula V from a compound of Formula V-l) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene, etc.), aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0567] In some embodiments, the base is an amine base. In some embodiments, the base is 1,8-diazabicyclo(5.4.0)undec-7-ene.

[0568] In some embodiments, the reaction (e.g., the reaction for proving a compound of Formula V from a compound of Formula V-l) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, etc.).

[0569] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0570] In some embodiments, the reaction (e.g., the reaction for proving a compound of Formula V from a compound of Formula V-l) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0571] In some embodiments, the reaction (e.g., the reaction for proving a compound of Formula V from a compound of Formula V-l) occurs in the presence of a methylation agent such as methyl iodide, a base such as an amine base (e.g., l,8-diazabicyclo(5.4.0)undec-7-ene), a solvent such as a polar aprotic solvents (e.g., N-methyl-2-pyrrolidone), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0572] In some embodiments, a compound of Formula V-2 is a compound of Formula V-2-Brwherein R is (+) -menthyl, (-)-l -phenylethyl, or a C1-3 alkyl.

[0573] In some embodiments, provided is a process for preparing a compound of Formula V-2-BrAttorney Docket No.: 1583-US-NP / WO-PCTwherein R is (+) -menthyl, (-)-l -phenylethyl, or a C1-3 alkyl,or a salt thereof, comprising:(a) subjecting Compound VI-2or a salt thereof to a cyclization condition to form Compound VI-3or a salt thereof;(b) contacting Compound VI-3 or a salt thereof with an alcohol to form a compound of Formula VI-4vi-4wherein R is (+)-menthyl, (-)-l -phenylethyl, or a C1-3 alkyl,or a salt thereof;(c) contacting a compound of Formula VI-4 or a salt thereof with phenyl chloroformate to form a compound of Formula VI-5wherein R is (+)-menthyl, (-)-l -phenylethyl, or a C1-3 alkyl,or a salt thereof; and(d) contacting a compound of Formula VI-5 or a salt thereof with Compound VII-Bror a salt thereof to form a compound of Formula V-2-Br or a salt thereof.

[0574] In some embodiments, R is (+)-menthyl or (-)-l -phenylethyl. In some embodiments, R is (+)-menthyl. In some embodiments, R is (-)-l -phenylethyl.Attorney Docket No.: 1583-US-NP / WO-PCT

[0575] In some embodiments, R is a C1-3 alkyl. In some embodiments, R is ethyl. In some embodiments, R is isopropyl.

[0576] In some embodiments, the process comprises subjecting Compound VI-2 or a salt thereof to a cyclization condition to form Compound VI-3 or a salt thereof.

[0577] The cyclization condition (e.g., the cyclization condition for providing Compound VI-3 from Compound VI-2) may comprise a carbonyl (or thionyl) source such as 1,1’ -carbonyldiimidazole, carbon monoxide, phosgene, triphosgene, or thionyl chloride.

[0578] In some embodiments, the carbonyl source is 1,1’ -carbonyldiimidazole.

[0579] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound VI-3 from Compound VI-2) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, toluene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.).

[0580] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.

[0581] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound VI-3 from Compound VI-2) comprises a temperature of about 0 °C to about 50 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0582] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing Compound VI-3 from Compound VI-2) comprises a carbonyl (or thionyl) source such as 1,1’-carbonyldiimidazole, a solvent such as an ether solver (e.g., tetrahydrofuran), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0583] In some embodiments, the process comprises contacting Compound VI-3 or a salt thereof with an alcohol to form Compound VI-4 or a salt thereof.

[0584] The alcohol (e.g., the alcohol for providing Compound VI-4 from Compound VI-3) may be a chiral alcohol that is optically pure, such as (+)-menthol or (-)-l -phenylethanol. Additionally or allernali vely, the alcohol may be ethanol or isopropanol.

[0585] In some embodiments, the reaction (e.g., the reaction for providing Compound VI-4 from Compound VI-3) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g.,Attorney Docket No.: 1583-US-NP / WO-PCT dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.).

[0586] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.

[0587] In some embodiments, the reaction (e.g., the reaction for providing Compound VI-4 from Compound VI-3) occurs at a temperature of about 10 °C to about 100 °C. In some embodiments, the temperature is about 40 °C to about 60 °C. In some embodiments, the temperature is about 50 °C.

[0588] In some embodiments, the reaction (e.g., the reaction for providing Compound VI-4 from Compound VI-3) occurs in the presence of an alcohol (e.g., (+)-menthol, (-)-l -phenylethanol, ethanol, or isopropanol), a solvent such as an ether solver (e.g., tetrahydrofuran), and at a suitable temperature such as a temperature of about 40 °C to about 60 °C (e.g., about 50 °C).

[0589] In some embodiments, the process comprises contacting Compound VI-4 or a salt thereof with phenyl chloroformate to form a compound of Formula VI-5 or a salt thereof.

[0590] In some embodiments, the reaction (e.g., the reaction between Compound VI-4 and phenyl chloroformate) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.) amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, 2,6-di-tert-butylpyridine, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0591] In some embodiments, the base is a basic aromatic compound. In some embodiments, the base is pyridine.

[0592] In some embodiments, the reaction (e.g., the reaction between Compound VI-4 and phenyl chloroformate) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, toluene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.).

[0593] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.

[0594] In some embodiments, the reaction (e.g., the reaction between Compound VI-4 and phenyl chloroformate) occurs at a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 30 °C to about 50 °C. In some embodiments, the temperature is about 40 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0595] In some embodiments, the reaction (e.g., the reaction between Compound VI-4 and phenyl chloroformate) occurs in the presence of a base such as basic aromatic compound (e.g., pyridine), a solvent such as an ether solvent (e.g., tetrahydrofuran), and at a suitable temperature such as a temperature of about 30 °C to about 50 °C (e.g., about 40 °C).

[0596] In some embodiments, the process comprises contacting a compound of Formula VI-5 or a salt thereof with Compound VII-Br or a salt thereof to form a compound of Formula V-2-Br or a salt thereof.

[0597] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-5 and Compound VII-Br) occurs in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0598] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0599] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-5 and Compound VII-Br) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and aromatic solvents (e.g., benzene, toluene, trifluorotoluene, etc.).

[0600] In some embodiments, the solvent is an aromatic solvent. In some embodiments, the solvent is trifluorotoluene.

[0601] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-5 and Compound VII-Br) occurs at a temperature of about 20 °C to about 100 °C. In some embodiments, the temperature is about 60 °C to about 80 °C. In some embodiments, the temperature is about 70 °C.

[0602] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-5 and Compound VII-Br) occurs in the presence of a base such as an amine base (e.g., triethylamine), a solvent such as an aromatic solvent (e.g., trifluorotoluene), and at a suitable temperature such as a temperature of about 60 °C to about 80 °C (e.g., about 70 °C).Attorney Docket No.: 1583-US-NP / WO-PCT Asymmetric Cyclization Route B

[0603] Additionally or alternatively, Compound V-Ior a salt thereof may be prepared by a process comprising one or more or all of the following steps: (a) converting pyridine-3,4-dicarboxylic acid into an anhydride intermediate that is furo[3,4-c]pyridine- 1,3 -dione;(b) contacting the anhydride intermediate with an chiral auxiliary to form a compound of Formula VI-6wherein AUX is a residue from the chiral auxiliary,or a salt thereof;(b) contacting a compound of Formula VI-6 or a salt thereof with Compound VII-Ior a salt thereof to form a compound of Formula V-5wherein AUX is a residue from the chiral auxiliary,or a salt thereof;(c) subjecting a compound of Formula V-5 or a salt thereof to a cyclization condition to form Compoundor a salt thereof;Attorney Docket No.: 1583-US-NP / WO-PCT (d) contacting Compound V-l-I or a salt thereof with a methylation agent to form Compound V-Ior a salt thereof.

[0604] In some embodiments, the process comprises converting pyridine-3,4-dicarboxylic acid into an anhydride intermediate that is furo[3,4-c]pyridine-l, 3-dione according to a process described anywhere herein.

[0605] In some embodiments, the process comprises contacting the anhydride intermediate (i.e., furo[3,4-c]pyridine-l, 3-dione) with an chiral auxiliary to form a compound of Formula VI-6 or a salt thereof.

[0606] As used here, term “chiral auxiliary” refers to a chemical compound or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis.

[0607] Suitable chiral auxiliaries (e.g., chiral auxiliaries for reacting with furo[3,4-c]pyridine-l, 3-dione) include, but are not limited to, (tert-butoxycarbonyl)-D-threoninate esters (e.g., methyl (tert-butoxycarbonyl)-D-threoninate, isopropyl (tert-butoxycarbonyl)-D-threoninate, tert-butyl (tert-butoxycarbonyl)-D-threoninate, diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, benzyl (tert-butoxycarbonyl)-D-threoninate, 1-phenylethyl (tert-butoxycarbonyl)-D-threoninate, etc.), methyl (methoxycarbonyl)-D-threoninate, and chiral oxazolidinones (e.g., (S)-(-)-4-isopropyl-2-oxazolidinone, (S)-(+)-4-phenyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (4S)-(-)-4-isopropyl-5,5-diphenyl-2-oxazolidinone), (S)-4-benzylthiazolidine-2-thione, (1 S)-(-)-2, 10-camphorsultam, (R)- 1 -(anthracen-9-yl)-2,2,2-trifluoroethan- 1 -ol, (R)-2-methyl- 1 -phenylpropan- 1 -ol, etc.).

[0608] In some embodiments, the chiral auxiliary is a (tert-butoxycarbonyl)-D-threoninate ester. In some embodiments, the chiral auxiliary is methyl (tert-butoxycarbonyl)-D-threoninate, isopropyl (tert-butoxycarbonyl)-D-threoninate, tert-butyl (tert-butoxycarbonyl)-D-threoninate, or diphenylmethyl (tert-butoxycarbonyl)-D-threoninate.

[0609] In some embodiments, a compound of Formula VI-6 is a compound of Formula VI-7wherein R1is Ci-6 alkyl or diphenylmethyl; anda compound of Formula V-5 is a compound of Formula V-6Attorney Docket No.: 1583-US-NP / WO-PCTwherein R1is Ci-6 alkyl or diphenylmethyl.

[0610] In some embodiments, R1is methyl, isopropyl, tert-butyl, or diphenylmethyl.

[0611] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), hydrocarbons (e.g., benzene, toluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide).

[0612] In some embodiments, the chiral auxiliary is methyl (tert-butoxycarbonyl)-D-threoninate or isopropyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is a halogenated solvent. In some embodiments, the chiral auxiliary is methyl (tert-butoxycarbonyl)-D-threoninate or isopropyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is dichloromethane.

[0613] In some embodiments, the chiral auxiliary is tert-butyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is a hydrocarbon solvent. In some embodiments, the chiral auxiliary is tert-butyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is toluene.

[0614] In some embodiments, the chiral auxiliary is diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is an ether. In some embodiments, the chiral auxiliary is diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, and the solvent is tetrahydrofuran.

[0615] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0616] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the absence of a base.Attorney Docket No.: 1583-US-NP / WO-PCT

[0617] In some embodiments, the chiral auxiliary is methyl (tert-butoxycarbonyl)-D-threoninate, isopropyl (tert-butoxycarbonyl)-D-threoninate, or tert-butyl (tert-butoxycarbonyl)-D-threoninate, and the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the absence of a base.

[0618] In some embodiments, the chiral auxiliary is diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, and the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of an amine base. In some embodiments, the base is triethylamine.

[0619] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a catalyst, such as 4-(dimethylamino)pyridine, N-methylimidazole, pyridine, or l,8-diazabicyclo[5.4.0]undec-7-ene.

[0620] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the absence of a catalyst,

[0621] In some embodiments, the chiral auxiliary is methyl (tert-butoxycarbonyl)-D-threoninate, isopropyl (tert-butoxycarbonyl)-D-threoninate, or tert-butyl (tert-butoxycarbonyl)-D-threoninate, and the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the absence of a catalyst.

[0622] In some embodiments, the chiral auxiliary is diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, and the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a catalyst that is 4-(dimethylamino)pyridine.

[0623] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs at a temperature of about 0 °C to about 80 °C. In some embodiments, the temperature is about 30 °C to about 50 °C. In some embodiments, the temperature is about 40 °C.

[0624] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a chiral auxiliary such as methyl (tert-butoxycarbonyl)-D-threoninate or isopropyl (tert-butoxycarbonyl)-D-threoninate, a solvent such as a halogenated solvent (e.g. dichloromethane), and at a suitable temperature such as a temperature of about 30 °C to about 50 °C (e.g., about 40 °C).

[0625] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a chiral auxiliary such as tert-butyl (tert-butoxy carbonyl) -D-threoninate, a solvent such as a hydrocarbon solvent (e.g., toluene), and at a suitable temperature such as a temperature of about 30 °C to about 50 °C (e.g., about 40 °C).

[0626] In some embodiments, the reaction (e.g., the reaction between furo[3,4-c]pyridine-l, 3-dione and the chiral auxiliary) occurs in the presence of a chiral auxiliary such as diphenylmethyl (tert-butoxycarbonyl)-D-threoninate, a solvent such as an ether (e.g., tetrahydrofuran), a base such as an amineAttorney Docket No.: 1583-US-NP / WO-PCT base (e.g., triethylamine), a catalyst such as 4-(dimethylamino)pyridine, and at a suitable temperature such as a temperature of about 30 °C to about 50 °C (e.g., about 40 °C).

[0627] In some embodiments, the process comprises contacting a compound of Formula VI-6 or a salt thereof with Compound VII-I or a salt thereof to form a compound of Formula V-5 or a salt thereof.

[0628] In some embodiments, the compound of Formula VI-6 is a compound of Formula VI-7, the compound of Formula V-5 is a compound of Formula V-6, and the process comprises contacting a compound of Formula VI-7 or a salt thereof with Compound VII-I or a salt thereof to form a compound of Formula V-6 or a salt thereof.

[0629] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-7 and Compound VII-I) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, 4-methylmorpholine, etc.), and basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.).

[0630] In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine.

[0631] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-7 and Compound VII-I) occurs in the presence of an azide source, such as diphenylphosphoryl azide (DPP A), trimethylsilyl azide, sodium azide, or lithium azide.

[0632] In some embodiments, the azide source is diphenylphosphoryl azide (DPP A).

[0633] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-7 and Compound VII-I) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, toluene, trifluorotoluene, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), and halogenated solvents (e.g., dichloromethane, 1,2-dichloethane, chlorobenzene, etc.).

[0634] In some embodiments, the solvent is an aromatic solvent. In some embodiments, the solvent is trifluorotoluene.

[0635] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-7 and Compound VII-I) occurs at a temperature of about -10 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0636] In some embodiments, the reaction (e.g., the reaction between a compound of Formula VI-7 and Compound VII-I) occurs in the presence of a base such as an amine base (e.g., triethylamine), an azide source such as diphenylphosphoryl azide (DPP A), a solvent such as an aromatic solvent (e.g., trifluorotoluene), and at a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0637] In some embodiments, the process comprises subjecting a compound of Formula V-5 or a salt thereof to a cyclization condi lion to form Compound V-l-I or a salt thereof.

[0638] In some embodiments, the compound of Formula V-5 is a compound of Formula V-6, and process comprises subjecting a compound of Formula V-6 or a salt thereof to a cyclization condition to form Compound V-l-I or a salt thereof.

[0639] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing Compound V-l-I from a compound of Formula V-6) comprises a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), basic aromatic compounds (e.g., pyridine, 2,6-di-tert-butylpyridine, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0640] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate.

[0641] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing Compound V-l-I from a compound of Formula V-6) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile, etc.), and halogenated solvents (e.g., dichloromethane).

[0642] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0643] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing Compound V-l-I from a compound of Formula V-6) comprises a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0644] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing Compound V-l-I from a compound of Formula V-6) comprises a base such as a carbonate (e.g., potassium carbonate), a solvent such as a polar aprotic solvent (e.g., N-methyl-2-pyrrolidone), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0645] In some embodiments, the process comprises contacting Compound V-l-I or a salt thereof with a methylation agent to form Compound of V-I or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0646] In some embodiments, Compound V-l-I (e.g., Compound V-l-I obtained from step (c)) is subject to the methylation step without isolation and / or purification.

[0647] The methylation agent (e.g., the methylation agent for providing Compound of V-I from Compound V-l-I) may be methyl iodide, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, or dimethyl carbonate.

[0648] In some embodiments, the methylation agent is methyl iodide.

[0649] In some embodiments, the reaction (e.g., the reaction for providing Compound of V-I from Compound V-l-I) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C. Synthesis of Compound II and Synthetic Intermediates

[0650] Also provided are processes for preparing Compound II or a salt thereof (or a precursor for preparing Compound II or a salt thereof). In some embodiments, the Compound II or a salt thereof (or a precursor for preparing Compound II or a salt thereof) prepared according to a process described herein may be used for preparing Compound I or a salt thereof.Route A

[0651] In some embodiments, provided is a process for preparing Compound IIor a salt thereof, comprising:(a) contacting Compound VIIIor a salt thereof with Compound IXor a salt thereof in the presence of a catalytic system to provide Compound II-2Attorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof; and(b) subjecting Compound II-2 or a salt thereof into a hydrolysis condition to form Compound II or a salt thereof.

[0652] In some embodiments, the process comprises contacting Compound VIII or a salt thereof with Compound IX or a salt thereof in the presence of a calalylic system to provide Compound II-2 or a salt thereof.

[0653] In some embodiments, the catalytic system (e.g., the catalytic system for providing Compound II-2 from Compound VIII) comprises a catalyst. In some embodiments, the catalyst is a palladium catalyst. Suitable palladium catalysts include, but are not limited to, a palladium(II) source (e.g., palladium(II) acetate, palladium(II) chloride, etc.) and a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.).

[0654] In some embodiments, the catalyst is a palladium(II) source. In some embodiments, the catalyst is palladium(II) acetate.

[0655] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-2 from Compound VIII) comprises a ligand. In some embodiments, the ligand is a monodentate or bidentate phosphine ligand. Exemplary phosphine ligands include, but are not limited to, 2-dicyclohexylphosphino-2’ -6’ -diisopropoxybiphenyl (RuPhos), 2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl (rac-BINAP), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-l,l'-biphenyl)] methanesulfonate (SPhos G3), [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-lj'-biphenyl)] methanesulfonate (XantPhos G3), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2', 4', 6'- triisopropyl- l,r-biphenyl)-2-(2'-amino-l,r -biphenyl)] methanesulfonate (BrettPhos G3), methanesulfonato 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino- 1 , 1 '-biphenyl-2-yl) (DavePhos G3), tri-tert-butylphosphine (T'BuG, and{(R)-l-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl] ethyldi -tert-butylphosphine } [2-(2'-amino- 1 , 1 '-biphenyl)] methanesulfonate (JosiPhos G3).

[0656] In some embodiments, the ligand is 2-dicyclohexylphosphino-2’-6’-diisopropoxybiphenyl (RuPhos).

[0657] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-2 from Compound VIII) comprises a base. Suitable bases include, but are not limited to, amines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, etc.), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodiumAttorney Docket No.: 1583-US-NP / WO-PCT methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium tert-butoxide, potassium ethoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), lithium bis(trimethylsilyl)amide, hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.), and any combination thereof.

[0658] In some embodiments, the base is a combination of an carbonate and an amine base. In some embodiments, the base is a combination of cesium carbonate and tripropylamine.

[0659] In some embodiments, the catalytic system (e.g., the catalytic system for providing Compound II-2 from Compound VIII) comprises a phase transfer catalyst. Suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium salts (e.g., tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, etc.), potassium tetrafluoroborate, potassium hexafluorophosphate, lithium bromide, benzyltributylammonium bromide, and phosphonium salts (e.g., tetrabutylphosphonium chloride, etc.).

[0660] In some embodiments, the catalytic system (e.g., the catalytic system for providing Compound II-2) does not comprise a phase transfer catalyst.

[0661] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-2 from Compound VIII) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), esters (e.g., isopropyl acetate, etc.), aromatics (e.g., toluene, trifluorotoluene, etc.), polar aprotic solvents (e.g., N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, etc.), halogenated (e.g., dichloromethane, 1,2-dichloroethane, etc.), hydrocarbons (e.g., n-heptane, pentane, etc.), any combination thereof, and a combinations of any of the foregoing with water.

[0662] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of toluene and N-methyl-2-pyrrolidone.

[0663] In some embodiments, the reaction between Compound VIII or a salt thereof and Compound IX or a salt thereof occurs at a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 85 °C to about 105 °C. In some embodiments, the temperature is about 95 °C.

[0664] In some embodiments, the reaction between Compound VIII or a salt thereof and Compound IX or a salt thereof occurs at a suitable temperature such as a temperature of about 85 °C to about 105 °C (e.g., about 95 °C), and in the presence of a catalytic system comprising a catalyst such as a palladium(II) source (e.g., palladium(II) acetate), a ligand such as a monodentate or bidentate phosphine ligand (e.g., 2-dicyclohexylphosphino-2’-6’-diisopropoxybiphenyl (RuPhos), a base such as a mixture of a carbonate (e.g., cesium carbonate) and an amine base (e.g., tripropylamine), and a solvent such as a mixture of toluene and N-methyl-2-pyrrolidone.Attorney Docket No.: 1583-US-NP / WO-PCT

[0665] In some embodiments, the process further comprises subjecting Compound II- 2 or a salt thereof into a hydrolysis condition to form Compound II or a salt thereof.

[0666] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) comprises a base. Suitable bases include, but are not limited to, hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc.), carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), and phosphates (e.g., potassium phosphate, sodium phosphate, etc.).

[0667] In some embodiments, the base is a hydroxide. In some embodiments, the base is sodium hydroxide.

[0668] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) comprises a phase transfer catalyst. Exemplary phase transfer catalysts include, but are not limited to, tetrabutylammonium salts (e.g., tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, etc.), potassium tetrafluoroborate, potassium hexafluorophosphate, lithium bromide, benzyltributylammonium bromide, and phosphonium salts (e.g., tetrabutylphosphonium chloride, etc.).

[0669] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) does not comprise a phase transfer catalyst.

[0670] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) comprises a solvent, Suitable solvents include, but are not limited to, alcohols (e.g., methanol, etc.), ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, etc.), ketones (e.g., acetone, 2-butanone, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), aromatic solvents (e.g., benzene, toluene, etc.), and a combination of any of the foregoing with water.

[0671] In some embodiments, the solvent is a mixed solvent. In some embodiments, the solvent is a mixture of water, toluene, and methanol.

[0672] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0673] In some embodiments, the hydrolysis condition (e.g., the hydrolysis condition for providing Compound II from Compound II-2) comprises a base such as a hydroxide (e.g., sodium hydroxide), a solvent such as a mixture of water, toluene, and methanol, and a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0674] In some embodiments, Compound VIII or a salt thereof is prepared by contacting 4-bromo-2-fluoro-6-methylbenzoic acid or a salt thereof with a methylation agent.

[0675] Suitable methylation agent (e.g., methylation agent for providing Compound VIII) include, but are not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, diazomethane, dimethyl sulfate, and dimethyl carbonate.

[0676] In some embodiments, the methylation agent is methyl iodide.

[0677] In some embodiments, the methylation reaction (e.g., the methylation reaction for providing Compound VIII) occurs in the presence of a base. Suitable bases include, but are not limited to, amines (e.g., N,N-diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, etc.), basic aromatic compounds (e.g., pyridine, 2,64utidine, imidazole, etc.), carbonates (e.g., potassium carbonate, lithium carbonate, sodium carbonate, cesium carbonate, etc.), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and phosphates (e.g., sodium phosphate, potassium phosphate, etc.).

[0678] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate.

[0679] In some embodiments, the methylation reaction (e.g., the methylation reaction for providing Compound VIII) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, 1,4-dioxane, etc.), aromatic solvents (e.g., trifluorotoluene), sulfolane, halogenated solvents (e.g., dichloromethane, 1 ,2-dichloroethane, etc.), hydrocarbons (e.g., n-heptane, pentane), and ketones (e.g., acetone, 2-butanone, etc.).

[0680] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide.

[0681] In some embodiments, , the methylation reaction (e.g., the methylation reaction for providing Compound VIII) occurs at a temperature of about -10 °C to about 60 °C. In some embodiments, the temperature is about 5 °C to about 25 °C. In some embodiments, the temperature is about 15 °C.

[0682] In some embodiments, the methylation reaction (e.g., the methylation reaction using methyl iodide for providing Compound VIII) occurs in the presence of a base such as a carbonate (e.g., potassium carbonate), and a solvent such as a polar aprotic solvents (e.g., N,N-dimethylformamide).

[0683] In some embodiments, the process further comprises recrystallizing Compound IX or a salt thereof. In some embodiments, the process further comprises recrystallizing Compound IX HC1 salt. The recrystallization may be performed using a solvent such as nitriles (e.g., acetonitrile, benzonitrile, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), alcohols (e.g.,Attorney Docket No.: 1583-US-NP / WO-PCT ethanol, 2-propanol, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), or halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.).

[0684] In some embodiments, the recrystallization is performed using a nitrile solvent (e.g., acetonitrile).

[0685] The recrystallization may be performed at a temperature of about 20 °C to about 80 °C, such as a temperature of about 35 °C to about 55 °C. In some embodiments, the recrystallization is performed at a temperature of about 45 °C.

[0686] In some embodiments, the process further comprises recrystallizing Compound IX or a salt thereof (e.g., Compound IX HC1 salt) from a solvent such as a nitrile solvent (e.g., acetonitrile) at a suitable temperature such as a temperature of about 35 °C to about 55 °C (e.g., about 45 °C).Route B

[0687] Also provided is a process for preparing Compound II,or a salt thereof, comprising:(a) contacting Compound VIIIor a salt thereof with morpholin-3-one in the presence of a catalytic system to form Compound II-3or a salt thereof;(b) contacting Compound II-3 with a tri lluoroinelhylalion agent;(c) subjecting a product from step (b) into an elimination condition to form Compound II-4Attorney Docket No.: 1583-US-NP / WO-PCT or a salt thereof;(d) subjecting Compound II-4 into an asymmetric hydrogenation condition to form Compound II-2or a salt thereof.

[0688] In some embodiments, the process comprises contacting Compound VIII or a salt thereof with morpholin-3-one in the presence of a catalytic system to form Compound II-3 or a salt thereof.

[0689] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprises a catalyst. In some embodiments, the catalyst is a copper catalyst (e.g., Cu(I) or Cu(II) salts). Suitable copper catalysts include, but are not limited to, Cut, CuBr, CuBr2, CuCl, CuCl2, CU(OAC)2, CU2O, CUO, and CuSO4.

[0690] In some embodiments, the catalyst is Cui.

[0691] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprising a copper catalyst further comprises a ligand. Suitable ligands include, but are not limited to, diamines (e.g., trans-N,N'-bis-methyl-l,2-cyclohexanediamine, trans-N,N-dimethylcyclohexane- 1 ,2-diamine, trans-cyclohexane- 1 ,2-diamine, N,N'-dimethylethylenediamine, N,N-dimethylethylenediamine, ethylenediamine, N,N,N',N'-tetramethyl ethylenediamine, N-cyclohexyl-N-methylethane-l,2-diamine, dimethyl- l,2-diphenylethane-l,2-diamine, etc.), 1,10-phenanthroline, [(2,6-dimethylphenyl)amino](oxo)acetic acid (DMPAO), and a-amino acids (e.g., L-hydroxyproline, etc.).

[0692] In some embodiments, the ligand is a diamine ligand. In some embodiments, the ligand is transit, N'-bis-methyl- 1 ,2-cyclohexanediamine.

[0693] In some embodiments, the catalytic system (e.g., the catalytic system for providing Compound II-3 from Compound VIII) comprising a copper catalyst further comprises a base, such as an inorganic or organic base (e.g. triethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium bicarbonate, tripotassium phosphate, sodium tert-butoxide, cesium carbonate, sodium methoxide, potassium hydroxide, sodium hydroxide, etc.).

[0694] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate.

[0695] In some embodiments, the catalytic system (e.g., the catalytic system for providing Compound II-3 from Compound VIII) comprising a copper catalyst further comprises a solvent. Suitable solvents include, but are not limited to, toluene, dioxane, N,N-dimethylformamide, pyridine, dimethyl sulfoxide, nitrobenzene, glycol, diglyme, acetonitrile, water, and ethanol.Attorney Docket No.: 1583-US-NP / WO-PCT

[0696] In some embodiments, the solvent is toluene.

[0697] In some embodiments, the reaction between Compound VIII and morpholin-3-one occurs at a temperature of about -50 °C to about 150 °C. In some embodiments, the temperature is about 90 °C to about 110 °C. In some embodiments, the temperature is about 100 °C.

[0698] In some embodiments, the reaction between Compound VIII and morpholin-3-one occurs at suitable temperature such as a temperature of about 90 °C to about 110 °C (e.g., about 100 °C), and in the presence of a calalylic system comprising a catalyst such as a copper catalyst (e.g., Cui), a ligand such as a diamine ligand (e.g., trans-N,N'-bis-methyl-l,2-cyclohexanediamine), a base such as a carbonate (e.g., potassium carbonate), and a solvent such as toluene.

[0699] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprises a catalyst. In some embodiments, the catalyst is a palladium catalyst. Suitable palladium catalysts include, but are not limited to, palladium(II) sources (e.g., XantPhos Pd G4, palladium(II) chloride, etc.) and palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.).

[0700] In some embodiments, the catalyst is a XantPhos Pd G4 (9-{ [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenyl-lambda-phosphanyl}-8-methyl-8-aza-9-palladatricyclo[8.4.0.0(2),]tetradeca-l(14),2,4,6,10,12-hexaen-9-yl methanesulfonate).

[0701] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprising a palladium catalyst further comprises a ligand. Suitable ligands include, but are not limited to, XantPhos, monodentate phosphine ligands (e.g., triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, etc.), and bidentate phosphine ligands (e.g., 1,2-bis(diphenylphosphino)ethane, 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, 1,1'-bis(diphenylphosphino)ferrocene, etc.).

[0702] In some embodiments, the ligand is XantPhos (e.g., from the XantPhos Pd G4 catalyst).

[0703] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprising a palladium catalyst further comprises a base, such as an inorganic or organic base (e.g. triethylamine, pyridine, sodium carbonate, sodium bicarbonate, cesium bicarbonate, tripotassium phosphate, sodium tert-butoxide, cesium carbonate, sodium methoxide, potassium hydroxide, sodium hydroxide, etc.).

[0704] In some embodiments, the base is a carbonate. In some embodiments, the base is cesium carbonate.

[0705] In some embodiments, the catalytic system (e.g., the calalylic system for providing Compound II-3 from Compound VIII) comprising a palladium catalyst further comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g. tetrahydrofuran, methyl tert-butyl ether, dioxane, cyclopentylAttorney Docket No.: 1583-US-NP / WO-PCT methyl ether, etc.), aromatics (e.g. toluene, etc.), alcohols (e.g., methanol, ethanol, etc.), amide (N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylacetamide, etc.), and ester (e.g. isopropyl acetate, ethyl acetate, etc.).

[0706] In some embodiments, the solvent is an aromatic solvent. In some embodiments, the solvent is toluene.

[0707] In some embodiments, the reaction between Compound VIII and morpholin-3-one occurs at a temperature of about 20 °C to about 150 °C. In some embodiments, the temperature is about 75 °C to about 95 °C. In some embodiments, the temperature is about 85 °C.

[0708] In some embodiments, the reaction between Compound VIII and morpholin-3-one occurs at a suitable such as a temperature of about 75 °C to about 95 °C (e.g., about 85 °C), and in the presence of a catalytic system comprising a catalyst such as a palladium catalyst (e.g., XantPhos Pd G4), a ligand such as XantPhos ((from the XantPhos Pd G4 catalyst), a base such as a carbonate (e.g., cesium carbonate), and a solvent such as toluene.

[0709] In some embodiments, the process comprises contacting Compound II-3 with a trifluoromethylation agent. Suitable tri lluoroinelhylalion agents include, but are not limited to, trifluoroacetophenone, trifluoromethyllithium, (trifluoromethyl)trimethylsilane, and (trifluoromethyl)triethylsilane.

[0710] In some embodiments, the tri lluoroinelhylalion agent is (trifluoromethyl)trimethylsilane.

[0711] In some embodiments, the tri lluoroinelhylalion reaction (e.g., the trifluoromethylation of Compound II-3) occurs in the presence of an initiator. Suitable initiators include, but are not limited to, fluoride sources (e.g., cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenylsilicate, potassium fluoride, sodium fluoride, lithium fluoride, etc.), carboxylates (e.g., potassium ethylhexanoate, sodium ethylhexanoate, etc.), and alkoxides (e.g., potassium tert-butoxide, sodium tert-butoxide, etc.).

[0712] In some embodiments, the initiator is a fluoride source. In some embodiments, the initiator is cesium fluoride.

[0713] In some embodiments, the tri lluoroinelhylalion reaction (e.g., the trifluoromethylation of Compound II-3) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, cyclopentyl methyl ether, etc.) and aromatic solvents (e.g., toluene, etc.).

[0714] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is 2-methyltetrahydrofuran.Attorney Docket No.: 1583-US-NP / WO-PCT

[0715] In some embodiments, the trifluoromethylation reaction (e.g., the trifluoromethylation of Compound II-3) occurs at a temperature of about -78 °C to about 50 °C. In some embodiments, the temperature is about -15 °C to about 15 °C.

[0716] In some embodiments, the trifluoromethylation reaction (e.g., the trifluoromethylation of Compound II-3) occurs in the presence of a trifluoromethylation agent (e.g., (trifluoromethyl)trimethylsilane), a initiator such as a fluoride source (e.g., cesium fluoride), a solvent such as an ether solvent (e.g., 2-methyltetrahydrofuran), and at a suitable temperature such as a temperature of about -15 °C to about 15 °C.

[0717] In some embodiments, the process comprises subjecting a product from step (b) into an elimination condilion to form Compound II-4 or a salt thereof.

[0718] In some embodiments, the elimination condilion (e.g., the elimination condition for proving Compound II-4) comprises an acid. Suitable acids include, but are not limited to, hydrogen chloride solutions (e.g., hydrogen chloride solution in dioxane, hydrogen chloride solution in cyclopentyl methyl ether, hydrogen chloride solution in ethanol, hydrogen chloride solution in 2-propanol, etc.), mineral acids (e.g., hydroiodic acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (e.g., p-toluenesulfonic acid, etc.), and carboxylic acids (e.g., acetic acid, pivalic acid, iril'luoroacclic acid, etc.).

[0719] In some embodiments, the acid is a hydrogen chloride solution. In some embodiments, the acid is hydrogen chloride solution in dioxane.

[0720] In some embodiments, the elimination condilion (e.g., the elimination condilion for proving Compound II-4) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, etc.), aromatic solvents (e.g., toluene, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.).

[0721] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0722] In some embodiments, the elimination condilion (e.g., the elimination condilion for proving Compound II-4) comprises a temperature of about 0 °C to about 50 °C. In some embodiments, the temperature is about 5 °C to about 25 °C. In some embodiments, the temperature is about 15 °C.

[0723] In some embodiments, the elimination condition (e.g., the elimination condilion for proving Compound II-4) comprises an acid such as a hydrogen chloride solution (e.g., hydrogen chloride solulion in dioxane), a solvent such as an ether solvent (e.g., 2-methyltetrahydrofuran), and a suitable temperature such as a temperature of about 5 °C to about 25 °C (e.g., about 15 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0724] In some embodiments, the process comprises subjecting Compound II-4 or a salt thereof into an asymmetric hydrogenation condition to form Compound II-2 or a salt thereof.

[0725] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a catalyst. Suitable catalysts include, but are not limited to, rhodium catalysts (e.g., bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate, etc.), iridium catalysts (e.g., cyclooctadiene iridium chloride dimer, etc.), ruthenium catalysts (e.g., bis(2-methylallyl)(l,5-cyclooctadiene)ruthenium(II), etc.), nickel catalysts (e.g., nickel(II) acetate, nickel(II) nitrate, etc.), and palladium catalysts (e.g., palladium(II) trifluoroacetate, palladium(II) acetate, etc.).

[0726] In some embodiments, the catalyst is a rhodium catalyst. In some embodiments, the catalyst is bis( 1 ,5-cyclooctadiene)rhodium(I) tetrafluoroborate.

[0727] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a ligand. Suitable ligands include, but are not limited to, (R)-(+)-l-[(R)-2-(2’-dicyclohexylphosphinophenyl)ferrocenyl]ethylbis(3,5-trifhioromethylphenyljphosphine (SL-W008-1), (lS)-l-[(lR)-l-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(dicyclohexylphosphino)phenyl]ferrocene, (ISp)-l-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(lR)-l-(dicyclohexylphosphino)ethyl]ferrocene, (lR,rR)-l,r-Bis[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2,2’-bis[(R)-(dimethylamino)phenylmethyl]ferrocene, 1 ,2-Bis((2R,5R)-2,5-diisopropylphospholan- 1 -yljethane, 1,1’-[(5aR,8aR,14aR)-5a,6,7,8,8a,9-Hexahydro-5H-[l]benzopyrano[3,2-d]xanthene-l,13-diyl]bis[l,l-diphenyl -phosphine] , (R)-5,5’-Bis(diphenylphosphino)-4,4’-bibenzo[d] [ 1 ,3]dioxole, (S)-(-)-2,2’-Bis[di(3,5-di-t-butylphenyl)phosphino] -6,6’-dimethoxy- 1 , 1 ’-biphenyl, 1 - { (2R)- 1 -[( 1 IbR)-8,9,10,ll,12,13,14,15-Octahydrodinaphtho[2,l-d:r,2’-f][l,3,2]dioxaphosphepin-4-yloxy]propan-2-yl}-3-phenylurea, and N-[(llbS)-Dinaphtho[2,l-d:r,2’-f][l,3,2]dioxaphosphepin-4-yl]-l,l,l-trifluoromethanesulfonamide .

[0728] In some embodiments, the ligand is (R)-(+)-l-[(R)-2-(2’-dicyclohexylphosphinophenyl)ferrocenyl]ethylbis(3,5-trifluoromethylphenyl)phosphine (SL-W008-1).

[0729] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a hydrogen source. Suitable hydrogen source includes, but is not limited to, hydrogen gas, formic acid, sodium formate, tetrabutylammonium formate, tetrahydroxydiboron, triethylsilane, phenylsilane, and hydrazine.

[0730] In some embodiments, the hydrogen source is hydrogen gas.

[0731] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises an additive. Suitable additives include, but are not limited to, acids (e.g., acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, formic acid, etc.), bases (e.g., triethylamine, N,N-diisopropylethylamine,Attorney Docket No.: 1583-US-NP / WO-PCT pyridine, potassium bicarbonate, sodium bicarbonate, etc.), and iodine and iodide salts (e.g., sodium iodide, cesium iodide, potassium iodide, tetrabutylammonium iodide, etc.).

[0732] In some embodiments, the asymmetric hydrogenation condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) does not comprise an additive.

[0733] In some embodiments, the asymmetric hydrogenation condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, cyclopentyl methyl ether, etc.), aromatic solvents (e.g., toluene, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, 2,2,2-trifluoroethanol, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), and ester solvents (e.g., ethyl acetate, isopropyl acetate, etc.).

[0734] In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is 2,2,2-trifluoroethanol.

[0735] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a temperature of about 20 °C to about 100 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0736] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises an elevated pressure. In some embodiments, the pressure is about 15 psi to about 200 psi. In some embodiments, the pressure is about 120 psi.

[0737] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving Compound II-2) comprises a hydrogen source such as hydrogen gas, a catalyst such as a rhodium catalyst (e.g., bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate), a ligand such as SL-W008-1, a solvent such as an alcohol solvent (e.g., 2,2,2-trifluoroethanol), a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C), and an elevated pressure such as about 120 psi.

[0738] In some embodiments, the process further comprises converting Compound II-2 or a salt thereof to Compound II or a salt thereof according to a process described anywhere herein.Synthesis of Compound IX and Derivatives

[0739] Also provided are processes for preparing Compound IX or a salt thereof.Chiral Resolution Route

[0740] For example, Compound IX or a salt thereof may be prepared via chiral resoludon.Attorney Docket No.: 1583-US-NP / WO-PCT

[0741] In some embodiments, provided herein is a process preparing Compound IXor a salt thereof, comprising(a) optionally, free basing a salt of Compound IXa; and(b) contacting Compound IXa free base with a chiral acid that is optically pure to form Compound IX chiral acid salt.

[0742] In some embodiments, the process comprises free basing a salt of Compound IXa. In some embodiments, the process comprises free basing Compound IXa HC1 salt.

[0743] In some embodiments, free basing a salt of Compound IXa is performed in the presence of a base. Suitable bases include, but are not limited to, carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), phosphates (e.g., sodium phosphate, potassium phosphate, etc.), and hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.).

[0744] In some embodiments, the base is a carbonate. In some embodiments, the base is cesium carbonate.

[0745] In some embodiments, free basing a salt of Compound IXa is performed in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1 ,2-dichloroethane, chlorobenzene, etc.), or a combination of any of the foregoing with water.

[0746] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane .

[0747] In some embodiments, free basing a salt of Compound IXa is performed at a temperature of about 0 °C to about 80 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0748] In some embodiments, free basing a salt of Compound IXa is performed in the presence of a base such as a carbonate (e.g., cesium carbonate), a solvent such as a halogenated solvent (e.g., dichloromethane), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0749] In some embodiments, the process comprises contacting Compound IXa free base with a chiral acid that is optically pure to form Compound IX chiral acid salt.

[0750] Suitable chiral acids include, but are not limited to, (+)-Camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-malic acid, N-acetyl-L-leucine, (+)-mandelic acid, and dibenzoyl-L-tartaric acid.

[0751] In some embodiments, the chiral acid is (+)-Camphorsulfonic acid. In some embodiments, the Compound IX chiral acid salt is Compound IX (+) -Camphor sulfonic acid salt.

[0752] In some embodiments, the contacting (e.g., the contacting of Compound IXa free base and a chiral acid) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), ketones (e.g., methyl ethyl ketone, acetone, 2-butanone, 4-methyl-2-pentanone, etc.), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and alcohols (e.g., 2-propanol, 2-butanol, etc.).

[0753] In some embodiments, the solvent is a ketone. In some embodiments, the solvent is methyl ethyl ketone.

[0754] In some embodiments, the contacting (e.g., the conlacling of Compound IXa free base and a chiral acid) occurs at a temperature of about 0 °C to about 80 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0755] In some embodiments, the conlacling (e.g., the conlacling of Compound IXa free base and a chiral acid such as (+)-Camphorsulfonic acid) occurs in the presence of a solvent such as a ketone solvent (e.g., methyl ethyl ketone) at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0756] In some embodiments, Compound IXa or a salt thereof is prepared by a process compressing: (a) subjecting Compound IX-2-BnC° N1 CF3Bn IX-2-Bnor a salt thereof to a hydrogenation condition to form Compound IX-3a-BnC° N1 CF3Bn IX-3a-Bnor a salt thereof;(b) subjecting Compound IX-3a-Bn to a deprotection condition; and(c) subjecting the reaction mixture from step (b) to an acidic condition to form Compound IXaAttorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof.

[0757] In some embodiments, the hydrogenation condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-2-Bn) comprises a catalyst. Suitable catalysts include, but are not limited to, solid-supported transition metals (e.g., palladium on carbon, platinum on carbon, etc.), Raney Nickel, and transition metal catalysts (e.g., (SP-4)-(r|2,r|2-cycloocta-l,5-diene) (pyridine)(tricyclohexylphosphine)iridium( 1 +) hexafluoridophosphate( 1 -) , (SP-4) -chloridotris(triphenylphosphene)rhodium), a palladium(II) source such as palladium(II) chloride, a palladium(O) source such as tetrakis(triphenylphosphine)palladium(0), a nickel(II) source such as nickel(II) chloride, or a nickel(O) source such as bis(cyclooctadiene)nickel(0), etc.).

[0758] In some embodiments, the catalyst is solid-supported transition metals. In some embodiments, the catalyst is palladium on carbon.

[0759] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from Compound IX-2-Bn) comprises a reductant. The reductant may be a hydrogen source such as hydrogen gas, formic acid, sodium formate, or tetrabutylammonium formate.

[0760] In some embodiments, the reductant is hydrogen gas.

[0761] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from Compound IX-2-Bn) comprises a solvent. The solvent may be alcohols, such as methanol, ethanol, 2-propanol, tert-butanol, or tert-amyl alcohol.

[0762] In some embodiments, the solvent is ethanol.

[0763] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from Compound IX-2-Bn) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0764] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from Compound IX-2-Bn) comprises a catalyst such as a solid-supported transition metal catalyst (e.g., palladium on carbon), a reductant such as hydrogen gas, a solvent such as ethanol, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0765] In some embodiments, the obtained Compound IX-3a-Bn is subject to the next step without isolation and / or purification.Attorney Docket No.: 1583-US-NP / WO-PCT

[0766] In some embodiments, the deprotection condition (e.g., the condition for step (b)) comprises a catalyst. Suitable catalysts include, but are not limited to, solid-supported transition metals (e.g., palladium on carbon, platinum on carbon, etc.), Raney Nickel, and transition metal catalysts (e.g., (SP-4)-(r|2,r|2-cycloocta-l,5-diene)(pyridine)(tricyclohexylphosphine)iridium(l-i-) hexafluoridophosphate(l-), (SP-4)-chloridotris(triphenylphosphene)rhodium), a palladium(II) source such as palladium(II) chloride, a palladium(O) source such as tetrakis(triphenylphosphine)palladium(0), a nickel(II) source such as nickel(II) chloride, or a nickel(O) source such as bis(cyclooctadiene)nickel(0), etc.).

[0767] In some embodiments, the catalyst is solid-supported transition metals. In some embodiments, the catalyst is palladium on carbon.

[0768] In some embodiments, the deprotection condition (e.g., the condition for step (b)) comprises a reductant. The reductant may be a hydrogen source such as hydrogen gas, formic acid, sodium formate, or tetrabutylammonium formate.

[0769] In some embodiments, the reductant is hydrogen gas.

[0770] In some embodiments, the deprotection (e.g., the condition for step (b)) comprises a solvent. The solvent may be alcohols, such as methanol, ethanol, 2-propanol, tert-butanol, or tert-amyl alcohol.

[0771] In some embodiments, the solvent is ethanol.

[0772] In some embodiments, the deprotection condition (e.g., the condition for step (b)) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0773] In some embodiments, the deprotection condition (e.g., the condition for step (b)) comprises a catalyst such as a solid-supported transition metal catalyst (e.g., palladium on carbon), a reductant such as hydrogen gas, a solvent such as methanol, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0774] The acid used in the acidic condition (e.g., the condition for step (c)) may be hydrochloric acid, p-toluenesulfonic acid, or oxalic acid.

[0775] In some embodiments, the acid is hydrochloric acid, and the salt of Compound IXa is Compound IXa HC1 salt.

[0776] In some embodiments, the acidic condition (e.g., the condition for step (c)) comprises a solvent. The solvent may be alcohols, such as methanol, ethanol, 2-propanol, tert-butanol, or tert-amyl alcohol.

[0777] In some embodiments, the solvent is methanol.

[0778] In some embodiments, the acidic condition (e.g., the condition for step (c)) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0779] In some embodiments, the acidic condition (e.g., the condition for step (c)) comprises an acid such as hydrochloric acid, a solvent such as methanol, and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0780] Additionally or alternatively, Compound IX-3a-Bnor a salt thereof may be prepared by a process comprising:subjecting Compound IX-2-BnC° N1 CF3Bn IX-2-Bnor a salt thereof to a hydrogenation condilion to form Compound IX-3a-Bn or a salt thereof.

[0781] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from IX-2-Bn) comprises a catalyst such as an iron catalyst. The catalyst may be an iron(III) source such as iron(III) chloride or tris(acetylacetonato)iron(III).

[0782] In some embodiments, the catalyst is tris(acetylacetonato)iron(III).

[0783] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from IX-2-Bn) comprises an addili ve that is thiophenol.

[0784] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from IX-2-Bn) comprises a hydrogen source such as an organosilane compound. The organosilane may be diphenylsilane, triethylsilane, or phenylsilane.

[0785] In some embodiments, the hydrogen source is phenylsilane.

[0786] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from IX-2-Bn) comprises a solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, etc.).

[0787] In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is ethanol.

[0788] In some embodiments, the hydrogenation condition (e.g., the condilion for providing Compound IX-3a-Bn from IX-2-Bn) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0789] In some embodiments, the hydrogenation condition (e.g., the condition for providing Compound IX-3a-Bn from IX-2-Bn) comprises a catalyst such as an iron catalyst (e.g., tris(acetylacetonato)iron(III)), an additive that is thiophenol, a hydrogen source such as an organosilane compound (e.g., phenylsilane), a solvent such as an alcohol (e.g., ethanol), and a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).

[0790] Additionally or alternatively, Compound IX-3a-BnC° N1 CF3Bn IX-3a-Bnor a salt thereof may be prepared by a process comprising:subjecting Compound IX-4aor a salt thereof to a reductive condition to form Compound IX-3a-Bn or a salt thereof.

[0791] In some embodiments, the reductive condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-4a) comprises a Lewis acid. Suitable Lewis acids include, but are not limited to, boron trifluoride complexes (e.g., boron trifluoride dietherate, boron trifluoride tetrahydrofuran, etc.), aluminum salts (e.g., aluminum trichloride, etc.), zinc salts (e.g., zinc(II) chloride, etc.), and scandium salts (e.g., scandium(III) triflate, etc.).

[0792] In some embodiments, the Lewis acid is a boron trifluoride complex. In some embodiments, the Lewis acid is boron trifluoride dietherate.

[0793] In some embodiments, the reductive condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-4a) comprises a reductant. The reductant may be sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.

[0794] In some embodiments, the reductant is sodium borohydride.

[0795] In some embodiments, the reductive condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-4a) comprises a solvent. Suitable solvents include, but are not limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc), esters (e.g., ethyl acetate, isopropyl acetate, methyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.).

[0796] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.Attorney Docket No.: 1583-US-NP / WO-PCT

[0797] In some embodiments, the reductive condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-4a) comprises a temperature of about -30 °C to about 50 °C. In some embodiments, the temperature is about -10 °C to about 30 °C. In some embodiments, the temperature is about 0 °C to about 20 °C.

[0798] In some embodiments, the reductive condition (e.g., the condition for providing Compound IX-3a-Bn from Compound IX-4a) comprises a Lewis acid such as a boron trifluoride complex (e.g., boron trifluoride dietherate), a reductant such as sodium borohydride, a solvent such as an ether solvent (e.g., tetrahydrofuran), and a suitable temperature such as a temperature of about -10 °C to about 30 °C (e.g., about 0 °C to about 20 °C).Asymmetric Hydrogenation Route

[0799] Additionally or alternatively, Compound IX or a salt thereof may be prepared via asymmetric hydrogenation.

[0800] In some embodiments, provided is a process for preparing Compound IXor a salt thereof, comprising:(a) contacting a compound of Formula IX- 1or a salt thereof with a tri fluoromethy lalion agent to form a compound of Formula IX-2or a salt thereof;(b) subjecting the compound of Formula IX-2 or a salt thereof to an asymmetric hydrogenation condition to form a compound of Formula IX-3Attorney Docket No.: 1583-US-NP / WO-PCTo.„N 'CF3PG IX-3wherein PG is benzylor a salt thereof; and(c) subjecting the compound of formula IX-3 or a salt thereof to a deprotection condition to form Compound IX or a salt thereof, wherein step (c) occurs in the presence of a chiral acid.

[0801] In some embodiments, PG is benzyl. In some embodiments,

[0802] In some embodiments, the process comprises contacting a compound of Formula IX- 1 or a salt thereof with a trifluoromethylation agent. Suitable trifluoromethylation agents include, but are not limited to, trifluoromethyl silanes (e.g., (trifluoromethyl)trimethylsilane, (trifluoromethyl)triethylsilane, (trifluoromethyl)n-propyldimethylsilane, (trifluoromethyl)triisopropylsilane, (trifluoromethyl)t-butyldimethylsilane, etc.) and fluoroform.

[0803] In some embodiments, the trifluoromethylation agent is a trifluoromethyl silane compound. In some embodiments, the trifluoromethylation agent is (trifluoromethyl)trimethylsilane.

[0804] In some embodiments, the reaction between a compound of Formula IX- 1 or a salt thereof and a trifluoromethylation agent occurs in the presence of a base. Suitable bases include, but are not limited to, fluorides (e.g., lithium fluoride, potassium fluoride, cesium fluoride, etc.), tetrabutylammonium salts (e.g., tetrabutylammonium fluoride, tetrabutylammonium acetate, etc.), tetramethylammonium salts (e.g., tetramethylammonium fluoride, tetramethylammonium acetate, etc.), tert-butoxides (e.g., sodium tert-butoxide, potassium tert-butoxide, etc.), acetates (e.g., lithium acetate, sodium acetate, potassium acetate, etc.), carbonates (e.g., potassium carbonate, cesium carbonate, etc.), phosphates (e.g., potassium phosphate, lithium phosphate, cesium phosphate, etc.), and amides (e.g., potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0805] In some embodiments, the base is a tert-butoxide base. In some embodiments, the base is potassium tert-butoxide.

[0806] In some embodiments, the reaction between a compound of Formula IX- 1 or a salt thereof and a trifluoromethylation agent occurs in the presence of a solvent. Suitable solvents include, but are not limited to, aromatic solvents (e.g., toluene), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-Attorney Docket No.: 1583-US-NP / WO-PCT dioxane, etc.), chlorinated (e.g., dichlor omethane, 1,2-dichloroethane, trifluorotoluene, etc.), polar aprotic (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), and nitriles (e.g., acetonitrile).

[0807] In some embodiments, the solvent is an aroinalic solvent. In some embodiments, the solvent is toluene.

[0808] In some embodiments, the reaction between a compound of Formula IX- 1 or a salt thereof and a trifluoromethylation agent occurs at a temperature of about -20 °C to about 50 °C. In some embodiments, the temperature is about -10 °C to about 10 °C. In some embodiments, the temperature is about 0 °C.

[0809] In some embodiments, the reaction between a compound of Formula IX- 1 or a salt thereof and a trifluoromethylation agent (e.g., a trifluoromethyl silane compound such as (trifluoromethyl)trimethylsilane) occurs in the presence of a base such as a tert-butoxide base (e.g., potassium tert-butoxide), a solvent such as an aroinalic solvent (e.g., toluene), and at a suitable temperature such as a temperature of about -10 °C to about 10 °C (e.g., about 0 °C).

[0810] In some embodiments, the process comprises subjecting the compound of Formula IX-2 or a salt thereof to an asymmetric hydrogenation condition.

[0811] In some embodiments, the asymmetric hydrogenation condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a catalyst. Suitable catalysts include, but are not limited to, ruthenium catalyst (e.g., (l,5-cyclooctadiene)bis(2-methylallyljruthenium, etc.), rhodium catalyst (e.g., bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate, etc.), iridium catalyst (e.g., bis(l,5-cyclooctadiene)diiridium(I) dichloride, etc.), nickel catalyst (e.g., nickel(II) acetate, nickel(II) acetate tetrahydrate, nickel(II) trifluoromethanesulfonate, etc.), and palladium catalyst (e.g., palladium on carbon, etc.).

[0812] In some embodiments, the catalyst is a nickel catalyst. In some embodiments, the catalyst is nickel(II) acetate.

[0813] In some embodiments, the asymmetric hydrogenation condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a ligand. Suitable ligands include, but are not limited to, Josiphos ligands (e.g., (S)-l-[(Rp)-2-(diphenylphosphino)ferrocenyl]-ethyldi-tert-butylphosphine (CAS 277306-29-3), (S)-(+)-l-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (CAS 162291-02-3), (S,S)-1-(dicyclohexylphosphino)-2-[l-(diphenylphosphino)ethyl]ferrocene (CAS 162291-01-2), (S)-l-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine (CAS 246231-77-6), (S)-l-{(R)-2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl}ethyldicyclo (CAS 849923-88-2), etc.), BPE ligands (e.g., (-)-l,2-bis((2R,5R)-2,5-diphenylphospholano)ethane, l,2-bis[(2R,5R)-2,5-dimethyl-l-phospholanyl]ethane, etc.), DUPHOS ligands (e.g., (-)-l,2-bis[(2R,5R)-2,5-dimethylphospholano] benzene, (+)-l,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene, etc.),Attorney Docket No.: 1583-US-NP / WO-PCT SEGPHO ligands (e.g., (R)-(+)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3-benzodioxole, etc.), SKP ligands (e.g., (+)-l,13-bis(diphenyl)phosphino-(5aR,8aR,14aR)-5a,6,7,8,8a,9-hexahydro-5H-[l]benzopyrano [3, 2-d] xanthene, etc.).

[0814] In some embodiments, the ligand is a Josiphos ligand. In some embodiments, the ligand is CAS 277306-29-3.

[0815] In some embodiments, the asymmetric hydrogenation condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a hydrogen source.Suitable hydrogen source includes, but is not limited to, hydrogen gas and hydrogen precursors (e.g., formic acid, sodium formate, or tetrabutylammonium formate).

[0816] In some embodiments, the hydrogen source is hydrogen gas.

[0817] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises an additive such acids (e.g., acetic acid, etc.).

[0818] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) does not comprise an additive.

[0819] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a solvent. Suitable solvents include, but are not limited to, alcohol (e.g., methanol, ethanol, 2,2,2-trifluoroethanol, etc.) and ether (e.g., cyclopentyl methyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, etc.).

[0820] In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is 2,2,2-trifluoroethanol.

[0821] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a temperature of about 20 °C to about 120 °C. In some embodiments, the temperature is about 50 °C to about 70 °C. In some embodiments, the temperature is about 60 °C.

[0822] In some embodiments, the asymmetric hydrogenalion condition (e.g., the asymmetric hydrogenation condition for proving a compound of Formula IX-3) comprises a hydrogen source such as hydrogen gas, a catalyst such as a nickel catalyst (e.g., nickel(II) acetate), a ligand such as a Josiphos ligand (e.g., CAS 277306-29-3), a solvent such as an alcohol solvent (e.g., 2,2,2-trifluoroethanol), and a suitable temperature such as a temperature of about 50 °C to about 70 °C (e.g., about 60 °C).

[0823] In some embodiments, the process comprises subjecting the compound of formula IX-3 or a salt thereof to a deprotection condition to form Compound IX or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT

[0824] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound IX) comprises an acid. Suitable acids include, but not limited to, (+) -Camphor sulfonic acid, p-toluenesulfonic acid, oxalic acid, and hydrogen chloride.

[0825] In some embodiments, the acid is a chiral acid. In some embodiments, the acid is (+)-Camphorsulfonic acid.

[0826] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound IX) comprises a catalyst. Suitable catalysts include, but are not limited to, solid-supported transition metals (e.g., platinum on carbon, palladium on carbon, etc), Raney Nickel, transition metal catalysts (e.g., (S -4)-(r|2,r|2-cycloocta-l,5-diene)(pyridine)(tricyclohexylphosphine)iridium(l-i-) hexafluoridophosphate(l-), (SP-4)-chloridotris(triphenylphosphene)rhodium, etc.), a palladium(II) source (e.g., palladium(II) chloride, etc.), a palladium(O) source (e.g., tetrakis(triphenylphosphine)palladium(0), etc.), a nickel(II) source (e.g., nickel(II) chloride, etc.), and a nickel(O) source (e.g., bis(cyclooctadiene)nickel(0), etc.).

[0827] In some embodiments, the catalyst is a solid-supported transition metal. In some embodiments, the catalyst is palladium on carbon.

[0828] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound IX) comprises a hydrogen source such as hydrogen gas, an organosilane (e.g., triethylsilane, etc.), formic acid, a formate (e.g., sodium formate, tetrabutylammonium formate, etc).

[0829] In some embodiments, the hydrogen source is hydrogen gas.

[0830] In some embodiments, the deprotection condition (e.g., the deprolcclion condition for providing Compound IX) comprises a solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, tert-butanol, t-amyl alcohol, etc.), esters (e.g., isopropyl acetate, etc.), halogenated solvents (e.g., dichloromethane, 1,2-di chloroethane, chlorobenzene, etc.), hydrocarbons (e.g., toluene, heptane, etc.).

[0831] In some embodiments, the solvent is an alcohol solvent. In some embodiments, the solvent is methanol.

[0832] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound IX) comprises a temperature of about 0 °C to about 60 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0833] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound IX) comprises an acid such as a chiral acid (e.g., (+) -Camphor sulfonic acid), a catalyst such as palladium on carbon, a reductant such as a hydrogen source (e.g., hydrogen gas), a solvent such as an alcohol solvent (e.g., methanol), and at a suitable temperature such as a temperature of about 10 °C to about 30 °C (e.g., about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0834] In some embodiments, the product from step (c) is Compound IX (+)-camphorsulfonic acid salt.

[0835] In some embodiments, the compound of Formula IX- 1 is Compound IX-l-Np.

[0836] In some embodiments, the process further comprises preparing Compound IX-l-Np by contacting morpholin-3-one with a naphthalenylmethyl precursor. The naphthalenylmethyl precursor may be l-(chloromethyl)naphthalene, l-(bromomethyl)naphthalene, l-(iodomethyl)naphthalene, or 1-(hydroxymethyl)naphthalenes activated as sulfonates or phosphates.

[0837] In some embodiments, the naphthalenylmethyl precursor is l-(chloromethyl)naphthalene.

[0838] In some embodiments, the reaction between morpholin-3-one and the naphthalenylmethyl precursor occurs in the presence of a base. Suitable bases include, but are not limited to, hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkoxides (e.g., lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), n-butyllithium, hydrides (e.g., sodium hydride, potassium hydride), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0839] In some embodiments, the base is an amide base. In some embodiments, the base is lithium bis(trimethylsilyl)amide.

[0840] In some embodiments, the reaction between morpholin-3-one and the naphthalenylmethyl precursor occurs in the presence of a catalyst, Suitable catalysts include, but are not limited to, sodium iodide and tetrabutylammonium salts (e.g., tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, etc.).

[0841] In some embodiments, the catalyst is sodium iodide.

[0842] In some embodiments, the reaction between morpholin-3-one and the naphthalenylmethyl precursor occurs in the presence of a solvent. Suitable solvents include, but are not limited to, hydrocarbons (e.g., toluene, benzene, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl sulfoxide, etc.).

[0843] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.

[0844] In some embodiments, the reaction between morpholin-3-one and the naphthalenylmethyl precursor occurs at a temperature of about -20 °C to about 60 °C. In some embodiments, the temperature is about -10 °C to about 50 °C. In some embodiments, the temperature is about 0 °C to about 40 °C.Attorney Docket No.: 1583-US-NP / WO-PCT

[0845] In some embodiments, the reaction between morpholin-3-one and the naphthalenylmethyl precursor (e.g., l-(chloromethyl)naphthalene) occurs in the presence of a base such as an amide base (e.g., lithium bis(trimethylsilyl)amide), a catalyst such as sodium iodide, a solvent such as an ether solvent (e.g., tetrahydrofuran), and at a suitable temperature such as a temperature of about -10 °C to about 50 °C (e.g., about 0 °C to about 40 °C).

[0846] In some embodiments, the compound of Formula IX- 1 is Compound IX-l-Bn.

[0847] In some embodiments, the process further comprises preparing Compound IX-l-Bn by contacting morpholin-3-one with a benzyl precursor. The benzyl precursor may be benzyl chloride, benzyl bromide, benzyl iodide, benzyl tosylate, or benzyl mesylate.

[0848] In some embodiments, the benzyl precursor is benzyl bromide.

[0849] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor occurs in the presence of a base. Suitable bases include, but are not limited to, hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkoxides (e.g., lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), n-butyllithium, hydrides (e.g., sodium hydride, potassium hydride), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0850] In some embodiments, the base is a hydride base. In some embodiments, the base is sodium hydride.

[0851] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor occurs in the presence of a catalyst. The catalyst may be a tetrabutylammonium salt, such as tetrabutylammonium iodide, tetrabutylammonium bromide, or tetrabutylammonium chloride.

[0852] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor occurs in the absence of a catalyst.

[0853] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor occurs in the presence of a solvent. Suitable solvents include, but are not limited to, hydrocarbons (e.g., toluene, benzene, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl sulfoxide, etc.).

[0854] In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is tetrahydrofuran.Attorney Docket No.: 1583-US-NP / WO-PCT

[0855] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor occurs at a temperature of about -20 °C to about 60 °C. In some embodiments, the temperature is about -0 °C to about 20 °C. In some embodiments, the temperature is about 10 °C.

[0856] In some embodiments, the reaction between morpholin-3-one and the benzyl precursor (e.g., benzyl bromide) occurs in the presence of a base such as a hydride base (e.g., sodium hydride), a solvent such as an ether solvent (e.g., tetrahydrofuran), and at a suitable temperature such as a temperature of about 0 °C to about 20 °C (e.g., about 10 °C).Mitsunobu Cyclization Route

[0857] Additionally or alternatively, Compound IX or a salt thereof may be prepared via a compound of Formula IX-5a or a salt thereof by using Mitsunobu cyclization.

[0858] In some embodiments, provided is a process for preparing a compound of Formula IX-5aor a salt thereof, wherein PGN is a nitrogen protecting group;the process comprises one or more or all of the following steps:(a) contacting Compound XIII- 1OH NHiBoc XIII- 1or a salt thereof with Compound XIII-2L^CF3 XIII-2or a salt thereof to provide Compound XII- 1Boc xil- 1or a salt thereof;(b) subjecting Compound XII- 1 or a salt thereof to a deprotection condition to provide Compound XII-2Attorney Docket No.: 1583-US-NP / WO-PCTCompound XII-2or a salt thereof;(c) converting Compound XII-2 or a salt thereof to a compound of Formula XII-3or a salt thereof, wherein PGN is a nitrogen protecring group; and(d) subjecting a compound of Formula XII-3 or a salt thereof to a cyclization condition to provide a compound of Formula IX-5a.

[0859] The nitrogen protecting group (PGN) (e.g., the PGN group of Formula IX-5a) can be a sulfonyl group, acyl group, or carbamate group. For example, the PGN may be p-toluenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, benzenesulfonyl, triflouromethylsulfonyl, acetyl, trifluoroacetyl, benzoyl, pivaloyl, benzyloxycarbonyl, or tert-butyloxy carbonyl.

[0860] In some embodiments, PGN is a sulfonyl group. In some embodiments, PGN is p-toluenesulfonyl or 4-nitrobenzenesulfonyl.

[0861] In some embodiments, the process comprises contacting Compound XIII- 1 or a salt thereof with Compound XIII-2 or a salt thereof to provide Compound XII- 1 or a salt thereof.

[0862] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the presence of a base. Suitable bases include, but are not limited to, hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkoxides (e.g., alkali salts of methanol, ethanol, tert-butanol, etc.), carbonates (e.g., potassium carbonate, cesium carbonate, etc.), alkyllithium reagents (e.g., n-butyllithium, t-butyllithium, etc.), hydrides (e.g., sodium hydride, potassium hydride, etc.), and amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.).

[0863] In some embodiments, the base is a hydride. In some embodiments, the base is sodium hydride.

[0864] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the presence of a catalyst. In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the presence of a catalyst and in the absence of a base. Suitable catalysts include, but are not limited to, Lewis acids (e.g., boron trifluoride etherate, aluminum triflate, trimethylsilyl triflate, titanium tetrachloride, cobalt salen, zeolites, etc.) and proticAttorney Docket No.: 1583-US-NP / WO-PCT acids (e.g., sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, non-aqueous solutions of hydrochloric acid, etc.).

[0865] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the absence of a catalyst.

[0866] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, hydrocarbons (e.g., toluene, benzene, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), and polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl sulfoxide, etc.).

[0867] In some embodiments, the solvent is an ether. In some embodiments, the solvent is tetrahydrofuran.

[0868] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs at a temperature of about -60 °C to about 60 °C. In some embodiments, the temperature is about -10 °C to about 10 °C. In some embodiments, the temperature is about 0 °C.

[0869] In some embodiments, the reaction (e.g., the reaction between Compound XIII-1 and Compound XIII-2) occurs in the presence of a base such as a hydride (e.g., sodium hydride), a solvent such as an ether (e.g., tetrahydrofuran), and at a suitable temperature such as a temperature of about -10 °C to about 10 °C (e.g., about 0 °C).

[0870] In some embodiments, Compound XII- 1 is obtained as a racemic mixture. In some embodiments, Compound XII-1 is obtained as a single enantiomer (e.g., a single (S)-enantiomer).

[0871] In some embodiments, the process comprises subjecting Compound XII-1 or a salt thereof to a deprotection condition to provide Compound XII-2 or a salt thereof.

[0872] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound XII-2 from Compound XII-1) comprises a deprolcclion reagent. Suitable deprotection reagents include, but are not limited to, hydrogen chloride in an anhydrous solvent (e.g., hydrogen chloride in dioxane, etc.), mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylic acids (e.g., acetic acid, pivalic acid, trifluoroacetic acid, etc.), sulfonic acids (e.g., p-toluenesulfonic acid, etc.), oxalyl chloride, Lewis acids (e.g., boron trifluoride diethyl etherate, boron trifluoride THF complex, aluminum trichloride, silicon tetrachloride, etc.), and metal salts (e.g., iron(III) chloride, zinc(II) bromide, etc.).

[0873] In some embodiments, the deprotection reagent is hydrogen chloride in an anhydrous solvent. In some embodiments, the deprotection reagent is hydrogen chloride in dioxane.

[0874] In some embodiments, the deprotection condition (e.g., the deprolcclion condition for providing Compound XII-2 from Compound XII-1) comprises a solvent. Suitable solvents include, but are notAttorney Docket No.: 1583-US-NP / WO-PCT limited to, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.), nitriles (e.g., acetonitrile), halogenated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, etc.), and any combi nalion thereof.

[0875] In some embodiments, the solvent is an ether. In some embodiments, the solvent is tetrahydrofuran.

[0876] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound XII-2 from Compound XII- 1) comprises a temperature of about -40 °C to about 40 °C. In some embodiments, the temperature is about -10 °C to about 30 °C. In some embodiments, the temperature is about 0 °C to about 20 °C.

[0877] In some embodiments, the deprotection condition (e.g., the deprotection condition for providing Compound XII-2 from Compound XII- 1) comprises a deprotection reagent such as hydrogen chloride in an anhydrous solvent (e.g., hydrogen chloride in dioxane), a solvent such as an ether (e.g., tetrahydrofuran), and a suitable temperature such as a temperature of about -10 °C to about 30 °C (e.g., about 0 °C to about 20 °C).

[0878] In some embodiments, the process comprises converting Compound XII-2 or a salt thereof to a compound of Formula XII-3 or a salt thereof.

[0879] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the presence of a protecting group source. The protecting group source may be a sulfonyl source such as sulfonyl chlorides (e.g., p-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, etc.), sulfonyl bromides, sulfonyl fluorides, sulfonyl anhydrides, or N-phenyltriflimides. Additionally or alternatively, the protecting group source may be an acyl source such as acyl chlorides or acyl anhydrides. The protecting group source may also be a carbamate source such as benzyl chloroformate or di-tert-butyl dicarbonate.

[0880] In some embodiments, the protecting group source is a sulfonyl source. In some embodiments, the protecting group source is p-toluenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

[0881] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the presence of a base. Suitable bases include, but are not limited to, aromatic amines (e.g., pyridine, picoline isomers, lutidine isomers, collidine isomers, indole, isoindole, quinolone, isoquinoline, etc.) and amines (e.g., N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,4-diazabicyclo[2.2.2]octane, etc.).

[0882] In some embodiments, the base is an amine base. In some embodiments, the base istriethylamine.Attorney Docket No.: 1583-US-NP / WO-PCT

[0883] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the presence of a catalyst. Suitable catalysts include, but are not limited to, N-methylimidazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine.

[0884] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the absence of a catalyst.

[0885] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the presence of a solvent. Suitable solvents include, but are not limited to, esters (e.g., ethyl acetate, isopropyl acetate, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, etc.), halogenated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), and nitriles (e.g., acetonitrile).

[0886] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane.

[0887] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs at a temperature of about -40 °C to about 80 °C. In some embodiments, the temperature is about -10 °C to about 30 °C. In some embodiments, the temperature is about 0 °C to about 20 °C.

[0888] In some embodiments, the reaction (e.g., the reaction for providing a compound of Formula XII-3 from Compound XII-2) occurs in the presence of a protecting group source such as a sulfonyl source (e.g., p-toluenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride), a base such as an amine base (e.g., triethylamine), a solvent such as a halogenated solvent (e.g., dichloromethane), and at a suitable temperature such as a temperature of about -10 °C to about 30 °C (e.g., about 0 °C to about 20 °C).

[0889] In some embodiments, the process comprises subjecting a compound of Formula XII-3 or a salt thereof to a cyclization condition to provide a compound of Formula IX-5a or a salt thereof.

[0890] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises a reductive activator.Suitable reductive activators include, but are not limited to, arylphosphines (e.g., triphenylphosphine, 4-(diphenylphosphino)benzoic acid, l,2-bis(diphenylphosphino)ethane, 4-(dimethylamino)phenyldiphenylphosphine, etc.), alkylphosphines (e.g., trimethylphosphine, tricyclohexylphosphine, tributylphosphine, etc.), and resin-bound analogues thereof.

[0891] In some embodiments, the reductive activator is an arylphosphine. In some embodiments, the reductive acli valor is triphenylphosphine.Attorney Docket No.: 1583-US-NP / WO-PCT

[0892] In some embodiments, the cyclization condition (e.g., the cyclization condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises a reagent such as azodicarboxylates (e.g., diisopropyl azodicarboxylate, diethyl azodicarboxylate, di-2-methoxyethyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate, di-tert-butylazodicarboxylate, etc.), azo-type reagents (e.g., l,l-(azodicarbonyl)dipiperidine, 4,4’ -azopyridine, ethyl 2-(3,4-dichlorophenyl)azocarboxylate, etc.), or phosphonium ylides (e.g., (cyanomethylene)tributylphosphorane, (cyanomethylene)trimethylphosphorane, etc.).

[0893] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises diisopropyl azodicarboxylate.

[0894] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises a catalyst such as (2-hydroxybenzyl)diphenylphosphine oxide .

[0895] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) does not comprise a catalyst.

[0896] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises a solvent. Suitable solvents include, but are not limited to, esters (e.g., ethyl acetate, isopropyl acetate, etc.), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, etc.), hydrocarbons (e.g., toluene, n-heptane, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, etc.), halogenated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), and nitriles (e.g., acetonitrile, etc.).

[0897] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane.

[0898] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a from a compound of Formula XII-3) comprises a temperature of about -30 °C to about 100 °C. In some embodiments, the temperature is about -10 °C to about 30 °C. In some embodiments, the temperature is about 0 °C to about 20 °C.

[0899] In some embodiments, the cyclizalion condition (e.g., the cyclizalion condition for providing a compound of Formula IX-5a or a salt thereof from a compound of Formula XII-3 or a salt thereof) comprises a reductive activator (e.g., such as triphenylphosphine), a reagent (e.g., such as diisopropyl azodicarboxylate), a halogenated solvent (e.g., such as dichloromethane), and a suitable temperature such as a temperature of about -10 °C to about 30 °C (e.g., about 0 °C to about 20 °C).Attorney Docket No.: 1583-US-NP / WO-PCT

[0900] Additionally or alternatively, the process may comprise subjecting a compound of Formula XII-3 or a salt thereof to a cyclization condilion to provide a compound of Formula IX-5a or a salt thereof, wherein the cyclization condilion comprises (i) a sulfonylating reagent (e.g., sulfonyl chlorides, sulfonyl anhydrides, N-phenyltriflimide, etc.), an acylating reagent (e.g., acyl chlorides, anhydrides, etc.), a phosphorylating reagent (e.g., diphenylphosphoryl chloride, propanephosphonic acid anhydride, etc.), or an alkoxycarbonylaling reagent (e.g., methyl chloroformate, di-tert-butyl decarbonate, etc.); and (ii) an organic or inorganic organic base (e.g., pyridine, triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, potassium phosphate, sodium tert-butoxide, sodium hydroxide, etc.); and wherein PGN is an acyl group (e.g., acetyl, trifluoroacetyl, benzoyl, pivaloyl, etc.) or carbamate group (e.g., benzyloxy carbonyl, or tert-butyloxy carbonyl, etc.).

[0901] The process may further comprise converting a compound of Formula IX-5a or a salt thereof to Compound IXa or Compound IX or a salt thereof according to a process described anywhere herein. Synthesis of Compound X and Derivatives

[0902] Also provided is a process for preparing Compound Xor a salt thereof, comprising:contacting quinolin- 8 -amine with an ammonia source and a pyruvate source to form Compound X or a salt thereof.

[0903] Suitable ammonia source includes, but is not limited to, ammonium hydroxide, ammonium halide salts (e.g., ammonium chloride, ammonium bromide, etc.), ammonium carboxylate salts (e.g., ammonium formate, ammonium acetate, etc.), and ammonium phosphate.

[0904] In some embodiments, the ammonia source is an ammonium halide salt. In some embodiments, the ammonia source is ammonium chloride.

[0905] Suitable pyruvate source includes, but is not limited to, pyruvic acid and metal pyruvate salts (e.g., lithium pyruvate, sodium pyruvate, potassium pyruvate, etc.).

[0906] In some embodiments, the pyruvate source is a metal pyruvate salt. In some embodiments, the pyruvate source is sodium pyruvate.

[0907] In some embodiments, the reaction for providing Compound X occurs in the presence of a catalyst. In some embodiments, the catalyst is an enzyme. Suitable catalysts include, but are not limited to, tyrosine phenol lyase (e.g., C.freundii UniProt ID P31013 with additional mutations such as T124D / M288S / R381N / F448C, T124D / M288S / F448C, etc.), tryptophan synthase, and tryptophanase.Attorney Docket No.: 1583-US-NP / WO-PCT

[0908] In some embodiments, the catalyst is tyrosine phenol lyase (C.freundii UniProt ID P31013 with additional mutations T124D / M288S / R381N / F448C).

[0909] In some embodiments, the reaction for providing Compound X occurs in the presence of a cofactor that is pyridoxal phosphate.

[0910] In some embodiments, the reaction for providing Compound X occurs in the absence of an additive.

[0911] In some embodiments, the reaction for providing Compound X occurs in the presence of an additive. Suitable additives include, but are not limited to, reducing agents (e.g., beta-mer captoethanol, dithiothreitol, tris(2-carboxyethyl)phosphine, cysteine, glutathione, ascorbic acid, etc.), anti-foaming agents (e.g., poly(dialkylsiloxanes), polyalkylene glycols, etc.), and any combination thereof.

[0912] In some embodiments, the additive is a reducing agent. In some embodiments, the additive is beta-mercaptoethanol .

[0913] In some embodiments, the reaction for providing Compound X occurs in the presence of a buffer. Suitable buffers include, but are not limited to, potassium phosphate buffer, tris(hydroxymethyl)aminomethane buffer, 2-(N-morpholino)ethanesulfonic acid buffer, N-(2-acetamido)iminodiacetic acid buffer, 2, 2’ -(piperazine- l,4-diyl)di (ethane- 1 -sulfonic acid) buffer, 3-(morpholin-4-yl)propane-l -sulfonic acid buffer. The buffers may have a pH of about 5.0 to about 10.0 (e.g., about 8.0) and a concentration of about 0 M to about 4 M (e.g., about 0.1 M).

[0914] In some embodiments, the buffer is potassium phosphate, pH 8, 100 mM.

[0915] In some embodiments, the reaction for providing Compound X occurs at a temperature of about 0 °C to about 100 °C. In some embodiments, the temperature is about 10 °C to about 30 °C. In some embodiments, the temperature is about 20 °C.

[0916] In some embodiments, the reaction between quinolin-8-...

Claims

Attorney Docket No.: 1583-US-NP / WO-PCTWhat is Claimed is:

1. A process for preparing Compound Ior a salt thereof, comprising:coupling Compound IIor a salt thereof with Compound IIIor a salt thereof in the presence of a coupling agent to form Compound I.

2. The process of claim 1, wherein the coupling agent is thionyl chloride.

3. The process of claim 2, wherein Compound II is converted to Compound II- 1by the coupling agent prior to reacting with Compound III.

4. The process of any one of claims 1-3, which occurs in the presence of a base and a solvent.

5. The process of claim 4, wherein the base is triethylamine.

6. The process of claim 4, wherein the solvent is acetonitrile.Attorney Docket No.: 1583-US-NP / WO-PCT7. The process of any one of claims 1-6, which occurs at a temperature of about 5 °C to about 25 °C.

8. The process of any one of claims 1-7, which occurs at a temperature of about 15 °C.

9. A process for preparing Compound IIIor a salt thereof, comprising:(a) contacting Compound III- laBocor a salt thereof with ethanol in the presence of an acid to form Compound Illaor a salt thereof; and(b) crystallizing Compound Illa from a solvent to provide Compound III as a single atropisomer.

10. The process of claim 9, wherein the acid is methanesulfonic acid.

11. The process of claim 9 or 10, wherein ethanol is used as a solvent in step (a).

12. The process of any one of claims 9-11, wherein step (a) occurs at a temperature of about 65°C to about 85 °C.

13. The process of any one of claims 9-12, wherein step (a) occurs at a temperature of about 75°C.

14. The process of any one of claims 9-13, wherein Compound III-6a and / or Compound III-3aAttorney Docket No.: 1583-US-NP / WO-PCTBocare formed in step (a), each of which is independently subsequently converted to Compound Illa.

15. The process of any one of claims 9-14, wherein the solvent in step (b) is acetonitrile.

16. The process of any one of claims 9-15, wherein step (b) occurs at a temperature of about 60°C to about 10 °C.

17. The process of any one of claims 9-16, wherein step (b) occurs at a temperature of about 50°C to about 20 °C.

18. The process of any one of claims 9-17, wherein step (b) further comprises equilibrating Compound Illa prior to crystallization, wherein Compound Illa represents a mixture of atropisomers including Compound III.

19. The process of claim 18, wherein the equilibration step is performed under acidic or thermal condition.

20. The process of any one of claims 1-19, further comprising crystallizing Compound I.

21. The process of claim 20, wherein the process comprises crystallizing Compound I from an ethanol solvent at a temperature of about 50°C to about 20 °C.

22. The process of claim 20, wherein the process comprises crystallizing Compound I from a solvent that is a mixture of acetonitrile, tert-butyl methyl ether, and water, wherein the crystallization is performed in the presence of an acid and at a temperature of about 40°C to about 20 °C.

23.

23. The process of claim 22, wherein the acid is malonic acid and the crystallization step provides Compound I Mono-Malonate.

24. A process for preparing Compound III- laBocor a salt thereof, comprising:Attorney Docket No.: 1583-US-NP / WO-PCT(a) contacting Compound IV- 1Bocor a salt thereof with zinc; and(b) contacting a product from step (a) with a compound of Formula Vawherein X is Br or I,or a salt thereof in the presence of a catalytic system to form Compound III- 2aBocor a salt thereof.

25. The process of claim 24, wherein step (a) occurs in the presence of a solvent and an acli valor selected from methanesulfonic acid, iodine, 1,2-dibromoethane, and silyl chlorides.

26. The process of claim 25, wherein the activator is trimethylsilyl chloride.

27. The process of claim 25, wherein the solvent is a mixture of N.N-diinclhyllorinamidc and toluene.

28. The process of any one of claims 24-27, wherein step (a) occurs at a temperature of about 10°C to about 30 °C.

29. The process of any one of claims 24-28, wherein step (a) occurs at a temperature of about 20°C.

30. The process of any one of claims 24-29, wherein the product from step (a) is Compound IV-2 Bociv-2or a salt thereof.

31. The process of any one of claims 24-30, wherein the catalytic system in step (b) comprises a catalyst selected from a palladium catalyst and a nickel catalyst; a ligand; and a solvent.Attorney Docket No.: 1583-US-NP / WO-PCT32. The process of claim 31, wherein the catalyst is palladium(II) acetate.

33. The process of claim 31, wherein the ligand is 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (XPhos).

34. The process of claim 31, wherein the solvent is toluene.

35. The process of any one of claims 24-34, wherein step (b) occurs at a temperature of about 50 °C to about 70 °C.

36. The process of any one of claims 24-35, wherein step (b) occurs at a temperature of about 60 °C.

37. The process of any one of claims 24-36, further comprising subjecting Compound III-2aBocor a salt thereof to a hydrolysis condi lion to form Compound III- laBocor a salt thereof.

38. The process of claim 37, wherein the hydrolysis condition comprises a base and a solvent.

39. The process of claim 38, wherein the base is aqueous sodium hydroxide.

40. The process of claim 38, wherein the solvent is a mixture of toluene and 2-methyltetrahydrofuran.

41. The process of any one of claims 37-40, which occurs at a temperature of about -10 °C to about 10 °C.

42. The process of any one of claims 37-41, which occurs at a temperature of about 0 °C.

43. A process for preparing a compound of Formula VaAttorney Docket No.: 1583-US-NP / WO-PCTwherein X is Br or I,or a salt thereof, comprising:(a) contacting Compound VIor a salt thereof with a compound of Formula VIIwherein X is Br or I,or a salt thereof in the presence of an azide source or a deoxo-fluor to form a compound of Formula V-3wherein X is Br or I,or a salt thereof;(b) subjecting the compound of Formula V-3 or a salt thereof into a cyclization condition to provide a compound of Formula V-lawherein X is Br or I,or a salt thereof; and(c) contacting the compound of Formula V- la or a salt thereof with a methylation agent to form the compound of FormulaVa.

44. The process of claim 43, wherein step (a) occurs in the presence of an azide source that is diphenylphosphoryl azide (DPP A).

45. The process of claim 43 or 44, wherein step (a) occurs in the presence of a solvent and a base.Attorney Docket No.: 1583-US-NP / WO-PCT46. The process of claim 45, wherein the solvent is trifluorotoluene.

47. The process of claim 45, wherein the base is triethylamine.

48. The process of any one of claims 43-47, wherein step (a) occurs at a temperature of about 50 °C to about 70 °C.

49. The process of any one of claims 43-48, wherein step (a) occurs at a temperature of about 60 °C.

50. The process of any one of claims 43-49, wherein the cyclization condition in step (b) comprises a base and a solvent.

51. The process of claim 50, wherein the base is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

52. The process of claim 50, wherein the solvent is N-methyl-2-pyrrolidone.

53. The process of any one of claims 43-52, wherein the cyclization condition in step (b) comprises a temperature of about 10 °C to about 30 °C.

54. The process of any one of claims 43-53, wherein the cyclization condition in step (b) comprises a temperature of about 20 °C.

55. The process of any one of claims 43-54, wherein the methylation agent in step (c) is methyl iodide.

56. The process of any one of claims 43-55, wherein step (c) occurs in the presence of a base and a solvent.

57. The process of claim 56, wherein the base is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

58. The process of claim 56, wherein the solvent is N-methyl-2-pyrrolidone.

59. The process of any one of claims 43-58, wherein step (c) occurs at a temperature of about 10 °C to about 30 °C.

60. The process of any one of claims 43-59, wherein step (c) occurs at a temperature of about 20 °C.

61. The process of claim 37, wherein Compound III-2a or a salt thereof is subject to hydrolysis without isolation.

62. The process of claim 43, wherein the compound of Formula V-la or a salt thereof is subject to step (c) without isolation.Attorney Docket No.: 1583-US-NP / WO-PCT63. The process of claim 43, wherein the compound of Formula VI or a salt thereof is prepared from pyridine-3,4-dicarboxyhc acid through an anhydride intermediate that is furo[3,4-c]pyridine-l, 3-dione.

64. The process of claim 43, wherein the compound of Formula VII or a salt thereof is prepared by contacting quinolin- 8 -amine with an iodination agent or a bromination agent.

65. A process for preparing Compound IIIor a salt thereof, comprising:(a) contacting Compound IV-3Bociv-3or a salt thereof with zinc;(b) contacting a product from step (a) with Compound V-Ior a salt thereof in the presence of a catalytic system to form Compound III-3Bocor a salt thereof; and(c) subjecting Compound III-3 or a salt thereof to a deprotection condition to form Compound III or a salt thereof.

66. The process of claim 65, wherein step (a) occurs in the presence of a solvent and an ac ivator selected from methanesulfonic acid, iodine, 1,2-dibromoethane, and silyl chlorides.

67. The process of claim 66, wherein the activator is trimethylsilyl chloride.

68. The process of claim 66, wherein the solvent is a mixture of N,N-Dimethylformamide and toluene.Attorney Docket No.: 1583-US-NP / WO-PCT69. The process of any one of claims 65-68, wherein step (a) occurs at a temperature of about 10°C to about 30 °C.

70. The process of any one of claims 65-69, wherein step (a) occurs at a temperature of about 20°C.

71. The process of any one of claims 65-70, wherein the product from step (a) is Compound IV-4 Bocor a salt thereof.

72. The process of any one of claims 65-71, wherein the catalytic system in step (b) comprises a catalyst selected from a palladium catalyst and a nickel catalyst; a ligand; and a solvent.

73. The process of claim 72, wherein the catalyst is palladium(II) acetate.

74. The process of claim 72, wherein the ligand is 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (XPhos).

75. The process of claim 71, wherein the solvent is a mixture of toluene and N,N-dimethylformamide.

76. The process of any one of claims 65-75, wherein step (b) occurs at a temperature of about 50 °C to about 70 °C.

77. The process of any one of claims 65-76, wherein step (b) occurs at a temperature of about 60 °C.

78. The process of any one of claims 65-77, wherein the deprotection condition in step (c) comprises an acid and a solvent.

79. The process of claim 78, wherein the acid is phosphoric acid.

80. The process of claim 78, wherein the solvent is a mixture of ethanol and tetrahydrofuran.

81. The process of any one of claims 65-80, wherein step (c) occurs at a temperature of about 10 °C to about 30 °C.

82. The process of any one of claims 65-81, wherein step (c) occurs at a temperature of about 20 °C.

83. A process for preparing Compound III-3Attorney Docket No.: 1583-US-NP / WO-PCTBocor a salt thereof, comprising:(a) contacting Compound IV-5Bociv-5or a salt thereof with a benzoxazolium salt activator;(bl) contacting a product from step (a) with Compound V-l-Bror a salt thereof in the presence of a photosensitizer to provide Compound III-4Bocor a salt thereof; or(b2) contacting the product from step (a) with Compound V-Bror a salt thereof in the presence of a pholosensilizer to provide Compound III-3Bocor a salt thereof; andAttorney Docket No.: 1583-US-NP / WO-PCT(c) when step (bl) occurs, contacting Compound III-4 or a salt thereof with a methylation agent to form Compound III-3 or a salt thereof.

84. The process of claim 83, wherein the benzoxazolium salt activator is 5,7-di-tert-butyl-3-phenylbenzo [d] oxazol-3 -ium tetrafluoroborate .

85. The process of claim 83 or 84, wherein step (a) occurs in the presence of a solvent.

86. The process of claim 85, wherein the solvent is tert-butyl methyl ether.

87. The process of any one of claims 83-86, wherein step (a) occurs in the presence of a base.

88. The process of claim 86, wherein the base is pyridine.

89. The process of any one of claims 83-88, wherein step (a) occurs at a temperature of about 10 °C to about 30 °C.

90. The process of any one of claims 83-89, wherein step (a) occurs at a temperature of about 20 °C.

91. The process of any one of claims 83-90, wherein the photosensitizer in step (bl) or (b2) is 4CzIPN.

92. The process of any one of claims 83-91, wherein step (bl) or (b2) occurs under a light having a wavelength of about 450 nm.

93. The process of any one of claims 83-92, wherein step (bl) or (b2) occurs in the presence of a cocatalyst, a ligand, a base, a solvent, and an optional addili ve that is phthalimide or succinimide or a deri vali ve thereof.

94. The process of claim 93, wherein the co-catalyst is nickel (II) bromide ethylene glycol dimethyl ether.

95. The process of claim 93, wherein ligand is 4,4’ -dimethyl-2, 2’ -bipyridine.

96. The process of claim 93, wherein the base is 2,2,6,6-tetramethylpiperidine.

97. The process of claim 93, wherein the additive is phthalimide or succinimide.

98. The process of claim 93, wherein the solvent is mixture of tert-butyl methyl ether and dimethyl sulfoxide.

99. The process of any one of claims 83-98, wherein step (bl) or (b2) occurs at a temperature of about 15 °C to about 35 °C.Attorney Docket No.: 1583-US-NP / WO-PCT100. The process of any one of claims 83-99, wherein step (bl) or (b2) occurs at a temperature of about 25 °C.

101. The process of claim 83, wherein the methylation agent in step (c) is methyl iodide.

102. The process of any one of claims 83-101, wherein step (c) occurs in the presence of a base and a solvent.

103. The process of claim 102, wherein the base is potassium carbonate.

104. The process of claim 102, wherein the solvent is N-methyl-2-pyrrolidone.

105. The process of any one of claims 83-104, wherein step (c) occurs at a temperature of about 10 °C to about 30 °C.

106. The process of any one of claims 83-105, wherein step (c) occurs at a temperature of about 20 °C.

107. The process of claim 83, wherein step (bl) and step (c) occurs.

108. The process of claim 83, wherein step (b2) occurs.

109. The process of any one of claims 83-108, further comprising converting Compound III-3 or a salt thereof to Compound III or a salt thereof.

110. A process for preparing a compound of Formula V-lawherein R is a C1-3 alkyl and X is Br or I,or a salt thereof, comprising:subjecting a compound of Formula V-2wherein R is a C1-3 alkyl and X is Br or I,or a salt thereof into a cyclization condition to form a compound of Formula V-la or a salt thereof.

111. The process of claim 110, wherein the cyclization condi lion comprises an organocatalyst selected from squaramides, chiral guanidines, and chiral phase transfer catalysts; a base; and a solvent.Attorney Docket No.: 1583-US-NP / WO-PCT112. The process of claim 111, wherein the organocatalyst is a squaramide compound that is 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(8a,9S)-6’-methoxycinchonan-9-yl]amino]- 3-cyclobutene- 1,2-dione (CAS 1256245-84-7).

113. The process of claim 111, wherein the base is l,8-diazabicyclo(5.4.0)undec-7-ene or potassium carbonate.

114. The process of claim 111, wherein the solvent is N-methyl-2-pyrrolidone.

115. The process of any one of claims 110-114, wherein the cyclization condition further comprises a temperature of about 10 °C to about 30 °C.

116. The process of any one of claims 110-115, wherein the cyclization condition further comprises a temperature of about 20 °C.

117. A process for preparing Compound III-4Bocor a salt thereof, comprising:subjecting Compound III-5or a salt thereof into a cyclization condition to form Compound III-4Bocsalt thereof.

118. The process of claim 117, wherein the cyclization condition comprises an organocatalyst selected from squaramides, chiral guanidines, and chiral phase transfer catalysts; a base; and a solvent.

119. The process of claim 118, wherein the organocatalyst is 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[(8a,9s)-cinchonan-9-ylamino]-3-cyclobutene-l, 2-dione (CAS 1256245-86-9).Attorney Docket No.: 1583-US-NP / WO-PCT120. The process of claim 118, wherein the base is cesium carbonate.

121. The process of claim 118, wherein the solvent is N,N-dimethylformamide.

122. The process of any one of claims 117-121, wherein the cyclization condition further comprises a temperature of about 10 °C to about 30 °C.

123. The process of any one of claims 117-122, wherein the cyclization condition further comprises a temperature of about 20 °C.

124. The process of any one of claims 117-123, further comprises convening Compound III-4 or a salt thereof to Compound III or a salt thereof.

125. A process for preparing Compound IIor a salt thereof, comprising:(a) contacting Compound VIIIor a salt thereof with Compound IXor a salt thereof in the presence of a catalytic system to provide Compound II-2or a salt thereof; and(b) subjecting Compound II- 2 or a salt thereof into a hydrolysis condition to form Compound II or a salt thereof.Attorney Docket No.: 1583-US-NP / WO-PCT126. The process of claim 125, wherein the catalytic system comprises a palladium catalyst, a ligand, a base, a solvent, and an optional phase transfer catalyst.

127. The process of claim 126, wherein the solvent is a mixture of toluene and N-methyl-2-pyrrolidone.

128. The process of claim 126, wherein the base is a combination of cesium carbonate and tripropylamine.

129. The process of claim 126, wherein the palladium catalyst is palladium(II) acetate.

130. The process of claim 126, wherein the ligand is 2-dicyclohexylphosphino-2’-6’-diisopropoxybiphenyl (RuPhos).

131. The process of any one of claims 125-130, wherein step (a) occurs at a temperature of about 85 °C to about 105 °C.

132. The process of any one of claims 125-131, wherein step (a) occurs at a temperature of about 95 °C.

133. The process of claim 125, wherein the hydrolysis condition in step (b) comprises a base, a solvent and an oplional phase transfer catalyst.

134. The process of claim 133, wherein the base is aqueous sodium hydroxide.

135. The process of claim 133, wherein the solvent is a mixture of toluene and methanol.

136. The process of any one of claims 125-135, wherein the hydrolysis condition in step (b) further comprises a temperature of about 50 °C to about 70 °C.

137. The process of any one of claims 125-136, wherein the hydrolysis condition in step (b) further comprises a temperature of about 60 °C.

138. The process of claim 125, wherein Compound VIII or a salt thereof is prepared by contacting 4-bromo-2-fluoro-6-methylbenzoic acid or a salt thereof with a methylation agent.

139. The process of claim 125, further comprising recrystallizing Compound IX or a salt thereof.

140. The process of claim 125, wherein the Compound IX or a salt thereof is prepared by chiral resolution.

141. The process of claim 125, comprising contacting Compound IXa free baseAttorney Docket No.: 1583-US-NP / WO-PCTwith a chiral acid that is optically pure to form Compound IX chiral acid salt.

142. The process of claim 141, wherein the chiral acid is (+)-Camphorsulfonic acid and the Compound IX chiral acid salt is Compound IX (+)-Camphorsulfonic acid salt.

143. A process for preparing Compound IXor a salt thereof, comprising:(a) contacting compound of Formula IX- 1or a salt thereof with a tri fluoromethy lalion agent to form a compound of Formula IX-2or a salt thereof;(b) subjecting the compound of Formula IX-2 or a salt thereof to an asymmetric hydrogenation condition to form a compound of Formula IX-30.N CF3PG IX-3Attorney Docket No.: 1583-US-NP / WO-PCTwherein PG is benzylor a salt thereof; and(c) subjecting the compound of formula IX-3 or a salt thereof to a deprotection condition to form Compound IX or a salt thereof, wherein the deprotection condition in step (c) comprises a chiral acid.

144. The process of claim 143, wherein the trifluoromethylation agent in step (a) is (trifluoromethyl)trimethylsilane.

145. The process of claim 143 or 144, wherein step (a) occurs in the presence of a base and a solvent.

146. The process of claim 145, wherein the base is potassium tert-butoxide.

147. The process of claim 145, wherein the solvent is toluene.

148. The process of any one of claims 143-147, wherein step (a) occurs at a temperature of about -10 °C to about 10 °C.

149. The process of any one of claims 143-148, wherein step (a) occurs at a temperature of about 0 °C.

150. The process of any one of claims 143-149, wherein the asymmetric hydrogenation condition in step (b) comprises a catalyst, a ligand, a hydrogen source, a solvent, and an optional additive that is an acid.

151. The process of claim 150, wherein the catalyst is nickel (II) acetate.

152. The process of claim 150, wherein the ligand is (S)-l-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Josiphos).

153. The process of claim 150, wherein the hydrogen source is hydrogen gas.

154. The process of claim 150, wherein the solvent is 2,2,2-trifluoroethanol.

155. The process of any one of claims 143-154, wherein the asymmetric hydrogenation condition in step (b) further comprises a temperature of about 60 °C.

156. The process of any one of claims 143-155, wherein the deprotection condition in step (c) comprises a reductant, a catalyst, and a solvent.

157. The process of claim 156, wherein the reductant is hydrogen gas.Attorney Docket No.: 1583-US-NP / WO-PCT158. The process of claim 156 wherein the catalyst is palladium on carbon.

159. The process of claim 157, wherein the solvent is methanol.

160. The process of any one of claims 143-159, wherein the deprotection condition in step (c) further comprises a temperature of about 10 °C to about 30 °C.

161. The process of any one of claims 143-160, wherein the deprotection condition in step (c) further comprises a temperature of about 20 °C.

162. The process of any one of claims 143-161, wherein the chiral acid in step (c) is (+)-camphorsulfonic acid.

163. The process of claim 162, wherein a product from step (c) is Compound IX (+)-camphorsulfonic acid salt.

164. The process of claim 143, wherein165. The process of claim 164, wherein the compound of Formula I, which is prepared by contacting morpholin-3-one with l-(chloromethyl)naphthalene.

166. A process for preparing Compound II,or a salt thereof, comprising:(a) contacting Compound VIIIAttorney Docket No.: 1583-US-NP / WO-PCTor a salt thereof with morpholin-3-one in the presence of a catalytic system to form Compound II-3or a salt thereof;(b) contacting Compound II-3 with a trifluoromethylation agent;(c) subjecting a product from step (b) into an elimination condition to form Compound II-4or a salt thereof;(d) subjecting Compound II-4 into an asymmetric hydrogenation condition to form Compound II-2or a salt thereof.

167. The process of claim 166, wherein the catalytic system comprises a catalyst selected from a copper catalyst and a palladium catalyst; a ligand; a base; and a solvent.

168. The process of claim 167, wherein the catalyst is copper (I) iodide, the ligand is trans-N,N'-bis-methyl-l,2-cyclohexanediamine, the base is potassium carbonate, and the solvent is toluene.

169. The process of claim 168, which occurs at a temperature of about 100 °C.

170. The process of claim 167, wherein the catalyst is XantPhos Pd G4, the ligand is XantPhos from the XantPhos Pd G4 catalyst, the base is cesium carbonate, and the solvent is toluene.

171. The process of claim 170, which occurs at a temperature of about 85 °C.Attorney Docket No.: 1583-US-NP / WO-PCT172. The process of any one of claims 166-171, wherein the trifluoromethylation agent in step (b) is (trifluoromethyl)trimethylsilane.

173. The process of any one of claims 166-171, wherein step (b) occurs in the presence of a solvent and an initiator that is a fluoride source, a carboxylate, or an alkoxide.

174. The process of claim 172, wherein the solvent is 2-methyltetrahydrofuran.

175. The process of claim 172, wherein the initiator is cesium fluoride.

176. The process of any one of claims 166-174, wherein step (b) occurs at a temperature of about -15 °C to about 15 °C.

177. The process of any one of claims 166-175, wherein the elimination condition in step (c) comprises an acid and a solvent.

178. The process of claim 177, wherein the acid is hydrogen chloride solution in dioxane.

179. The process of claim 177, wherein the solvent is 2-methyltetrahydrofuran.

180. The process of any one of claims 166-179, wherein step (c) occurs at a temperature of about 15 °C.

181. The process of any one of claims 166-180, wherein the asymmetric hydrogenation condition in step (d) comprises a catalyst selected from a rhodium catalyst, an iridium, a ruthenium catalyst, a nickel, and a palladium catalyst; a ligand; a hydrogen source; a solvent; and an optional additive.

182. The process of claim 181, wherein the catalyst is bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate.

183. The process of claim 181, wherein the ligand is (R)-(+)-l-[(R)-2-(2’-dicyclohexylphosphinophenyl)ferrocenyl]ethylbis(3,5- trifluoromethylphenyl)phosphine.

184. The process of claim 181, wherein the hydrogen source is hydrogen gas.

185. The process of claim 181, wherein the solvent is 2,2,2-trifhioroethanol.

186. The process of any one of claims 166-185, wherein the asymmetric hydrogenation condition further comprises a temperature of about 50 °C to about 70 °C.

187. The process of any one of claims 166-186, wherein the asymmetric hydrogenalion condition further comprises a temperature of about 60 °C.Attorney Docket No.: 1583-US-NP / WO-PCT188. The process of any one of claims 166-187, wherein the asymmetric hydrogenation condition further comprises an elevated pressure.

189. The process of claim 188, wherein the elevated pressure is about 120 psi.

190. The process of any one of claims 166-189, further comprising subjecting Compound II-2or a salt thereof into a hydrolysis condition to form Compound IIor a salt thereof.

191. A process of for preparing Compound Xor a salt thereof, comprising:contacting quinolin- 8 -amine with an ammonia source and a pyruvate source to form Compound X or a salt thereof.

192. The process of claim 191 wherein the ammonia source is ammonium chloride.

193. The process of claim 191 wherein the pyruvate source is sodium pyruvate.

194. The process of claim 191 which occurs in the presence of an enzyme catalyst, a cofactor, an additive, and a buffer.

195. The process of claim 194 wherein the catalyst is Tyrosine phenol lyase M24.

196. The process of claim 194 wherein the cofactor is pyridoxal phosphate.

197. The process of claim 194, wherein the additive is beta-mercaptoethanol.Attorney Docket No.: 1583-US-NP / WO-PCT198. The process of claim 194, wherein the buffer is a potassium phosphate buffer.

199. The process of claim 191, which occurs at a temperature of about 20 °C.

200. A process of for preparing Compound X-3or a salt thereof, comprising:(a) contacting Compound IV-4Bociv-4or a salt thereof with Compound VII-2or a salt thereof in the presence of a catalytic system to provide Compound X-4Bocor a salt thereof; and(b) subjecting Compound X-4 or a salt thereof to a reductive condition to provide Compound X-3 or a salt thereof.

201. The process of claim 200, wherein the catalytic system comprises a catalyst, a ligand, and a solvent.

202. The process of claim 201, wherein the catalyst is tris(dibenzylideneacetone)dipalladium(0).

203. The process of claim 201, wherein the ligand is 2-dicyclohexylphosphino-2’, 6’ -dimethoxybiphenyl.

204. The process of claim 201, wherein the solvent is MN-diinclhyllorinamidc.

205. The process of any one of claims 200-204, wherein step (a) occurs at a temperature of about 45 °C to about 65 °C.Attorney Docket No.: 1583-US-NP / WO-PCT206. The process of any one of claims 200-205, wherein step (a) occurs at a temperature of about 55 °C.

207. The process of claim 200, wherein the reductive condition comprises a reducing agent and a solvent.

208. The process of claim 207, wherein the reducing agent is zinc powder in combination with ammonium chloride.

209. The process of claim 207, wherein the solvent is a mixture of ethanol and water.

210. The process of any one of claims 200-209, wherein the reductive condition further comprises a temperature of about 10 °C to about 30 °C.

211. The process of any one of claims 200-210, wherein the reductive condition further comprises a temperature of about 20 °C.

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