Process for producing a tetrahydropyran-substituted bicyclic pyrimidinedione compound

Abstract

The present invention relates to Compound 1, or salt thereof, which is useful in the treatment of hypertrophic cardiomyopathy and related cardiac disorders and / or diseases. The present invention further relates to synthetic processes for producing Compound 1, and to the novel intermediates of the synthetic process for producing Compound 1. The present invention also relates to synthetic processes for producing crystalline Form B of Compound 1.

Description

267224-558390PROCESS FOR PRODUCING A TETRAHYDROPYRAN-SUBSTITUTED BICYCLIC PYRIMIDINEDIONE COMPOUNDCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The application claims benefit under 35 U. S. C. § 119(e) and priority to U. S. Provisional Application No. 63 / 728,881 filed Dec. 6, 2024, U. S. Provisional Application No. 63 / 798,327 filed May 1, 2025, and U. S. Provisional Application No. 63 / 860,216 filed Aug. 8, 2025, each of which is incorporated herein by reference in its entirety.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to Compound 1, or a salt thereof, which is a tetrahydropyran-substituted bicyclic pyrimidinedione compound useful in the treatment of hypertrophic cardiomyopathy and related cardiac disorders and / or diseases. The present invention further relates to synthetic processes for producing Compound 1, and to the novel intermediates of the synthetic process for producing Compound 1. The present invention also relates to synthetic processes for producing crystalline Form B of Compound 1.BACKGROUND OF THE INVENTION

[0003] Genetic (heritable) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant myocardial diseases. HCM is caused by one or more of over 1,000 known point mutations in any one of the structural protein genes contributing to the functional unit of myocardium, the sarcomere. About 1 in 500 individuals in the general population are found to have left ventricular hypertrophy unexplained by other known causes (e.g., hypertension or valvular disease), and many of these can be shown to have HCM, once other heritable (e.g., lysosomal storage diseases), metabolic, or infdtrative causes have been excluded.

[0004] Sarcomere gene mutations that cause HCM are highly penetrant, but there is wide variability in clinical severity and clinical course. Some genotypes are associated with a more malignant course, but there is considerable variability between and even within families carrying the same mutation. Sex differences have also been noted, with male patients generally more severely affected than female patients. While many patients with HCM report minimal or no symptoms for extended periods of time, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of effort intolerance predominate, and can be exacerbated by exercise and other maneuvers that increase heart rate and / or decrease preload. As63018663 3267224-558390with many other disorders, symptoms tend to worsen with age. By far the most prevalent clinical burden for patients with HCM is exertional dyspnea, which limits their activities of daily living and can be debilitating.

[0005] Patients with HCM are often symptomatic in the absence of documented hemodynamic abnormalities like left ventricular outflow tract obstruction (with or without mitral regurgitation). Patients’ symptoms of exertional dyspnea can rapidly worsen with the onset of atrial fibrillation, a common complication of HCM that can precipitate acute pulmonary edema and increases the risk of systemic arterial thromboembolic disease, including stroke. Other adverse events associated with HCM include intolerance of hypovolemia or hypervolemia, and syncope.Concomitant coronary artery disease may confer a higher risk of acute coronary syndromes than in patients without HCM. Sudden cardiac death (SCD) in patients with HCM is both uncommon and difficult to predict but is a leading cause of non-traumatic death in young adults. For survivors of SCD, ICD placement is standard practice, and in other HCM patients risk profiling, while imprecise, is used to identify those for whom ICD placement for primary prevention is deemed prudent.

[0006] Medical therapy for HCM is limited to the treatment of symptoms and does not address the fundamental, underlying cause of disease, which are disruptions in normal sarcomere function. Currently available therapies are variably effective in alleviating symptoms but typically show decreased efficacy with increasing disease duration. Patients are thus empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers, and / or disopyramide. None of these agents carry labeled indications for treating HCM, and essentially no rigorous clinical trial evidence is available to guide their use. Compounding this unfortunate situation is the fact that no new medical therapies for HCM have been identified for many years. For patients with hemodynamically significant outflow tract obstruction (resting gradient >30 mm Hg), in appropriately selected patients surgical myectomy or alcohol septal ablation is usually required to alleviate the hemodynamic obstruction. The present disclosure provides novel synthetic methods for the production of Compound 1, a therapeutic agent that remedies the long-felt need for improved treatment of HCM and related cardiac disorders and / or diseases.SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention includes a process for producing Compound 1263018663 3267224-558390or a salt thereof, the process comprising contacting Compound 2Oor a salt thereof, with a compound having the structure*2, optionally in the presence of a solvent, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-, F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substituted phenyl)-C(O)O-,(optionally substituted phenyl)-O-, imidazole,or O

[0008] In one embodiment of this aspect, the process further comprises producing crystalline Form B of Compound 1 by:a. heating a mixture of solid Compound 1 in a solvent that is a combination of one or more organic solvents and water to dissolve the solid Compound 1;b. cooling the mixture formed in step a) to create a slurry;c. adding water to the mixture formed in step b);d. wet milling the slurry formed in step c);e. adding water to the slurry formed in step d);f. reducing the amount of solvent in the slurry formed in step e) by distillation at reduced pressure;g. adding water to the slurry formed in step f);h. cooling the slurry formed in step g); and363018663 3267224-558390i. isolating the solid Form B of Compound 1.

[0009] In another aspect, the invention includes a compound, or salt thereof, selected from the group consisting of0N — W N'Vi i n II J H N N H2N N H2Compound 2 Compound 3o OII J H II J H CI / ^N^'NH2CI^N^CICompound 4 Compound 5oO YYMHJ II J CI^N NHCompound 6 and Compound 7O II II H YY '' N NH2II J HCompound 8

[0010] In another aspect, the invention includes a process for producing Compound 2,Compound 2463018663 3267224-558390or a salt thereof, with high optical purity from Compound 2-racCompound 2-racthe process comprising contacting Compound 2-rac with an optically active acid in the presence of a solvent, and isolating the resulting Compound 2 acid addition salt.

[0011] In another aspect, the invention includes a process for producing Compound 1or a salt thereof, the process comprising contacting Compound 2-MACompound 2-MAOwith a compound having the structure*2, in the presence of a solvent and a salt selected from Ca(OTf)2, Mg(OTf)2, NaOTf; Zn(OTf)2 and KOTf, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-, F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substituted phenyl)-C(O)O-, (optionally substituted phenyl)-O-, imidazole, ON-0or O

[0012] In another aspect, the invention includes a process for producing Compound 2-rac:563018663 3267224-558390Compound 2-racthe process comprising reducing Compound 3Compound 3in the presence of a reducing agent to provide Compound 2-rac.DETAILED DESCRIPTION OF THE INVENTION

[0013] Definitions

[0014] As used herein, the following definitions shall apply unless otherwise indicated.

[0015] As used herein, " Compound 1" refers to the compound having the formula (or structure):Compound 1

[0016] Compound 1 has the chemical name: (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione.Compound 1, was described in U. S. Patent No. 11,034,693 and PCT Application Publication No. WO 2020 / 092208, each of which are incorporated by reference in their entirety herein.

[0017] Compound 1 has been shown to be useful in the treatment of hypertrophic cardiomyopathy and related cardiac disorders and / or diseases.

[0018] As used herein, the term "about", when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.663018663 3267224-558390

[0019] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in " Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0020] As used herein, the term "slurry" refers to a mixture comprising a liquid and a solid, wherein the solid is typically present as small particles.

[0021] It is noted that the use of the descriptors "first", "second", "third", or the like is used to differentiate separate elements (e.g., mixtures, solvents, reaction steps, processes, reagents, or the like) and may or may not refer to the relative order or relative chronology of the elements described.

[0022] As used herein, the term "solvent" refers to the liquid in which a solute is dissolved or slurried to form a solution.

[0023] As used herein, the unit of measure, “volume” or “V” refers to a unit of measurement for the amount of a liquid (typically the solvent) used with respect to the limiting reagent.Exemplary units for volumes (V) are, but not limited to, "mL / g" (mL of solvent per g of limiting reagent) or " L / kg" (Liters of solvent per Kg of limiting reagent. For example, 5 V of solvent with respect to 1 g of limiting reagent would equal 5 mL solvent.

[0024] As used herein, the term "neutralize" in acid-base chemistry refers to the act of adding an acid or a base to a mixture in order to change the pH to approximately 7 (for example, a pH of 6-8, 6.5-7.5, 6.8-7.2, or 6.9-7.1).

[0025] As used herein, the term "molar equivalent" refers to the ratio of the moles of one compound to the moles of another, typically the limiting reagent or reactant.

[0026] As used herein, the term "catalyst" refers to a substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change.

[0027] As used herein, the term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.763018663 3267224-558390

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0029] As used herein, the “reducing agent” refers to any substance that has the ability to reduce (or give electrons to) other substances. Examples of reducing agents include, without limitation, sodium borohydride, zinc amalgam, lithium aluminum hydride (LiAlPU), diborane, sodium amalgam, sodium lead alloy, nascent hydrogen, and thiosulfates.

[0030] As used herein, the term "oxidizing reagent" refers to any substance that has the ability to oxidize (or accept electrons from) other substances. Examples of oxidizing reagents include863018663 3267224-558390without limitation O2, oxone, NalC, metal bromates (e.g., alkali metal bromates, e.g., NaBrCh); metal dichromates (e.g., alkali metal dichromates, e.g., potassium dichromate); pyridinium chlorochromate (" PCC"); pyridinium dichromate (" PDC"); Dess-Martin periodinane; Swern oxidation agents (i.e., oxalyl chloride and DMSO followed by an treatment with an organic base (e g., EtsN)); Collins oxidation agents (i.e., chromium(VI) oxide with pyridine in dichloromethane); Jones oxidation agents (i.e., chromium trioxide in aqueous sulfuric acid added to acetone reaction solution); and the like.

[0031] Table of Abbreviations:Abbreviation Solvent, Reagent, or unit of measure 2-MeTHF 2-methyltetrahydrofuran9-BBN 9-Borabicyclo[3.3.1 ]nonane ACN / MeCN AcetonitrileBHT 2,6-di-tert-butyl-4-methylphenol BOP B enzotri azol e- 1 -y 1 -oxy-tri s- (dimethylamino)-phosphonium hexafluorophosphateBPPO N, N' -bi s(2-pheny Ipheny 1 ) oxal ami de BuOH ButanolC or °C Degrees CelciusCDI carbonyldiimidazoleCOMU 1 -[(l-(Cyano-2-ethoxy-2- oxoethy 1 ideneami nooxy ) dimethylaminomorpholino)] uronium hexafluorophosphateCPME Cyclopentyl methyl etherDCM DichloromethaneDIPEA DiisopropylethylamineDMAc DimethylacetamideDME Di methoxy ethaneDMF Dimethylformamide963018663 3267224-558390DMPAO (2,6-dimethylphenyl)carbamoyl]formic acid or 2,6- dimethylanilino(oxo)acetic acid DMPU N, N’ -Dimethylpropyleneurea DMSO DimethylsulfoxideEMM 2-(ethoxymethylene) malonodinitrile Et EthylEtOAc Ethyl acetateEtOH EthanolHATU l-[Bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl UroniumHBTU 2-( 1 H-B enzotri azol e- 1 -y 1)- 1, 1,3,3- tetramethyluronium hexafluorophosphateHCTU O-(lH-6-Chlorobenzotriazole-l-yl)- 1, 1, 3, 3 -tetramethy luronium hexafluorophosphateHMPA Hexamethylphosphoramidehr or h hour(s)IPA Isopropyl alcoholIPAC Isopropyl acetateKg kilogram(s)L liter(s)MAD methyl aluminum bis(2,6-di-te / 7- buty 1 -4-methy Iphenoxi de)Me Methyl1063018663 3267224-558390MEK Methyl ethyl ketoneMeOH methanolMIBK Methyl isobutyl ketoneMin minute(s)MTBE Methyl / m-butyl etherNMP N-Methyl-2-pyrrolidone or 1-methyl- 2-pyrrolidonePyBOP benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphatePyAOP (7 -Azab enzotri azol - 1 - yloxy)tripyrrolidinophosphonium hexafluorophosphatePyOxim Ethyl cyano(hydroxyimino)acetato- O2]tri-l-pyrrolidinylphosphonium hexafluorophosphateRPM Revolutions per minuteRt room temperature (e.g., from about 24.5 °C - 27.5 °C)THF TetrahydrofuranTSTU O-(N-Suc-cinimidyl)-l, 1,3,3- tetramethyl-uronium tetrafluoroborate V volumes

[0032] Methods of Synthesis of Compound 1

[0033] In one aspect, the invention includes a process for producing a compound of Formula IFormula I1163018663 3267224-558390or a salt thereof, comprising reducing a compound of Formula TIor a salt thereof, in the presence of a reducing agent, whereinRing A and Ring B are each independently selected from phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from R’, OH, halo, CN, NH2, NHR’, N(R’)2, OR’, C(O)H, C(O)R’, C(O)OR’, C(O)NH2, C(O)NHR’, and C(O)N(R’)2, wherein each R’ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halo, OH, oxo, and OC1-6 alkyl;each R is independently selected from OH, halo, CN, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl, C(O)H, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, C(O)NH2, C(O)NHCI-6 alkyl, and C(O)N(CI-6 alkyl)2; andeach p is 0, 1, or 2.

[0034] In one embodiment of this aspect, Ring A is selected from optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl.

[0035] In another embodiment, Ring A is selected from phenyl and 5-6 membered heteroaryl, wherein Ring A is optionally substituted with one or more substituents selected from Ci-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.

[0036] In another embodiment, Ring A is phenyl, optionally substituted with one or more substituents selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkynyl.

[0037] In one embodiment, Ring B is selected from optionally substituted 3-6 membered cycloalkyl, and optionally substituted 3-6 membered heterocycloalkyl.

[0038] In another embodiment, Ring B is selected from 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.1263018663 3267224-558390

[0039] In a further embodiment, Ring B is 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from O and N, wherein Ring B is optionally substituted with one or more substituents selected from Ci-6 alkyl, OH, halo, Ci-6 haloalkyl, and OCi-6 alkyl.

[0040] In still a further embodiment, Ring B is an unsubstituted tetrahydropyan-4-yl.

[0041] In one embodiment, each R is independently selected from OH, halo, CN, Ci-6 alkyl, Ci-6 haloalkyl, and OCi-6 alkyl.

[0042] In another embodiment, each R is independently selected from OH, halo, and Ci-6 alkyl.

[0043] In one embodiment, p is 1.

[0044] In a further embodiment, p is 1 and R is halo.

[0045] In one embodiment, the reduction is performed in the presence of an acid and a solvent.

[0046] In another embodiment, the solvent is selected from l-methyl-2-pyrrolidone, 2,5,7,10-tetraoxaundecane (TOU), Elcosol DM, and 1,3 -dioxolane. In a further embodiment, the solvent is l-methyl-2-pyrrolidone.

[0047] In another embodiment, the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

[0048] In a further embodiment, the acid is methanesulfonic acid.

[0049] In one embodiment, the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

[0050] In another embodiment, the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

[0051] In a further embodiment, the catalyst is selected from Pd / C, Pd / AhCh, Pt / C, Pt / AhCh, Rh / C, Rh / AICCh, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

[0052] In another embodiment, the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

[0053] In one aspect, the invention includes a process for producing a compound of Formula I1363018663 3267224-558390or a salt thereof, comprising reducing a compound of Formula IIor a salt thereof, in the presence of a first reducing agent to provide a compound of Formula IIIFormula IIIor a salt thereof, and then reducing the compound of Formula III in the presence of a second reducing agent to provide a compound of Formula 1,wherein Ring A and Ring B are each independently selected from phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from R’, OH, halo, CN, NH2, NHR’, N(R’)2, OR’, C(O)H, C(O)R’, C(O)OR’, C(O)NH2, C(O)NHR’, and C(O)N(R’)2, wherein each R’ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halo, OH, oxo, and OC1-6 alkyl;each R is independently selected from OH, halo, CN, C1-6 alkyl, C1-6 haloalkyl, OC1-6 alkyl, C(O)H, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, C(O)NH2, C(O)NHCI-6alkyl, and C(O)N(CI-6 alkyl)2; andeach p is 0, 1, or 2.1463018663 3267224-558390

[0054] In one embodiment of this aspect, Ring A is selected from optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl.

[0055] In another embodiment, Ring A is selected from phenyl and 5-6 membered heteroaryl, wherein Ring A is optionally substituted with one or more substituents selected from Ci-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.

[0056] In a further embodiment, Ring A is phenyl, optionally substituted with one or more substituents selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkynyl.

[0057] In one embodiment, Ring B is selected from optionally substituted 3-6 membered cycloalkyl, and optionally substituted 3-6 membered heterocycloalkyl.

[0058] In another embodiment, Ring B is selected from 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.

[0059] In a further embodiment, Ring B is 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from O and N, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, C1-6 haloalkyl, and OC1-6 alkyl.

[0060] In still a further embodiment, Ring B is an unsubstituted tetrahydropyan-4-yl.

[0061] In another embodiment, each R is independently selected from OH, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and OC1-6 alkyl.

[0062] In a further embodiment, each R is independently selected from OH, halo, and C1-6 alkyl.

[0063] In one embodiment, p is 1.

[0064] In a further embodiment, p is 1 and R is halo.

[0065] In one embodiment, the first reduction is performed in the presence of a first solvent, and the second reduction is performed in the presence of a second solvent.

[0066] In another embodiment, the first and second reducing agents are the same or different and are selected from dimethyl sulfide borane, dimethyl sulfide di chloroborane, dimethyl sulfide chloroborane, tetrahydrofuran borane, catechol borane, 9-borabicyclo[3.3.1]nonane, sodium triacetoxyborohydride, sodium borohydride, dissopinocampheylborane, trimethylamine borane, 2-methylpyridine borane, Zc / 7-butylamine borane, pyridine borane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with triphenylborane, trichlorosilane, dichlorosilane, phenylsilane, chlorophenyl silane, di chlorophenylsilane, diphenyl silane, triphenyl silane, 2, 4,6,8-1563018663 3267224-558390tetramethylcyclotetrasiloxane, tri ethoxy silane, polymethylhydrosiloxane (PMHS), 1, 1,3,3-tetramethyldisiloxane, and pentamethyldisiloxane.

[0067] In another embodiment, the first and second reducing agents are the same or different further and further comprise an acid selected from hydrochloride acid, pyridinium hydrochloride, and trifluoro acetic acid.

[0068] In a further embodiment, the first and second reducing agents are both trichlorosilane.

[0069] In one embodiment, the first solvent is acetonitrile.

[0070] In another embodiment, the second solvent is dichloromethane.

[0071] In one embodiment, the first reducing agent is trichlorosilane, and the second reducing agent is catechol borane.

[0072] In one embodiment, the first solvent is acetonitrile and the second solvent is 1,4-dioxane.

[0073] In one embodiment, Compound 3 is reduced to Compound 8 in the presence of N-hexyl imidazole.

[0074] In another embodiment, Compound 8 is reduced to Compound 2-rac in the presence of N-hexyl imidazole and (S)-2-pyrrolidone-5-carboxylic acid t-butyl ester.

[0075] In one aspect, the invention includes a process for producing Compound 1Compound 1or a salt thereof, the process comprising contacting Compound 2Compound 2or a salt thereof, with a compound having the structure*1 *2, optionally in the presence of a solvent, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-,1663018663 3267224-558390F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substituted phenyl)-C(O)O-, 0(optionally substituted phenyl)-O-, imidazole, or O ■

[0076] In one embodiment of this aspect, Xi and X2 are each independently selected fromchloro, bromo, CI3CO-, F3CO-, imidazole, 4-nitrophenoxy, pentafluorophenoxy, or O

[0077] In a further embodiment, Xi and X2 are both imidazole.

[0078] In one embodiment, the reaction is performed in the presence of an organic solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof.

[0079] In a further embodiment, the organic solvent is THF.

[0080] In one embodiment, the reaction is performed in the presence of an organic base.

[0081] In a further embodiment, the organic base is DIPEA.

[0082] In another embodiment, Compound 2 is present as a salt.

[0083] In a further embodiment, Compound 2 is present as the HC1 salt, Compound 2-HC1.

[0084] In another embodiment the reaction is performed in the presence of a salt selected from Ca(OTf)2, Mg(OTf)2, NaOTf; Zn(OTf)2 and KOTf In a further embodiment the reaction is performed in the presence of Ca(OTf)2. In still a further embodiment the reaction is performed in the presence of Ca(OTf)2, which is produced by adding a calcium salt and trifluoromethanesulfonic acid to the reaction.

[0085] In another embodiment, Compound 2 is present as a salt. In a further embodiment Compound 2 is present as the mandelic acid salt, Compound 2-MA.

[0086] In another embodiment of this aspect, the process further comprises producing crystalline Form B of Compound 1, the process comprising:a) heating a mixture of solid Compound 1 in a solvent that is a combination of one or more organic solvents and water to dissolve the solid Compound 1;1763018663 3267224-558390b) cooling the mixture formed in step a) to create a slurry;c) adding water to the mixture formed in step b);d) wet milling the slurry formed in step c);e) adding water to the slurry formed in step d);f) reducing the amount of solvent in the slurry formed in step e) by distillation at reduced pressure;g) adding water to the slurry formed in step f);h) cooling the slurry formed in step g); andi) isolating the solid Form B of Compound 1.

[0087] In a further embodiment, the solvent in step a) is a mixture of ethanol and water, and a third solvent selected from THF and DMSO.

[0088] In another embodiment, the solvent is a mixture of tetrahydrofuran, ethanol, and water.

[0089] In a further embodiment, the volume ratio of tetrahydrofuran to ethanol to water in the solvent is about 2.5:10:3.5.

[0090] In one embodiment, the volume of the solvent in step a) is about 17 volumes.

[0091] In another embodiment, the temperature of the mixture in step a) is heated to about 72 °C.

[0092] In another embodiment, the temperature of the mixture in step b) is cooled to about 60 °C.

[0093] In another embodiment, the amount of water added in step c) is about 2 volumes.

[0094] In a further embodiment, step b) further comprises adding a seed crystal to the mixture formed in step a).

[0095] In one embodiment, the wet milling in step d) is performed at approximately 23 m / s tip speed for 20 turnovers.

[0096] In another embodiment, the amount of water added in step e) is about 3 volumes.

[0097] In another embodiment, the mixture formed in step e) is reduced in step f) by about 5 volumes.

[0098] In another embodiment, the amount of water added in step g) is about 5 volumes.

[0099] In another embodiment, the slurry in step h) is cooled from about 60 °C to about 25 °C.

[0100] In one embodiment, the process further comprises producing Compound 2, or a salt thereof, with high optical purity from Compound 2-rac1863018663 3267224-558390Compound 2-racthe process comprising contacting Compound 2-rac with an optically active acid in the presence of a solvent, and isolating the resulting Compound 2 acid addition salt.

[0101] In one embodiment, the optically active acid is selected from L-mandelic acid, L-pyroglutamic acid, N-Acetyl-L-leucine, (+)-Camphanic acid, and (2R, 3R)-tartranilic acid.

[0102] In a further embodiment, the optically active acid is L-mandelic acid.

[0103] In another embodiment, the solvent is a polar organic solvent.

[0104] In one embodiment, the solvent is selected from methanol, acetone, dimethyl sulfoxide, ethyl acetate, acetonitrile, methylene chloride, dimethylformamide, diethyl ether, acetic acid, isopropanol, methyl ethyl ketone, methyl acetate, dimethylacetamide, and isopropyl acetate, or any combination thereof.

[0105] In a further embodiment, the solvent is acetonitrile, dimethylformamide, or a combination thereof.

[0106] In some embodiments, the reaction is seeded with Compound 2-MA.

[0107] In another embodiment, the process further comprises exchanging the optically active anion of the Compound 2 acid addition salt for chloride by contacting the Compound 2 acid addition salt with hydrochloric acid in the presence of an aprotic solvent, and isolating the Compound 2-HC1 salt.

[0108] In one embodiment, the aprotic solvent is selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof.

[0109] In a further embodiment, the aprotic solvent is THF.

[0110] In one embodiment, the process further comprises reducing Compound 31963018663 3267224-558390Compound 3in the presence of a reducing agent to provide Compound 2-rac.

[0111] In one embodiment, the reduction is performed in the presence of an acid and a solvent.

[0112] In one embodiment, the solvent is selected from the group consisting of NMP, DMA, acetic acid, methanol, ethanol, THF, and water, or a combination thereof.

[0113] In one embodiment, the solvent is selected from l-methyl-2-pyrrolidone, 2,5,7,10-tetraoxaundecane (TOU), Elcosol DM, and 1,3-dioxolane. In a further embodiment, the solvent is l-methyl-2-pyrrolidone.

[0114] In another embodiment, the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

[0115] In a further embodiment, the acid is methanesulfonic acid.

[0116] In one embodiment, the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

[0117] In another embodiment, the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

[0118] In one embodiment, the reducing agent is selected from hydrogen in the presence of catalyst selected from the group consisting of selected from Pd / C, Pd / AhCh, Pt / C, Pt / AhCh, Rh / C, Rh / AlCCh, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

[0119] In a further embodiment, the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

[0120] In one embodiment, the process further comprises reducing Compound 32063018663 3267224-558390Compound 3in the presence of a first reducing agent to provide Compound 8Compound 8and then reducing Compound 8 in the presence of a second reducing agent to provide Compound 2-rac.

[0121] In one embodiment, the first reduction is performed in the presence of a first solvent, and the second reduction is performed in the presence of a second solvent.

[0122] In a further embodiment, the first and second reducing agents are the same or different and are selected from dimethyl sulfide borane, dimethyl sulfide dichloroborane, dimethyl sulfide chloroborane, tetrahydrofuran borane, catechol borane, 9-borabicyclo[3.3.1]nonane, sodium triacetoxyborohydride, sodium borohydride, dissopinocampheylborane, trimethylamine borane, 2-methylpyridine borane, Zc / 'Z-butylamine borane, pyridine borane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with triphenylborane, trichlorosilane, dichlorosilane, phenylsilane, chlorophenylsilane, dichlorophenylsilane, diphenylsilane, triphenyl silane, 2,4,6, 8-tetramethylcyclotetrasiloxane, triethoxysilane, polymethylhydrosiloxane (PMHS), 1,1,3,3-tetramethyldisiloxane, and pentamethyldisiloxane.

[0123] In another embodiment, the first and second reducing agents are the same or different further and further comprise an acid selected from hydrochloride acid, pyridinium hydrochloride, and trifluoro acetic acid.

[0124] In one embodiment, the first and second reducing agents are both trichlorosilane.

[0125] In one embodiment, first solvent is acetonitrile.

[0126] In one embodiment, the second solvent is di chloromethane.2163018663 3267224-558390

[0127] In one embodiment, Compound 3 is reduced to Compound 8 in the presence of N-hexyl imidazole. In a further embodiment, Compound 8 is reduced to Compound 2-rac in the presence of N-hexyl imidazole and (S)-2-pyrrolidone-5-carboxylic acid t-butyl ester.

[0128] In one embodiment, the first reducing agent is trichlorosilane, and the second reducing agent is catechol borane.

[0129] In one embodiment, the first solvent is acetonitrile and the second solvent is 1,4-di oxane.

[0130] In one embodiment, the process further comprises reacting Compound 4Compound 4with (2-fluoro-5-methylphenyl)boronic acid to provide Compound 3.

[0131] In one embodiment, the reaction of Compound 4 with (2-fluoro-5-methylphenyl)boronic acid is performed in the presence of a catalyst and / or ligand, a base, and a solvent.

[0132] In one embodiment, the catalyst comprises palladium or nickel.

[0133] In another embodiment, the catalyst is selected from Pd(PPh3)4, PdCl2(PPh3)2, Ni(PPh3)2(naph)Cl, Ni(o-Tol)(Cl)(PPh3)2, Ni(o-Tol)(Cl)(TMEDA).

[0134] In a further embodiment, the catalyst is PdCl2(PPh3)2.

[0135] In another embodiment, the catalyst or ligand is selected from Pd(OAc)2, [Pd(crotyl)Cl]2, SPhos-Pd-G3, XPhos-Pd(crotyl)Cl, XPhos-Pd-G3, PPh3, CPhos, CyJohnPhos, XPhos, SPhos, PPh2Cy, P(p-F-Ph)3, P(p-Anis)3. In another embodiment, the catalyst may be [Pd(allyl)Cl]2or CyJohnPhos-Pd(crotyl)Cl.

[0136] In some embodiments, the ligand is a phosphine ligand.

[0137] In one embodiment, the base is selected from Na2CO3, K2CO3, DBU, KOH, NaOH, TEA, DIPEA, NaH, Na3PO4, and K3PO4.

[0138] In a further embodiment, the base is K3PO4.

[0139] In another embodiment, the solvent is selected from MeTHF, iPAc, MeOH, and THF.

[0140] In a further embodiment, the solvent is THF.2263018663 3267224-558390

[0141] In one embodiment, the process further comprises aminating Compound 5Cl^hf xDICompound 5to provide a compound of Formula AiRFormula Awherein R is hydrogen or an amine protecting group.

[0142] In one embodiment, the amination is performed with a compound of the formula NH2R.

[0143] In one embodiment, the amination is performed in the presence of Cui, a base, and a solvent.

[0144] In another embodiment, the process further comprises the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO), N, N'-bis(2-phenylphenyl) oxalamide (BPPO), or N, N'-bis-phenyl oxalamide (BPO).

[0145] In a further embodiment, the process further comprises the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO).

[0146] In one embodiment, the base is selected from a cesium, sodium or potassium salt of methoxide, ethoxide, / / V-butoxide, CO32, PO43', H', or OH'.

[0147] In a further embodiment, the base is potassium tert-butoxide or K3PO43'.

[0148] In one embodiment, the solvent is selected from THF, diethylether, acetonitrile, NMP, dioxane, DMA, DMF, DMSO, and water, or a combination thereof.

[0149] In a further embodiment, the solvent is THF.

[0150] In another further embodiment, the solvent is a combination of THF and water.

[0151] In another embodiment, the THF and water are present in a ratio of about 1:1.

[0152] In another embodiment, the Cui is present in about 10 mol%.2363018663 3267224-558390

[0153] In one embodiment, R is hydrogen, and the compound of Formula A is Compound 4.

[0154] In another embodiment, R is an amine protecting group, and the process further comprises deprotecting the compound of Formula A to produce Compound 4.

[0155] In a further embodiment, R is an amine protecting group selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), / c / v-buty I oxy carbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, tosyl (Ts), tri chloroethyl chloroformate (TROC), and 2,4-dimethoxybenzyl.

[0156] In still a further embodiment, R is 2,4-dimethoxybenzyl and the compound of Formula A is Compound 7Compound 7

[0157] In one embodiment, the 2,4-dimethoxybenzyl protecting group is removed by contacting the compound of Formula A with a strong acid in the presence of an organic solvent.

[0158] In a further embodiment, the 2,4-dimethoxybenzyl protecting group is removed by contacting the compound of Formula A with methanesulfonic acid in acetonitrile.

[0159] In another embodiment, the process further comprises isolating the methanesulfonic acid salt of Compound 4, and deprotonating the salt with a base to produce Compound 4.

[0160] In one embodiment, the process further comprises coupling Compound 6Compound 6with 4-aminotetrahydropyran, or a salt thereof, in the presence of a coupling reagent, a base, and a solvent, to provide Compound 5.2463018663 3267224-558390

[0161] In another embodiment, the 4-aminotetrahydropyran is present as the hydrochloride salt.

[0162] In one embodiment, the coupling agent is selected from BOP, COMU, HATU, HBTU, HCTU, PyBOP, PyAOP, PyOxim, TSTU, and CDI.

[0163] In a further embodiment, the coupling reagent is CDI.

[0164] In one embodiment, the solvent is DMF, DMA, or NMP.

[0165] In a further embodiment, the solvent is DMF.

[0166] In one embodiment, the base is triethylamine or DIPEA.

[0167] In one embodiment, the process further comprises chlorinating Compound 6Compound 6with a chlorinating reagent, optionally in the presence of a solvent, to provide Compound 8OWciCI^N^CICompound 8and contacting Compound 8 with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base and a solvent to produce Compound 5.

[0168] In another embodiment, the 4-aminotetrahydropyran is present as the hydrochloride salt.

[0169] In one embodiment, the chlorinating reagent is selected from thionyl chloride, oxalyl chloride, PCh, PCh, POCI3, PhPO(Cl)2, phosgene, and Cyanuric chloride.

[0170] In a further embodiment, Compound 8 is contacted with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base selected from tri ethylamine, DIPEA, DBU, and pyridine, and a solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof, to produce Compound 5.2563018663 3267224-558390

[0171] In one aspect, the invention includes a process for producing Compound 1, comprisinga) contacting Compound 6Compound 6with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base selected from triethylamine and DIPEA, a coupling reagent selected from BOP, COMU, HATU, HBTU, HCTU, PyBOP, PyAOP, PyOxim, TSTU, and CDI, and a solvent selected from DMF, DMA, and NMP, to provide Compound 5;b) contacting Compound 5Compound 5with NH3in the presence of Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, / / V-butoxide, COs2', PO43', H', or OH', and a solvent selected from THF, diethylether, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 4, orcontacting Compound 5 with 2,4-dimethoxybenzyl amine in the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO) or N, N'-bis(2-phenylphenyl) oxalamide (BPPO), Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, zc / 7-butoxide, CO32', PO43', H', or OH', and a solvent selected from THF, diethylether, NMP, dioxane, DMA, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 72663018663 3267224-558390Compound 7and treating Compound 7 with methanesulfonic acid in a polar aprotic solvent, followed by a neutralizing base to produce Compound 4;c) reacting Compound 4Compound 4with (2-fluoro-5-methylphenyl)boronic acid in the presence of PdC12(PPh3)2, abase selected from Na2CO3, K2CO3, DBU, KOH, NaOH, TEA, DIPEA, NaH, Na3PO4, and K3PO4, and a solvent selected from MeTHF, IP AC, MeOH, and THF, to provide Compound 3;d) reducing Compound 3Compound 3in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water, an acid selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, tri fluoroacetic acid, and acetic acid, and a solvent that is 1-methyl-2-pyrrolidone, to provide Compound 2-rac;e) contacting Compound 2-rac2763018663 3267224-558390Compound 2-racwith L-mandelic acid in acetonitrile and optionally dimethylformamide, and isolating Compound 2-MA;f) exchanging the L-mandelate anion in Compound 2-MACompound 2-MAfor chloride by contacting the Compound 2-MA with hydrochloric acid in the presence of an aprotic solvent selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof, and isolating Compound 2-HC1; andg) contacting Compound 2-HC1F<,Compound 2-HC1with carbonyldiimidazole in the presence of THF and a base selected from tri ethylamine and DIPEA to provide Compound 12863018663 3267224-558390

[0172] In a further embodiment, the 2,4-dimethoxybenzyl protecting group is removed in step b) by contacting Compound 7 with methanesulfonic acid in acetonitrile.

[0173] In a further embodiment, the acid in step d) is methanesulfonic acid.

[0174] In a further embodiment, the solvent in step f) is THF.

[0175] In another embodiment of this aspect, the process further comprises:h) heating a mixture of solid Compound 1 in a solvent that is a mixture of tetrahydrofuran, ethanol, and water to about 72 °C to dissolve the solid Compound 1; i) cooling the mixture formed in step a) to about 60 °C and adding a seed crystal of crystalline Form B of Compound 1 to the mixture to create a slurry;j) adding water to the mixture formed in step b);k) wet milling the slurry formed in step c) at approximately 23 m / s tip speed for 20 turnovers;l) adding water to the slurry formed in step d);m) reducing the amount of solvent in the slurry formed in step e) by about 5 volumes by distillation at reduced pressure;n) adding water to the slurry formed in step f);o) cooling the slurry formed in step g) from about 60 °C to about 25 °C; and p) isolating the solid Form B of Compound 1.

[0176] In a further embodiment, the volume ratio of tetrahydrofuran to ethanol to water in the solvent in step h) is about 2.5:10:3.5.

[0177] In a further embodiment, the volume of the solvent in step h) is about 17 volumes.

[0178] In a further embodiment, the amount of water added in step j) is about 2 volumes.

[0179] In a further embodiment, the amount of water added in step 1) is about 3 volumes.

[0180] In a further embodiment, the amount of water added in step n) is about 5 volumes.

[0181] In another aspect, the invention includes a process for producing Compound 1, comprisinga) contacting Compound 6OCompound 62963018663 3267224-558390with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base selected from triethylamine and DIPEA, a coupling reagent selected from BOP, COMU, HATU, HBTU, HCTU, PyBOP, PyAOP, PyOxim, TSTU, and CDI, and a solvent selected from DMF, DMA, and NMP, to provide Compound 5;b) contacting Compound 5Compound 5with NH3 in the presence of Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, te / 7-butoxide, COa2', PO43', H’, or OH', and a solvent selected from THF, diethylether, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 4, orcontacting Compound 5 with 2,4-dimethoxybenzyl amine in the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO) or N, N'-bis(2-phenylphenyl) oxalamide (BPPO), Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, / c / 7-butoxide, COa2', PO43', H', or OH', and a solvent selected from THF, diethylether, NMP, dioxane, DMA, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 7Compound 7and treating Compound 7 with methanesulfonic acid in a polar aprotic solvent, followed by a neutralizing base to produce Compound 4;c) reacting Compound 43063018663 3267224-558390Compound 4with (2-fluoro-5-methylphenyl)boronic acid in the presence of PdC12(PPh3)2, abase selected from Na2CO3, K2CO3, DBU, KOH, NaOH, TEA, DIPEA, NaH, Na3PO4, and K3PO4, and a solvent selected from MeTHF, IP AC, MeOH, and THF, to provide Compound 3;d) reducing Compound 3Compound 3in the presence of trichlorosilane, 1 -hexylimidazole, and a solvent, to provide Compound 8;e) contacting Compound 8Compound 8with catechol borane and a solvent to provide Compound 2-rac;f) contacting Compound 2-racCompound 2-racwith L-mandelic acid in acetonitrile and optionally dimethylformamide, and isolating Compound 2 -MA3163018663 3267224-558390g) exchanging the L-mandelate anion in Compound 2-MACompound 2-MAfor chloride by contacting the Compound 2-MA with hydrochloric acid in the presence of an aprotic solvent selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof, and isolating Compound 2-HC1; andh) contacting Compound 2-HC1Compound 2-HC1with carbonyldiimidazole in the presence of THF and a base selected from triethylamine and DIPEA to provide Compound 1

[0182] In a further embodiment, the 2,4-dimethoxybenzyl protecting group is removed in step b) by contacting Compound 7 with methanesulfonic acid in acetonitrile.

[0183] In a further embodiment, the solvent in step d) is acetonitrile.

[0184] In a further embodiment, the solvent in step f) is 1,4-dioxane.

[0185] In another embodiment of this aspect, the process further comprises:3263018663 3267224-558390i) heating a mixture of solid Compound 1 in a solvent that is a mixture of tetrahydrofuran, ethanol, and water to about 72 °C to dissolve the solid Compound 1;j) cooling the mixture formed in step a) to about 60 °C and adding a seed crystal of crystalline Form B of Compound 1 to the mixture to create a slurry;k) adding water to the mixture formed in step b);l) wet milling the slurry formed in step c) at approximately 23 m / s tip speed for 20 turnovers;m) adding water to the slurry formed in step d);n) reducing the amount of solvent in the slurry formed in step e) by about 5 volumes by distillation at reduced pressure;o) adding water to the slurry formed in step f);p) cooling the slurry formed in step g) from about 60 °C to about 25 °C; and q) isolating the solid Form B of Compound 1.

[0186] In a further embodiment, the volume ratio of tetrahydrofuran to ethanol to water in the solvent in step i) is about 2.5:10:3.5.

[0187] In a further embodiment, the volume of the solvent in step i) is about 17 volumes.

[0188] In a further embodiment, the amount of water added in step k) is about 2 volumes.

[0189] In a further embodiment, the amount of water added in step m) is about 3 volumes.

[0190] In a further embodiment, the amount of water added in step o) is about 5 volumes.

[0191] In some embodiments, where ammonia is used in the present methods, another source of ammonia may be used, such as a non-gaseous (e.g., liquid) source of ammonia.

[0192] In another aspect, disclosed herein is a process for producing Compound 2,Compound 2or a salt thereof, with high optical purity from Compound 2-rac3363018663 3267224-558390Compound 2-racthe process comprising contacting Compound 2-rac with an optically active acid in the presence of a solvent, and isolating the resulting Compound 2 acid addition salt.

[0193] In one embodiment, the optically active acid is selected from L-mandelic acid, L-pyroglutamic acid, N-Acetyl-L-leucine, (+)-Camphanic acid, and (2R, 3R)-tartranilic acid.

[0194] In a further embodiment, the optically active acid is L-mandelic acid.

[0195] In one embodiment, the solvent is a polar organic solvent.

[0196] In a further embodiment, the solvent is selected from methanol, acetone, dimethyl sulfoxide, ethyl acetate, acetonitrile, methylene chloride, dimethylformamide, diethyl ether, acetic acid, isopropanol, methyl ethyl ketone, methyl acetate, dimethylacetamide, and isopropyl acetate, or any combination thereof.

[0197] In a further embodiment, the solvent is acetonitrile, dimethylformamide, or a combination thereof.

[0198] In some embodiments, the reaction is seeded with Compound 2-MA.

[0199] In one embodiment, the process comprises exchanging the optically active anion of the Compound 2 acid addition salt for chloride by contacting the Compound 2 acid addition salt with hydrochloric acid in the presence of an aprotic solvent, and isolating the Compound 2-HC1 salt.

[0200] In a further embodiment, the aprotic solvent is selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof.

[0201] In a further embodiment the aprotic solvent is THF.

[0202] In another aspect, disclosed herein is a process for producing Compound 13463018663 3267224-558390Compound 1or a salt thereof, the process comprising contacting Compound 2-MACompound 2-MAwith a compound having the structureXl x2, in the presence of a solvent and a salt selected from Ca(OTf)2, Mg(OTf)2, NaOTf; Zn(OTf)2 and KOTf, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-, F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substituted phenyl)-C(O)O-, (optionally substituted phenyl)-O-, imidazole, O

[0203] In one embodiment, Xi and X2 are each independently selected from chloro, Obromo, CI3CO-, F3CO-, imidazole, 4-nitrophenoxy, pentafluorophenoxy, or O

[0204] In a further embodiment, Xi and X2 are both imidazole.

[0205] In one embodiment, the reaction is performed in the presence of an organic solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof.

[0206] In a further embodiment, the organic solvent is THF.

[0207] In one embodiment, the reaction is performed in the presence of Ca(OTf)2.

[0208] In another aspect, disclosed herein is a process for producing Compound 2-rac:3563018663 3267224-558390Compound 2-racthe process comprising reducing Compound 3Compound 3in the presence of a reducing agent to provide Compound 2-rac.

[0209] In one embodiment, the reduction is performed in the presence of an acid and a solvent.

[0210] In a further embodiment, the solvent is selected from l-methyl-2-pyrrolidone, 2,5,7, 10-tetraoxaundecane (TOU), Elcosol DM, and 1,3-dioxolane. In a further embodiment, the solvent is l-methyl-2-pyrrolidone.

[0211] In a further embodiment, the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

[0212] In a further embodiment, the acid is methanesulfonic acid.

[0213] In one embodiment, the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

[0214] In one embodiment, the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

[0215] In one embodiment, the catalyst is selected from Pd / C, Pd / Al2O3, Pt / C, Pt / Al2O3, Rh / C, Rh / Al2O3, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

[0216] In a further embodiment, the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.3663018663 3267224-558390

[0217] In some aspects, crystalline Form B of Compound 1 is produced by the processes disclosed herein.

[0218] In another aspect, Compound 1 or a salt thereof is produced by a process comprising:(1) contacting Compound 6 with a tetrahydro-2H-pyran-4-amine to form Compound 5,Compound 6 Compound 5(2) aminating Compound 5 with NH3 to form Compound 4,Compound 5 Compound 4 (3) coupling Compound 4 with (2-fluoro-5-methylphenyl)boronic acid to form Compound 3,Compound 4 Compound 3(4) reducing Compound 3 with H2 to form Compound 2-rac,Compound 3 Compound 2-rac3763018663 3267224-558390(5) contacting Compound 2-rac with (C)-Mandelic acid to form Compound 2-MA,Compound 2-rac Compound 2-MA(6) contacting Compound 2-MA with N, N’ -carbonyldiimidazole to form Compound 1, oCompound 2-MA Compound 1

[0219] In a further embodiment, the reaction contacting Compound 6 with a tetrahydro-2H-pyran-4-amine further comprises the presence of CDI in dimethylformamide as a solvent.

[0220] In a further embodiment, the reaction aminating Compound 5 with NH3 further comprises the presence of copper(I) iodide and potassium phosphate in tetrahydrofuran as a solvent.

[0221] In a further embodiment, the reaction coupling Compound 4 with (2-fluoro-5-methylphenyl)boronic acid further comprises the presence of potassium phosphate in a mixture of tetrahydrofuran and water as a solvent.

[0222] In a further embodiment, the reaction reducing Compound 3 with H2 further comprises the presence of a palladium / rhodium catalyst and methane sulfonic acid in N-methyl-2-pyrrolidone as a solvent.

[0223] In a further embodiment, the reaction contacting Compound 2-A with ( / .)-mandelic acid further comprises a mixture of acetonitrile and dimethylformamide as a solvent.

[0224] In a further embodiment, the reaction contacting Compound 2-MA with N, N’-carbonyldiimidazole further comprises the presence of calcium triflate in tetrahydrofuran as a solvent.

[0225] Characteristics of Form B of Compound 13863018663 3267224-558390

[0226] In one aspect, provided herein is the Form B polymorph of Compound 1, produced by the processes disclosed herein. Form B is an anhydrate form of the free base of Compound 1. Form B is the most thermodynamically stable anhydrate form of Compound 1.

[0227] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.5, 7.1, 9.3, and 19.0 °20± 0.2 °29.

[0228] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0, and 22.3 °20 ± 0.2 °26.

[0229] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 15.8, 16.2, 16.5, 17.2, 18.5, 19.0, 19.3, 22.3, 23.1, 23.4, 23.7, 26.2, 27.3, 27.9, and 30.1 °20 ± 0.2 °20.

[0230] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, having the peaks listed in Table 1.

[0231] Table 1: observed X-ray powder diffraction peaks of Compound 1 Form B3963018663 3267224-558390

[0232] In some embodiments, Form B is characterized by a DSC thermogram comprising an endotherm onset at about 307 °C.

[0233] In some embodiments, Form B is characterized by a single crystal x-ray analysis according to Table 2.

[0234] Table 2: Single crystal x-ray analysis data for Form BTable 2: Single Crystal X-ray Analysis for Form B77K 100Crystal System triclinicSpace Group PlUnit CellDimensions:a = 6.74 ± 0.10 A a = 83.9 ± 1.0°b = 12.74 ± 0.10 A p= 80.0± 1.0°c = 15.99 ± 0.10 A y = 75.1 ± 1.0°Volume 1303(20) A3Z 3DcalcJ g cm-31.4434063018663 3267224-558390

[0235] In some embodiments, Form B is substantially pure, i.e., substantially free of other solid forms of Compound 1 (including amorphous Compound 1 and other polymorphs of Compound 1).

[0236] In some embodiments, the processes described herein produce Form B that is substantially pure, i.e., substantially free of other solid forms of Compound 1 (including amorphous Compound 1 and other polymorphs of Compound 1).

[0237] Materials and Methods

[0238] XRPD data of Compound 2-MA, Form 1 were obtained using Bruker D8 Discover DaVinci with XYZ Stage. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation). Incident beam optics included Montel mirrors with a 0.3 mm collimator. Photons were counted using an Eiger2 R 500K Detector in 2D, 20 optimized mode. The sample-to-detector distance was 137.5 mm. Each sample was loaded into a glass capillary (1 mm diameter). Data were collected over a 20 range of approximately 3-33° with an exposure time of 1000 s and an approximate step size of 0.01°.

[0239] Characteristics of Form 1 of Compound 2-MA

[0240] In one aspect, provided herein is the Form 1 polymorph of Compound 2-MA, produced by the processes disclosed herein.

[0241] In some embodiments, Compound 2-MA, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 5.8 °20 ± 0.2 °20.

[0242] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 17.3 °20 ± 0.2 °20.

[0243] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 18.1 °20 ± 0.2 °20.

[0244] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 19.2 °20 ± 0.2 °20.4163018663 3267224-558390

[0245] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 20.6 °29 ± 0.2 °20.

[0246] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 24.2 °20 ± 0.2 °20.

[0247] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 24.9 °20 ± 0.2 °20.

[0248] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 8.8 °20 ± 0.2 °20.

[0249] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 11.5 °20 ± 0.2 °20.

[0250] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 13.7 °20 ± 0.2 °20.

[0251] In another embodiment, Compound 2-MA, Form 1 is further characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising a peak at 21.1 °20 ± 0.2 °20.

[0252] In some embodiments, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 17.3, 18.1, and 19.2 °20 ± 0.2 °20.

[0253] In some embodiments, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, and 19.2 °20 ± 0.2 °20.

[0254] In some embodiments, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, 19.2, 20.6, and 21.1 °20 ± 0.2 °20.4263018663 3267224-558390

[0255] In some embodiments, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, 19.2, 20.6, 21.1, 24.2, and 24.9 °20 ± 0.2 °29.

[0256] In some embodiments, Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, having the peaks listed in Table 3.

[0257] Table 3: observed X-ray powder diffraction peaks of Compound 2-MA, Form 1Table 3: Observed X-ray Powder Diffraction Peaksfor Compound 2-MA, Form 1 (°20)5.8 ± 0.28.8 ± 0.211.5 ± 0.212.1 ± 0.213.7 ± 0.217.3 ± 0.218.1 ± 0.219.2 ± 0.220.6 ± 0.221.1 ± 0.222.4 ± 0.223.0 ± 0.223.7 ± 0.224.2 ± 0.224.9 ± 0.226.8 ± 0.227.9 ± 0.229.4 ± 0.229.9 ± 0.231.3 ± 0.232.7 ± 0.24363018663 3267224-558390

[0258] In one embodiment, Compound 2-MA, Form 1 is characterized by a13C ssNMR having a peak at 178.86 ± 0.2 ppm.

[0259] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 178.86 ± 0.2 ppm.

[0260] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 168.71 ± 0.2 ppm.

[0261] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 165.14 ± 0.2 ppm.

[0262] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 160.65 ± 0.2 ppm.

[0263] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 158.68 ± 0.2 ppm.

[0264] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 142.34 ± 0.2 ppm.

[0265] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 136.34 ± 0.2 ppm.

[0266] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 131.07 ± 0.2 ppm.

[0267] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 129.42 ± 0.2 ppm. ppm.

[0268] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 128.50 ± 0.2 ppm.

[0269] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 126.78 ± 0.2 ppm.

[0270] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 122.11 ± 0.2 ppm.

[0271] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 115.46 ± 0.2 ppm.

[0272] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 84.35 ± 0.2 ppm.4463018663 3267224-558390

[0273] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 83.09 ± 0.2 ppm.

[0274] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 73.11 ± 0.2 ppm.

[0275] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 67.36 ± 0.2 ppm.

[0276] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 50.84 ± 0.2 ppm.

[0277] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 46.81 ± 0.2 ppm.

[0278] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 45.77 ± 0.2 ppm.

[0279] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 32.92 ± 0.2 ppm.

[0280] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 31.73 ± 0.2 ppm.

[0281] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 25.88 ± 0.2 ppm.

[0282] In another embodiment, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having a peak at 18.42 ± 0.2 ppm.

[0283] In a further embodiment, Compound 2-MA, Form 1 is characterized by a13C ssNMR having peaks at 178.86 ± 0.2, 168.71 ± 0.2, 165.14 ± 0.2, 160.65 ± 0.2, 158.68 ± 0.2, 142.34 ± 0.2, 136.34 ± 0.2, 131.07± 0.2, 129.42 ± 0.2, 128.50± 0.2, 126.78 ± 0.2, 122.11 ± 0.2, 115.46 ± 0.2, 84.35 ± 0.2, 83.09 ± 0.2, 73.11 ± 0.2, 67.36 ± 0.2, 50.84 ± 0.2, 46.81 ± 0.2, 45.77 ± 0.2, 32.92 ± 0.2, 31.73 ± 0.2, 25.88 ± 0.2, and 18.42 ± 0.2 ppm.

[0284] In some embodiments, Compound 2-MA, Form 1 is further characterized by a13C ssNMR having the peaks listed in Table 4.

[0285] Table 4: observed13C ssNMR peaks of Compound 2-MA, Form 1Table 4: Observed13C ssNMR Peaks forCompound 2-MA, Form 1 (ppm)178.86 ± 0.24563018663 3267224-558390Table 4: Observed13C ssNMR Peaks forCompound 2-MA, Form 1 (ppm)168.71 ± 0.2165.14 ± 0.2160.65 ± 0.2158.68 ± 0.2142.34 ± 0.2136.34 ± 0.2131.07 ± 0.2129.42 ± 0.2128.50 ± 0.2126.78 ± 0.2122.11 ± 0.2115.46 ± 0.284.35 ± 0.283.09 ± 0.273.11 ± 0.267.36 ± 0.250.84 ± 0.246.81 ± 0.245.77 ± 0.232.92 ± 0.231.73 ± 0.225.88 ± 0.218.42 ± 0.2

[0286] In some embodiments, Compound 2-MA, Form 1 is substantially pure, i.e., substantially free of other solid forms of Compound 2-MA (including amorphous Compound 2-MA and other polymorphs of Compound 2-MA).

[0287] In another aspect, the invention includes a compound, or salt thereof, selected from the group consisting of4663018663 3267224-5583900N1 1 H II J H NT N H2^rj^j^N NH2Compound 2 Compound 3O O r^OII J H 11 1hCI^N NH2CI^^N^CICompound 4 Compound 5O O II J H CI^N NHCompound 6 XXand Compound 70F>i / XirII IIhl\t N H2H J HCompound 8EXAMPLES

[0288] Methods and equipment

[0289] NMR data for1H,13C,15N, and19F were acquired on either a Bruker Avance III 500, Bruker Avance Neo 600 or a Bruker Avance Neo 700 spectrometer.NMR data were referenced to the residual DMSO-ds signal at 2.50 ppm.13C NMR data were referenced to the DMSO-de signal at 39.51 ppm.15N NMR data were externally referenced to NEL at 0.0 ppm, and19F NMR data were externally referenced to CFCh at 0.0 ppm. All data were acquired in DMSO-de at 298K.4763018663 3267224-558390

[0290] Example 1: synthesis of 2,6-dichloro-5-fluoro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (Compound 5)Compound 6 Compound 5

[0291] To a 20 L jacketed glass reactor was charged 400.3 g of 2,6-dichloro-5-fluoronicotinic acid (Compound 6; 1.05 equiv., 1887.4 mmol, 99 mass%) followed by 2.42 L of N, N-dimethylformamide (9.5 mL / g-of input). After stirring at 20-25 °C for 0.5 h, a light-yellow solution was generated. 318.2 g (1.07 equiv., 1923.3 mmol) of l,l'-carbonyldiimidazole was charged in portions over a 20-minute period to control off-gassing. After stirring for 2 h at 20-25 °C, 326 mb of triethylamine (1.30 equiv., 2336.7 mmol) was added followed by 255.0 g of 4-aminotetrahydropyran hydrochloride (1.00 equiv., 1797.5 mmol). Note: exotherm from 22.5 to 26.8 °C (jacket temperature 22 °C) observed. The reaction mixture was then stirred at 22 °C for over 16 h. The jacket temperature was then adjusted to 5 °C followed by the addition of 2000 mb water over a 0.5 h period. Note: a ~10 °C exotherm was observed. After 15 minutes of stirring, a slurry formed, and water (3.88 L) was then added in 10 portions (388 mL x 10) over a 1 h period. Once the addition of water was complete, jacket temperature was adjusted to 20 °C, and stirred for 2.5 h. The resulting slurry was filtered, and the solids washed with water (6 x 1 L) followed by heptane (1 x 750 mL). The solids were then dried at 50 °C under vacuum. The final product (456.0 g, 86.5% yield) was isolated as an off-white solid.

[0292] JH NMR (600 MHz, DMSO-6?6, 25°C); 58.67 (d, J = 7.5 Hz, 1H), 8.23 (d, J= 7.8 Hz, 1H), 3.95 (tdt, J= 10.6, 7.5, 4.3 Hz, 1H), 3.85 (ddd, J= 11.4, 4.3, 3.4 Hz, 2H), 3.41 (ddd, J = 11.4x2, 1.9 Hz, 2H), 1.81 (dddd, J= 12.9, 4.3, 3.4, 1.9 Hz, 2H), 1.49 (dddd, 12.9, 11.4, 10.6, 4.3 Hz, 2H).13C NMR (151 MHZ, DMSO-flfc, 25°C); 5 162.0, 153.5 (d, J= 259.7 Hz), 140.1 (d, J = 3.4 Hz), 136.3 (d, J= 21.6 Hz), 134.0 (d, J= 3.1 Hz), 127.5 (d, J= 22.0 Hz), 65.6 (2 C), 45.7, 32.0 (2 C) ppm.15N NMR (61 MHz, DMSO-tL, 25°C); 8305.5, 136.4.19F NMR (659 MHz, DMSO-fifc, 25°C); 8 -122.3 (d, J= 7.8 Hz) ppm. HRMS calc m / z 293.02544 [M + H]+; found 293.02598.

[0293] Example 2: Synthesis of 2-amino-6-chloro-5-fluoro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (Compound 4)4863018663 3267224-558390Compound 5 Compound 4

[0294] 80g Compound 5 (274 mmol, limiting reagent) was charged to a 2 L pressure vessel, followed by 5.1g cuprous iodide (27 mmol, 0.1 eq.) and 1.12 L tetrahydrofuran (14 L / kg) solvent under inert conditions. 116.3 g of tribasic potassium phosphate (548 mmol, 2 eq.) was then added to the pressure vessel with agitation. The vessel was sealed and pressurize to 70 psi with >99% ammonia gas and allowed to equilibrate at room temperature for at least 30 minutes with agitation. The reaction mixture was heated to 40 °C and agitated at 70 psi for at least 20 hours, and until >99% conversion. The reaction mixture was cooled to 24 °C, and the ammonia gas was vented slowly and purged with N2 gas. The reaction mixture was filtered through a 3 cm pad of silica to partially remove copper and colored species, and then washed through a silica pad with 3 x 320 mL THF (3 x4 L / kg). The solvent was then swapped to obtain a 7 L / kg acetonitrile solution with THF <1%, and then heated to reflux (jacket temperature 80 °C). An additional 1 L / kg of water was added to dissolve everything at ~70 °C followed by additional 20 L / kg of water to crystallize out the product. The mixture was then cooled to 24 °C and the solids were collected to provide the product in 79.2% yield with 99.5% LCAP, 98.5% NMR potent.

[0295] 'H (600 MHz DMSO-tfc) d 8.30 (d, J= 7.4, 1H), 8.09 (d, J= 9.3, 1H), 7.36 (s, 2H), 3.94 (tdt, J= 10.8, 7.8, 4.3, 1H), 3.86 (br d, J= 11.4, 2H), 3.36 (ddd, J= 11.7x2, 1.4, 2H), 1.74 (m, 2H), 1.53 (dddd J= 12.0x3, 4.1, 2H);13C (151.04 MHz, DMSO-t / 6) d 155.2 (d, J= 1.0 Hz), 108.7, 126.0 (d, J= 21.3 Hz), 144.7 (d, J= 242.8 Hz), 136.9 (d, J= 19.9 Hz), 165.0 (d, J= 0.9 Hz), 45.8, 32.2, 66.1.19F NMR (376 MHz, DMSO) 8 -139.37 (d, J = 3.1 Hz). ESLHRMS m / z calcd. for C11H14O2N3CIF [M + H]+274.07531, found 274.07550, dppm= 0.70.

[0296] Example 3: First Alternative Synthesis of 2-amino-6-chloro-5-fluoro-N- (tetrahydro-2H-pyran-4-yl)nicotinamide (Compound 4)Compound 5 Compound 44963018663 3267224-558390

[0297] 60g Compound 5 (205 mmol, limiting reagent) was charged to an ace glass pressure vessel, followed by 11.7 g cuprous iodide (61.4 mmol, 0.3 eq.), 111 g of tribasic potassium phosphate (512 mmol, 2.5 eq.), and then 300 mL DMA (5 L / kg) and 36 mL water (0.6 L / kg). A Parr reactor or similar Hastelloy reactor with mechanical stirring is preferred. The reactor was then cooled to 0-5 °C and without agitation, 138 mL of aqueous ammonium hydroxide (2.3 L / kg) was layered on top, and the vessel was sealed. Cooling the vessel and not stirring helps to prevent loss of ammonia gas from and rapid degassing. The reaction mixture was then agitated slowly and heated to 35 °C overnight. Solution phase was biphasic. The reactor was cooled again and carefully vented until depressurized. 700 mL of MeTHF (12 L / kg) and 700 mL of 5 wt% brine (12 L / kg) was added and the reaction mixture was stirred for 30 minutes at rt and three liquid phases formed. The bottom blue layer (-200 mL of viscious blue liquid) was discarded, and the middle aqueous layers and organic layer was retained. The aqueous layer was removed and washed with an additional 300 mL of MeTHF (5 L / kg), and the organic layers combined. The combined organic layers were washed with 9 L / kg of a solution consisting of 10 wt% NH4OH and 25 wt% brine, and then with an additional 240 mL (4 L / kg) 25 wt% brine. The solvent was swapped to 360 mL of acetonitrile (6 L / kg) and refluxed to dissolve all solids. 75 mL of water (1.25 L / kg) was added at reflux (jacket temperature 80°C). An additional 175 mL water (3 L / kg) was added, the reaction seeded, and add an additional 225 mL of water was added over 1 hr (3.75 L / kg). The reaction was stirred for an additional 1 hr and cooled overnight, filtered and washed with 250 mL of 3: 1 Water / MeCN (4 L / kg), and an additional 50 mL heptane (0.8 L / kg). After drying, 45.6 g product was obtained (72% yield) with 99.6 LCAP. An additional 4.5 g was obtained by concentrating the mother liquor and resubjecting the material to the crystallization conditions (7.2% yield).

[0298] JH (600 MHz DMSO-tL) d 8.30 (d, J= 7.4, 1H), 8.09 (d, J= 9.3, 1H), 7.36 (s, 2H), 3.94 (tdt, J= 10.8, 7.8, 4.3, 1H), 3.86 (br d, J= 11.4, 2H), 3.36 (ddd, J= 11.7x2, 1.4, 2H), 1.74 (m, 2H), 1.53 (dddd J= 12.0x3, 4.1, 2H);13C (151.04 MHz, DMSO- e) d 155.2 (d, J= 1.0 Hz), 108.7, 126.0 (d, J= 21.3 Hz), 144.7 (d, J= 242.8 Hz), 136.9 (d, J= 19.9 Hz), 165.0 (d, J= 0.9 Hz), 45.8, 32.2, 66.1. ESLHRMS m / z calcd. for C11H14O2N3CIF [M + H]+274.07531, found 274.07550, 8ppm= 0.70.

[0299] Example 4: Second Alternative Synthesis of 2-amino-6-chloro-5-fluoro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (Compound 4)5063018663 3267224-558390Compound 5 Compound 4

[0300] 2,6 -dichloro-5-fluoro-N-tetrahydropyran-4-yl-pyridine-3-carboxamide (75.0 g, 255.9 mmol, limiting reagent), copper (I) iodide (3.41 g, 17.91 mmol, 7 mol %), and 2,6-dimethylanilino(oxo)acetic acid (DMPAO ligand, 3.46 g, 17.91 mmol, 7 mol %) were added to a reactor under nitrogen. DMA (300 mL, 4 L / kg), THF (38 mL, 0.51 L / kg), and then 2,4-dimethoxybenzylamine (48.02 g, 281.5 mmol, 1.1 equiv.) were added neat. The mixture was stirred for 10 minutes then cooled to 0 - 5 °C. A solution of potassium t-butoxide in THF (I N, 295 mL, 295 mmol, 1.15 equiv.) was added over 15 minutes. The mixture was then heated to 60 °C. After the reaction completed (in 2 - 4 h), the mixture was cooled to 20 °C. 2-MeTHF (1.20 L, 16 L / kg), 20% aqueous NH4Cl (450 mL, 6 L / kg), 28% aqueous NH4OH (225 mL, 3 L / kg), and water (225 mL, 3 L / kg) were added to reaction mixture. After stir for 15 min, the organic layer was separated. THF (300 mL, 4 L / kg) was added to the organic layer, which was then washed with a mixture of 20% aqueous NH4CI (600 mL, 8 L / kg) and 28% aqueous NH4OH (300 mL, 4 L / kg) followed by wash with 20% aqueous NH4CI (900 mL, 12 L / kg). The organic layer was concentrated to give a 450 mL slurry. Acetonitrile (188 mL, 2.5 L / kg) and 1,3-dimethoxybenzene (168 mL, 1279 mmol, 5 equiv.) were added to the slurry. After stirring for 5 minutes, MSA (36.8 mL, 563 mmol, 2.2 equiv.) was added to the mixture, which was then stirred at rt for 16 h. 2-MeTHF (1125 mL, 15 L / kg) and 12% aqueous K3PO4 (726 mL, 10 L / kg) were added to reaction mixture which was stirred for 15 minutes. The organic layer was separated and then washed with 600 mL 20% aqueous sodium chloride (8 L / kg). The organic layer was concentrated to 500 mL and toluene (900 mL, 12 L / kg) was added followed by concentration to 600 mL. 1.2 L of toluene (16 L / kg) was then added and the mixture was stirred at 60 C for 1 h then cooled to rt for 5 h. The solid was collected by fdtration, wash with toluene (225 mL, 3 L / kg), and dry at 50 °C under vacuum to give 59.1 g (84.0%) dry product.

[0301] 'H (500MHz DMSO-t / 6) 88.67 (t, J = 5.6 Hz, 1H), 8.38 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.3, 2.4 Hz,5163018663 3267224-5583901H), 4.41 (d, J = 5.5 Hz, 2H), 3.94 (tdt, J = 11.4, 8.2, 4.2 Hz, 1H), 3.87 (ddd, J = 11.7, 4.3, 2.1 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.35 (td, J= 11.9, 1.7 Hz, 2H), 1.74 (ddd, J = 12.5, 4.4, 2.0 Hz, 2H), 1.59 - 1.48 (m, 2H).13C NMR (126 MHz, DMSO) 5 165.60 (d, J= 1.0 Hz), 159.53 (d, J = 226 Hz), 154.16, 145.82, 143.90, 137.38 (d, J= 19.9 Hz), 129.88, 126.64 (d, J= 21.8 Hz), 119.15, 109.52, 104.82, 98.95, 66.51, 55.92, 55.63, 46.28, 32.65. TOF-HRMS m / z calcd. for C11H14O2N3CIF [M + H]+424.1434, found 424.1435, 5ppm= 2.

[0302] Example 5: Synthesis of 2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamideO 1 HCompound 4 Compound 3

[0303] 2 -amino-6-chloro-5-fluoro-N-tetrahydropyran-4-yl-pyridine-3-carboxamide (100 g, 1.0 eq, 365 mmol) was charged to a 5-liter reactor, followed by (2-fluoro-5-methyl-phenyl)boronic acid (66.0 g, 1.15 eq, 420 mmol, 98%), 142.0 g potassium phosphate tribasic (1.80 eq, 656 mmol, 98%), and 3.08 g bis(triphenylphosphine)palladium(II) dichloride (0.012 eq, 4.4 mmol). The vessel was purged with nitrogen gas, and then charged with 1 L of THF under nitrogen. The mixture was purged with nitrogen for an additional 5 min, and then charged with 500 mL water (pre-sparged with nitrogen for 10 min). The mixture was heated to 50 C for 2 h, and then charged with 20.0 g of N-acetyl-L-cysteine (122 mmol) and heated to 60 C for 3 h. The mixture was then cooled to 22 C, and the organic layer separated. 1.40 L of 2-MeTHF was added, and the organic layer was washed with 1 L 5% aq NaHCOa, 1 L 5% brine, and then 700 mL 25% brine. The organic layer was concentrated under vacuum at < 30 C to 700 mL volume, and 700 mL heptane was added, and the mixture heated to 60 C for 1 h, then cooled to 22 C for >2 h. The solid product was collected by filtration, the wet cake was washed with 400 mL 2:1 heptane-2-MeTHF, and then dried at 50 C under vacuum to give 116.8 g (92% yield) dry product as a light-yellow solid.

[0304] 3H NMR (600 MHz, DMSO4, 25°C); 58.36 (d, J= 7.5 Hz, 1H), 8.00 (d, J= 10.2 Hz, 1H), 7.34 ( br d, J= 6.9 Hz, 1H), 7.32 (m, 1H), 7.19 (dd, J= 10.0, 8.6 Hz, 1H), 7.09 (br5263018663 3267224-558390s, 2H), 3.98 (tn, 1H), 3.88 (br d, J= 11.4 Hz, 2H), 3.38 (td, J= 11.6, 1.8 Hz, 2H), 2.33 (s, 3H), 1.77 (m, 2H), 1.56 (qd, J= 12.1, 4.4 Hz, 2H).13C NMR (151 MHz, DMSO-t / e, 25°C); 165.6 (d, J= 0.8 Hz), 157.6 (d, J= 246.0 Hz), 155.4, 148.4 (d, J= 243.0 Hz), 142.0 (d, J= 16.3 Hz), 133.6 (d, J= 3.3 Hz), 131.7 (d, J = 8.0 Hz), 131.4 (d, J= 2.5 Hz), 124.6 (d, J = 22.8 Hz), 122.5 (dd, J= 15.5, 4.6 Hz), 115.4 (d, J= 22.0 Hz), 109.6 (d, J= 1.6 Hz), 66.1 (2 C), 45.7, 32.3, (2 C), 20.0 ppm.19F NMR (659 MHz, DMSO-t / s, 25°C); 5 -139.4 (dd, J= 29.4, 10.2 Hz), -119.5 (m) ppm. HRMS calc for C18H20O2N3F2 [M+H]+m / z 348.15247 [M + H]+; found 348.15176.

[0305] Example 6: Synthesis of (5S,6S)-2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide (Compound 2-rac)Compound 3 Compound 2-rac

[0306] To a 300 mL Hastelloy reactor was charged Compound 3 (10 g, 28.79 mmol, 100.0 mass%), l-methyl-2-pyrrolidone (150 mL, 1557 mmol, 100 mass%), methanesulfonic acid (3.32 g, 34.5 mmol, 100 mass%), a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water (1 g, 100 mass%). The reactor was sealed under air and placed on the Automate reaction station. The reactor was purged three times with 30 psi N2, then three times with 30 psi H2 before pressuring up the reactor to 60 psi with H2. The jacket temperature was set to 53 °C and stirred at 700 rpm for 16 hours, and then let cool to rt. After the content temperature decreased to below 25C, the headspace was purged with 30 psi N2 three times. The reaction mixture was filtered with vacuum setup under a N2 pad. A portion of the reaction mixture (50 mL, 3.125 g scale based on compound 3) was then transferred to a 100 mL reactor, 20 mL K2CO3 / KHCO3 buffer (0.45 mol / L and 0.45 mol / L) was added to the reaction mixture over 10 min. Compound 8 seed (150 mg, 4.8% seeding) was then added to the crystallization mixture. The antisolvent, water (30 mL, 9.6 V), was added in three portions. Each portion (10 mL, 3.2 V) was added to the reaction mixture over 30 min, followed by a 90 min hold. The resulting slurry was stirred for another 18 hours at ambient temperature. The solid product was collected by filtration and the wet cake was washed with 10 mL NMP / water (1:1 vol ratio), 10 mL water, 105363018663 3267224-558390mL water and 10 mL 2-MeTHF and dried at 40-degrees under vacuum for 24 h to give 1.64 g (57.8% yield) dry product as a white solid.

[0307] 1H NMR (600 MHz, 19:1 DMSO-tfcTFA, 25°C); 8 10.28 (s, 0.56H), 10.16 (s, 0.44H), 9.17 (s, 0.44H), 9.08 (s, 0.56H), 9.06 (s, 0.56H), 8.93 (s, 0.44H), 8.49 (d, J= 7.3 Hz, 0.56H), 8.15 (d, J= 7.5 Hz, 0.44H), 7.92 (s, 1H), 7.11-7.25 (overlapped, 3H), 5.06-5.25 (overlapped, 2H), 3.73-3.87 (overlapped, 4H), 3.30-3.40 (overlapped, 2H), 2.32-2.62 (overlapped, 2H), 2.30 (s, 1.7H), 2.30 (s, 1.3H), 1.62-1.82 (overlapped, 2H), 1.34-1.51 (overlapped, 2H).13C{’H} NMR (151 MHZ, 19:1 DMSO-t / 6: TFA, 25°C); 8 167.4 (s), 166.9 (s), 164.6 (s), 164.4 (s), 158.1 (d, J = 244.3 Hz), 157.8 (d, J = 244.3 Hz), 133.7 (d, J= 3.3 Hz), 133.4 (d, J = 3.3 Hz), 130.9 (d, J= 8.1 Hz), 130.6 (d, J= 8.1 Hz), 130.0 (br s), 129.7, (br s), 122.3 (dd, J= 12.8, 3.8 Hz), 122.1 (dd, J= 12.4, 1.9 Hz), 115.4 (d, J= 21.4 Hz), 115.1 (d, J= 21.4 Hz), 85.3 (d, J= 178.0 Hz), 83.9 (d, J= 178.0 Hz), 65.9 (s), 65.8 (s), 65.8 (s), 65.7 (s), 52.4 (m), 45.8 (s), 45.5 (s), 39.9 (overlap with DMSO-c / e), 32.3 (s), 32.2 (s), 32.2 (s), 32.0 (s), 28.5 (d, J= 21.0 Hz), 28.3 (d, J= 19.8 Hz), 20.4 (s), 20.3 (s).15N NMR (61 MHz, DMSO-fifc, 25°C); 8 133.4, 126.7, 118.2, 118.0, 113.5, 111.1.19F NMR (565 MHz, DMSO-r / e, 25°C); 8 -122.8 (m, 0.56F), - 124.0 (m, 0.44F), -190.4 (m, 0.44F), -196.1 (m, 0.56F). HRMS: exact mass calculated for C18H23N3F2O2 ([M+H]+), 352.1831; found 352.1832. IR: 3500, 3250, 3000, 1620, 1550, 1020 cm'1

[0308] Example 7: Alternative synthesis of (5S,6S)-2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide (Compound 2-rac)Compound 3 Compound 2-rac

[0309] To a 3 L Hastelloy reactor was charged Compound 3 (100 g, 287.9 mmol, 1 eq ), l-methyl-2-pyrrolidone (1.4 L), methanesulfonic acid (33.2 g, 345 mmol, 1.2 eq.), and inerted by performing nitrogen pressurization (30 psig) and vent cycle three times. The reaction mixture was stirred for 30 min and a clear light yellow solution is observed. Under nitrogen, to the reactor containing a homogeneous solution was then added a catalyst comprising 4.5 wt% Pd and5463018663 3267224-5583900.5 wt% Rh on carbon, and 50 wt% water (10 g, 10 wt%). The reactor was sealed and was inerted by performing nitrogen pressurization (30 psig) and vent cycle three times. The reactor was then purged three times with 30 psi H2 before pressuring up the reactor to 60 psi with H2. The jacket temperature was set to 53 °C and the reaction was stirred at 700 rpm for 16 hours. After 16 hours the reaction was let cool to rt, and the headspace was vented to a scrubber containing aqueous KOH (0.5M) under a flow of nitrogen. The reaction mixture was fdtered through a cartridge (Whatman 2803 T), to remove heterogeneous catalyst, and a clear fdtrate stream was collected in a 5 L chemglass reactor under N2. To the Hastelloy 3 L Buchi reactor was added l-methyl-2-pyrrolidone (0.2 L, 2080 mmol) for the reactor rinse, and the rinse solution was passed through the fdtration train and combined with fdtrate in chemglass reactor. The fdtrate was then cooled to 0 °C, and triethylamine (43.7 g, 432 mmol) in water (0.64 L) was added over 2 hours, while maintaining batch at 0 °C under N2. Compound 2-rac seed (0.2 g, 0.2 wt%) was then added, and the stream was aged for 1 hour. Water (1.76 L) was then added over 8 hours, while maintaining batch at 0 °C under N2. The mixture was allowed to desaturate for 3 hours, and fdtered. To the chemglass reactor was added water (0.18 L) and l-methyl-2-pyrrolidone (0.12 L) and agitated for the reactor rinse, and the rinse solution was transferred from reactor to fdter cake and fdtered. The wetcake was further washed with water (0.3 L) twice, and dried under vacuum at 40 °C to afford compound 2-rac as white crystalline solid.

[0310] 1HNMR(600 MHz, 19:1 DMSO-t / 6: TFA, 25°C); 6 10.28 (s, 0.56H), 10.16 (s, 0.44H), 9.17 (s, 0.44H), 9.08 (s, 0.56H), 9.06 (s, 0.56H), 8.93 (s, 0.44H), 8.49 (d, J= 7.3 Hz, 0.56H), 8.15 (d, J= 7.5 Hz, 0.44H), 7.92 (s, 1H), 7.11-7.25 (overlapped, 3H), 5.06-5.25 (overlapped, 2H), 3.73-3.87 (overlapped, 4H), 3.30-3.40 (overlapped, 2H), 2.32-2.62 (overlapped, 2H), 2.30 (s, 1.7H), 2.30 (s, 1.3H), 1.62-1.82 (overlapped, 2H), 1.34-1.51 (overlapped, 2H).13C{’H} NMR (151 MHz, 19:1 DMSO-cATFA, 25°C); 8 167.4 (s), 166.9 (s), 164.6 (s), 164.4 (s), 158.1 (d, J = 244.3 Hz), 157.8 (d, J = 244.3 Hz), 133.7 (d, J= 3.3 Hz), 133.4 (d, J = 3.3 Hz), 130.9 (d, J= 8.1 Hz), 130.6 (d, J= 8.1 Hz), 130.0 (br s), 129.7, (br s), 122.3 (dd, J= 12.8, 3.8 Hz), 122.1 (dd, J= 12.4, 1.9 Hz), 115.4 (d, J= 21.4 Hz), 115.1 (d, J= 21.4 Hz), 85.3 (d, J= 178.0 Hz), 83.9 (d, J= 178.0 Hz), 65.9 (s), 65.8 (s), 65.8 (s), 65.7 (s), 52.4 (m), 45.8 (s), 45.5 (s), 39.9 (overlap with DMSO-6), 32.3 (s), 32.2 (s), 32.2 (s), 32.0 (s), 28.5 (d, J= 21.0 Hz), 28.3 (d, J= 19.8 Hz), 20.4 (s), 20.3 (s).15N NMR (61 MHz, DMSO-t / 6, 25°C); 8 133.4, 126.7, 118.2, 118.0, 113.5, 111.1.19F NMR (565 MHz, DMSO- e, 25°C); 8 -122.8 (m, 0.56F), -5563018663 3267224-558390124.0 (m, 0.44F), -190.4 (m, 0.44F), -196.1 (m, 0.56F). HRMS: exact mass calculated for C18H23N3F2O2 ([M+H]+), 352.1831; found 352.1832. IR: 3500, 3250, 3000, 1620, 1550, 1020 cm'1

[0311] Example 8: Alternative synthesis of (5S,6S)-2-amino-5-fluoro-6-(2-fluoro-5- methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide (Compound 2-rac)Compound 3 Compound 8 Compound 2-rac

[0312] Step 1: Synthesis of 2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N- (tetrahydro-2H-pyran-4-yl)-l,4-dihydropyridine-3 -carboxamide (Compound 8).

[0313] To a 500 mL reactor with over head stirring, 2-amino-5-fluoro-6-(5-fluoro-2-methyl-phenyl)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide (20 g, 57.57 mmol, 100 mass%) was charged with 120 mL acetonitrile (6 L / kg, 100 mass%, 94.0 g) and 10 mL 1 -hexylimidazole (1.1 equiv., 63.33 mmol, 98 mass%, 9.838 g). Reaction mixture is a stirred slurry. 12 mL of neat trichlorosilane was added dropwise and the reaction became homogeneous and yellow. A slight exotherm was observed with the temperature rising to 28 °C. Reaction was stirred over the weekend. To quench the reaction, the reactor was cooled to 10 °C and 15 mL of methanol (0.75 L / kg, 371 mmol, 100 mass%, 11.9 g) was added dropwise. The temperature rose to 22 °C with the methanol addition. 500 mL of toluene anti-solvent (25 L / kg, 100 mass%, 436 g) was then added over 2 hours at room temperature. The reactor was further cooled to -10 °C and let stir overnight. The product was then isolated via filtering on a 150 mL medium glass Buchner filter. Solids were washed further with an additional toluene (250 mL, 12.5 L / kg, 100 mass%, 218 g) and dried overnight at 35 °C to provide 16.1 g of the hydrochloride salt of Compound 8 with 85% potency. Material can be further purified to >95% purity by slurrying in 5V of an IPA solution with 5wt% H2O, filtering and drying overnight at 35 °C. Free base can be obtained by diluting in THF, adding an equivalent of triethylamine, filtering off the triethylamine hydrochloride salt and evaporating to dryness but material is unstable and needs to be handled in anhydrous and inert environment to prevent oxidation.5663018663 3267224-558390

[0314] 1HNMR (600 MHz, 19:1 DMSO- e: TFA, 25°C); 5 11.78 (s, 1H), 9.69 (s, 1H), 9.83 (s, 1H), 8.42 (d, J =7.4 Hz, 1H), 7.27 (m, 1H), 7.15 (overlapped, 1H), 7.15 (overlapped, 1H), 4.00 (m, 1H), 3.81 (m, 2H), 3.78 (m, 2H), 3.37 (overlapped, 1H), 3.32 (m, 1H), 2.82 (ddd, J = 17.3, 13.7, 1.2 Hz, 1H), 2.28 (s, 3H), 1.71 (m, 2H), 1.44 (m, 2H). ^C H} NMR (151 MHz, 19:1 DMSO-6fc: TFA, 25°C); 8 165.9, 161.6, 157.6 (d, J= 247.5 Hz), 146.5 (d, J= 258.9 Hz), 133.9 (d, J= 3.4 Hz), 132.2 (d, J= 8.0 Hz), 130.5, 116.3 (dd, J= 15.1, 2.4 Hz), 115.9 (d, J = 21.4 Hz), 112.6 (d, J = 32.7 Hz), 65.80, 65.77, 45.8, 43.3 (d, J= 6.0 Hz), 32.17, 32.15, 25.9 (d, J = 24.8 Hz), 20.0, 15.8.19F NMR (565 MHz, DMSO-cA, 25°C); -126.3 (brt, J= 15.7 Hz, IF), -117.2 (m, IF).15N NMR (61 MHz, DMSO-t / 6, 25°C); 8 128.2, 125.6, 117.9. HRMS-TOF m / z calcd. for C18H20F2N3O2 [M - H]' 348.1529, found 348.1518, 6ppm= 3.

[0315] Step 2: Synthesis of (5S,6S)-2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide (Compound 2-rac).

[0316] Option 1: In a 4 mb vial, was added 50 mg of the HC1 salt of compound 8 (0.0957 mmol, 75 mass%), followed by 0.75 mL of dichloromethane (15 L / kg, 1g, 100 mass%), 1.1 eq of N-hexyl imidazole (16.5 mg, 0.1064 mmol, 100 mass%), and 1.5 eq of (S)-2-pyrrolidone-5-carboxylic acid t-butyl ester (28 mg, 0.145 mmol, 100 mass%). The resulting mixture was allowed to stir for 15 minutes followed by the addition of 5 eq. of trichlorosilane (49 microliters, 0.484 mmol, 65 mg, 100 mass%). This was let stir overnight and full conversion to product was observed. Further analysis revealed racemic material to be produced.

[0317] Option 2: To a 100 mL reactor in an N2 glovebox, was added catecholborane (1.38 g, 11.5 mmol, 4 eq) and 1,4-dioxane (5 mL). The mixture was cooled to 5 °C, a slurry of compound 3 (1g, 2.88 mmol, 1 eq) in 1,4-dioxane (5 mL) was added, and the reaction was allowed to stir overnight at 5 °C. To the reaction mixture was then added 4 eq of HC1 (2.88 mL, 11.52 mmol, 4 N solution in 1,4-dioxane), and 1,4-dioxane (30 mL). The mixture was stirred at 35 °C for overnight and full conversion to compound 2-rac was observed.

[0318] Example 9: Synthesis of Form 1 of (55,6*S)-2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide-mendelic acid salt (Compound 2-MA, Form 1)5763018663 3267224-558390Compound 2-rac Compound 2-MA

[0319] Compound 2-rac (10.2 g, 29 mmol, 1.0 equiv.) was charged to a 250-mL jacked glass reactor under nitrogen at ambient temperature, followed by acetonitrile (155 mb, 15.3V), N, N-dimethylformamide (8 mL, 0.8 V) and L-mandelic acid (4.87 g, 32 mmol, 1.1 equiv.). The resulting mixture was stirred for 5 minutes at ambient temperature under nitrogen. The reaction was heated to 76 °C, cooled to 65 °C, and seeded with (S, S)-Compound 2-MA (100 mg, 0.29 mmol, 1.0 wt%). The reaction was held at 65 °C for 3 hours, cooled to 2 °C over 12 hours, and aged at 2 °C for 6 hours. The resulting slurry was filtered at 2 °C and the solids were washed twice with cold acetonitrile (30 mL, 3 V). The wet cake was dried in a vacuum oven at 50 °C overnight to give 8.9 g (41% yield) of (S, S)-Compound 2-MA, Form 1 as a white solid with an optical purity of 99.0: 1.0 er (S, S)-salt to (R, R)-salt.

[0320] ‘HNMR (500 MHz, 19:1 DMSO-tfcTFA, 25°C); 8 10.18 (s, 0.56H), 10.07 (s, O.44H), 9.17 (s, 0.44H), 9.07 (s, 0.56H), 8.92 (s, 0.56H), 8.80 (s, 0.44H), 8.46 (br d, J= 7.0 Hz, 0.56H), 8.14, (br d, J= 7.2 Hz, 0.44H), 7.43 (br d, J= 7.3 Hz, 2H), 7.34 (br t, 7.3 Hz, 2H), 7.28 (brt, J= 7.3 Hz, 1H), 7.11-7.26 (overlapped, 3H), 5.21 (m, 0.56H), 5.10 (m, 0.44H), 5.04 (s, 1H), 3.74-3.88 (overlapped, 4H), 3.34-3.41 (overlapped, 2H), 2.31-2.62 (overlapped, 2H), 2.31 (s, 3H), 1.63-1.83 (overlapped, 2H), 1.35-1.51 (overlapped, 2H).13C{JH} NMR(176 MHz, 19:1 DMSO-t / 6: TFA, 25°C); 8 174.3 (s), 167.5 (s), 167.0 (s), 164.7 (s), 164.5 (s), 158.2 (d,,7 = 243.4 Hz), 157.9 (d, J= 243.4 Hz), 85.3 (d, J= 178.2 Hz), 83.9 (d, J= 179.7 Hz), 72.6 (s), 66.0 (s), 65.9 (s), 65.8 (s), 65.7 (s), 52.5 (d, J= 18.4 Hz), 45.9 (s), 45.6 (s), 39.9 (overlap with DMSO-t / 6), 32.3 (s), 32.3 (s), 32.2 (s), 32.0 (s), 28.6 (d, J= 21.0 Hz), 28.4 (d, J= 19.8 Hz), 20.5 (s), 20.3 (s).15NNMR(71 MHZ, DMSO-t / 6, 25°C); 8 133.4, 126.7, 118.2, 118.0, 113.5, 111.1.19F NMR(659 MHz, DMSO-t / e, 25°C); 8 -122.8 (m, 0.56F), -124.0 (m, 0.44F), -190.4 (m, 0.44F), -196.1 (m, 0.56F). HRMS: exact mass calculated for C18H23N3F2O2 ([M+H]+), 352.1831; found 352.1834. IR: 3350, 1650, 1550, 1350, 1100 cm45863018663 3267224-558390

[0321] Example 10: Synthesis of (5A,64)-2-amino-5-fluoro-6-(2-fluoro-5-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-l,4,5,6-tetrahydropyridine-3-carboxamide - Hydrochloric acid salt (Compound 2-HC1)Compound 2-MA Compound 2-HC1

[0322] Compound 2-MA (2.0 g, 3.97 mmol, 1.0 equiv.) was charged to a 40 mL vial with stir bar, followed by THF (12.0 mL, 6V), and the mixture was stirred at 20 °C under a nitrogen atmosphere. Aqueous HC1 (6 N, 0.80 mL, 1.2 equiv.) was added, and the vial was heated to 45-50 °C under nitrogen atmosphere for not less than 15 minutes. During HC1 addition, the reaction mixture became clear and colorless, followed by rapid precipitation of the Compound 2-HC1 salt. MTBE (12.0 mL, 6V) was then added over about 2 minutes and the resulting reaction slurry was immediately cooled to 20 °C over 1 hour, and then allowed to age for 30 minutes at 20°C. The product was isolated by filtration over 10 pm filter paper, then washed with MTBE (10.0 mL, 5V), and allowed to de-liquor for 5-10 minutes.

[0323] Example 11: Synthesis of (65,75)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3- (tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahy dropyrido [2,3-d] py rimidine-2,4(l H,3H)-dione (Compound 1)Compound 2-HC1 Compound 1

[0324] The isolated product from the previous example was then slurried in THF (18.0 mL, 9V) in a 40 mL vial and stirred under a nitrogen atmosphere. N, N-Diisopropylethylamine (0.76mL, 1.1 equiv.) was then added, followed by CDI (0.71g, 1.1 equiv.), both reagents added all at once at 20 °C. The reaction mixture was flushed with nitrogen and stirred at 20°C for not less than 2h, until the reaction mixture became a clear yellow solution. The solution was5963018663 3267224-558390concentrated under vacuum to 3.75 V at about 40 °C, and ethanol (14.4 mL, 7.2V) was then added, followed by DI water (5.1 mL, 2.55V), and the solution heated to 72 °C to ensure complete dissolution, and then cool to 55 °C. Seed crystals of product were then added to the solution, DI water (7.5 mL, 3.75 V) was added, and the solution agitated at 50-55 °C for 30 minutes. DI water (9.0 mL, 4.5V) was then added and the solution agitated at 50-55 °C for 2 hours. Lhe slurry was cooled to 20 °C over 2 hours, and aged with agitation for 16 hours. Lhe product was isolated by filtration with 10 pm filter paper, and washed with 1: 1 ethanol:water (10.0 mL, 5V). The product was then dried in a vacuum oven at 50°C for 16 hours to provide a white solid (0.98g, 65% yield).

[0325] Example 12: Alternative synthesis of (6A,7Ky)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione (Compound 1)

[0326] To a clean 250 mL reactor was charged THF (72 mL, 9 V) followed by Compound 2-MA (8.0 g, 15.9 mmol, 1.0 equiv.). Calcium trifluoromethanesulfonate (5.4 g, 15.9 mmol, 1.0 equiv.) was added, followed by THF (32 mL, 4 V) as rinse. The reaction mixture was stirred at 25 °C, resulting in a clear, colorless solution. Next, 1,1’ -carbonyldiimidazole (2.9 g, 18.3 mmol, 1.25 equiv.) was added followed by THF (40 mL, 5 V) as a rinse. The reaction mixture was allowed to stir at 40 °C for 3 hours. After cooling to 25 °C, the reaction was sparged with nitrogen for 20 minutes. The mixture was subjected to the following washes: 1) 20 wt% aqueous ammonium chloride (96 mL, 12 V); 2) 20 wt% aqueous ammonium chloride (96 mL, 12 V) + THF (24 mL, 3V); 3) 20 wt% aqueous ammonium chloride (96 mL, 12 V) + THF (24 mL, 3V); 4) 20 wt% aqueous ammonium chloride (96 mL, 12 V) + THF (24 mL, 3V). Water (18.4 mL, 2.3 V) was charged to the reaction mixture, which was subsequently polish filtered and rinsed with THF (16 mL, 2V). Distill the batch to a target of 5.8 - 6.4 V and charge EtOH (80 mL, 10 V). The batch was heated to 65 - 72 °C to give full dissolution, cooled to 60 °C and seeded with Compound 1 (400 mg, 1.05 mmol, 5.0 wt%). The slurry was aged at 60 °C for 16063018663 3267224-558390hour and then DI water (96 mL, 12 V) was added slowly over 4 hours at 60 °C. After stirring for an additional 1 hour at 60 °C, the slurry was cooled to 10 °C over 2 hours and allowed to stir at 10 °C for 12 hours. The resulting slurry was fdtered and solids were washed with 1: 1 EtOH:water (24 mL, 3 V) and three times with water (40 mL, 5 V). The wet cake was dried in a vacuum oven at 55 - 60 °C overnight to give 5.0 g (83% yield) of Compound 1 as a white solid.

[0327] Example 13: Recrystallization and purification of (65, ZS)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione (Compound 1 Form B)

[0328] Crude Compound 1 from the previous example (24 g, 377.39 g / mol, 99% mass, 62.96 mmol) was charged to a 500 mL chemglass reactor with a half moon impeller. A premixed solution of tetrahydrofuran (4 V, 96 mL, 85.1 g, sigma Aldrich), ethanol (9.6 V, 230.4 mL, 182.0 g), and water (81.6 mL, 81.6 g, UPLC grade) was then added to the reactor and the resulting mixture was stirred at 300 RPM. The reactor was then heated to 72 °C over 20 minutes and stirred at 72 °C until all solids dissolved. The solution was then cooled from 72 °C to 60 °C over 1 hour and seeded with 3 wt% wet milled seeds (0.72 g, 1.889 mmol). The seed bed was then aged for 2 hours until the slurry thickened. Water (2 V, 48 mL, 48 g, UPLC grade) was slowly added above surface into the reactor over 1.2 hours, aged for 30 minutes, and then the slurry was wet milled using an IKA Magic Lab (3 stages / 2 fine, 1 pumping) at 14,400 RPM (23 m / sec tip speed) for 20 turnovers (5.11 minutes). The slurry was then aged for 30 minutes then water (3 V, 72 mL, 72 g, UPLC grade) was slowly added to the reactor over 1.8 hours. The slurry was then distilled at 60 °C under vacuum to remove 5 V of solvent (starting pressure: 500 mbar, final pressure: 450 mbar, jacket temperature 70-75°C). Water (5 V, 120 mL, 120 g, UPLC grade) was slowly added to the reactor over 3 hours, then the mixture was cooled from 60 °C to 25 °C over 2 hours. The product, Compound 1 Form B, was isolated by filtration using 10 pm filter paper. The reactor was rinsed with 1: 1 ethanol:water (4 V, 96 mL, 85.9 g, sigma Aldrich ethanol, UPLC grade water) and the reactor rinse used to wash the filtered product. The cake was further washed with 1: 1 ethanol:water (4 V, 96 mL, 85.9 g, sigma Aldrich ethanol, UPLC grade water), and dried in a vacuum oven at 60°C for at least 12 hours.

[0329] 'H NMR (700 MHz, DMSO-fifc) 3 10.20 (s, 1H), 7.24 (br d, J= 6.9 Hz, 1H), 7.21 (m, 1H), 7.13 (dd, J= 10.4, 8.4 Hz, 1H), 6.45 (s, 1H), 5.05 (br d, J= 47.7 Hz, 1H), 4.92 (br d, J = 26.3 Hz, 1H), 4.87 (tt, J= 12.0, 4.0 Hz, 1H), 3.91 (dd, J= 11.2, 4.3 Hz, 2H), 3.32 (ddd, J =6163018663 3267224-55839012.1, 12.1, 1.6 Hz, 2H), 2.72 / 2.63 / 2.61 (overlapped, 4H), 2.30 (s, 3H), 1.39 (m, 2H).13C NMR (176 MHz, DMSO-t / e) 6 162.4, 157.8 (d, J= 243.1 Hz), 150.1, 148.2, 133.4 (d, J= 3.3 Hz), 130.2 (d, J= 8.2 Hz), 129.0, 124.5 (d, J= 12.5 Hz), 115.0 (d, J= 21.7 Hz), 85.1 (d, J= 179.0 Hz), 76.9, 67.2, 50.2 (dd, J = 19.2, 2.7 Hz), 48.4, 28.7, 25.2 (d, J= 22.0 Hz), 20.4.19F NMR (659 MHz, DMSO-t / <>) <) -123.5 (m, IF), -191.3 (ddddd, J= 47.7, 38.3, 26.3, 15.9, 4.7 Hz, IF). HRMS (ESI+): [M+H]+ m / z calc’d for C19H22N3O3F2; 378.16237, found 378.16199.

[0330] Example 14

[0331] Another exemplary synthesis according to an embodiment of the invention is shown below.NH,™. Cui (5 mol%)NH3(70 psi) CDI (1.15 equiv.) K3PO4 (2 equiv) DMF (6 V) THF (14 V)85% yieldCyJohnphos-Pd(crotyl)CI (0.2 mol%) or CyJohnphos (0.2 mol%) / [Pd(crotyl)CI]2(0.1 mol%)84% yield6263018663 3267224-5583904.5% Pd / 0.5% Rh on carbon, JM23 (10 wt%) (L)-Mandelic acid MSA (1.2 equiv.) (1.05 equiv.) NMP (14 V) 19:1 MeCN: DMF (16 V) 60 psi H2, 50 °C 75 °C to 0 °C 85% yield (racemic) 41% yield -99:1 er

[0332] Process Advantages

[0333] The processes and process steps as disclosed herein possess one or more advantages over other processes, such as use of low cost reagents, fewer steps (e g., by use of direct crystallization and non-use of protecting groups), and ambient conditions, and such as high efficiency, high yield, high purity, stereoselectivity, and control of physical properties (e.g., particle size, crystal form). For example, the following are advantages of the processes and process steps as disclosed herein. Example 1 utilizes CDI, a low-cost coupling agent and the final product is crystallized directly from the process stream without the need of an aqueous work-up. Examples 2 and 3 are expedient, simple Cu-catalyzed amination with no protecting group. Example 4 is a batch homogeneous Cu-catalyzed amination at ambient pressure.Example 5 is a very efficient coupling to give a high yield of the desired product. Examples 6 and 7 provide access to a highly substituted tetrahydropyridine core using a saturated analog; the reaction conditions provide high compatibility with aryl fluorides, and other functional groups; and the reaction is stereoselective. Example 8 enables non-hydrogenation reductions to be performed and prevents the formation of hydrofluoric acid under acidic reaction conditions; it also does not require high-pressure vessels and may enable a diastereo- and enantioselective process. The Example 8 process step may allow for removal of downstream resolution process and significant loss of material may be avoided. Example 9 utilizes an inexpensive and readily available chiral resolving agent in L-mandelic acid to obtain the desired product with up to 97 er6363018663 3267224-558390and 40-45% recovery. Example 10, by converting to the HC1 salt, provides much higher in-process purity in the subsequent step (Example 11). Example 11 is performed in THF in order to streamline into an ethanol / water / THF crystallization without the need for solvent swaps. This ternary crystallization system provides the desired form of the API (Form B). Example 13 recrystallization allows for robust control of the crystal form through seeded crystallization and controlled anti-solvent addition and cooling. The process delivers API with good particle size control with favorable physical properties for drug formulation. The solvent used for this crystallization allows for the short cycle time while maintaining Form B crystals.OTHER EMBODIMENTS

[0334] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.6463018663 3

Claims

267224-558390WHAT IS CLAIMED IS:

1. A process for producing Compound 1or a salt thereof, the process comprising contacting Compound 2Oor a salt thereof, with a compound having the structureXl x2, optionally in the presence of a solvent, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-, F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substituted phenyl)-C(O)O-,(optionally substituted phenyl)-O-, imidazole,or O2. The process according to claim 1, wherein Xi and X2 are each independently selected from chloro, bromo, CI3CO-, F3CO-, imidazole, 4-nitrophenoxy, pentafluorophenoxy, or3. The process according to claim 2, wherein Xi and X2 are both imidazole.6563018663 3267224-5583904. The process according to any one of claims 1-3, wherein the reaction is performed in the presence of an organic solvent.

5. The process of claim 4, wherein the organic solvent is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, isobutyl acetate, methylisopropyl ketone, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof.

6. The process according to claim 4, wherein the organic solvent is THF.

7. The process according to any one of claims 1-6, wherein Compound 2 is present as a salt.

8. The process according to any one of claims 1-7, wherein the reaction is performed in the presence of an organic base or a trifluoromethanesulfonate salt.

9. The process according to claim 8, wherein the reaction is performed in the presence of an organic base, and the organic base is DIPEA.

10. The process according to claim 9, wherein Compound 2 is present as the HC1 salt, Compound 2-HC1.

11. The process according to claim 8, wherein the reaction is performed in the presence of a trifluoromethanesulfonate salt selected from Ca(OTf)2, Mg(OTf)2, and NaOTf.

12. The process according to claim 11, wherein the reaction is performed in the presence of Ca(OTf)2.

13. The process according to any one of claims 11-12, wherein Compound 2 is present as the mandelic acid salt, Compound 2 -MA.

14. The process according to any one of claims 11-13, wherein the reaction temperature is from about 20 °C to about 60 °C.

15. The process according to any one of claims 11-14, wherein the reaction volume is from about 5 V to about 20 V.6663018663 3267224-55839016. The process according to any one of claims 1-15, further comprising producing crystalline Form B of Compound 1, characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kot at room temperature, comprising peaks at 5.5, 7.1, 9.3, and 19.0 °20 ± 0.2 °20, the process comprising:a) heating a mixture of solid Compound 1 in a solvent that is a combination of one or more organic solvents and water to dissolve the solid Compound 1;b) cooling the mixture formed in step a) to create a slurry;c) adding water to the mixture formed in step b);d) wet milling the slurry formed in step c);e) adding water to the slurry formed in step d);f) reducing the amount of solvent in the slurry formed in step e) by distillation at reduced pressure;g) adding water to the slurry formed in step f);h) cooling the slurry formed in step g); andi) isolating the solid Form B of Compound 1.

17. The process according to claim 16, wherein the solvent in step a) is a mixture of ethanol and water, and a third solvent selected from THF and DMSO.

18. The process according to claim 17, wherein the solvent is a mixture of tetrahydrofuran, ethanol, and water.

19. The process according to claim 18, wherein the volume ratio of tetrahydrofuran to ethanol to water in the solvent is about 2.5: 10:3.5.

20. The process according to claim 16, wherein the volume of the solvent in step a) is about 17 volumes.

21. The process according to claim 16, wherein the temperature of the mixture in step a) is heated to about 72 °C.

22. The process according to claim 16, wherein the temperature of the mixture in step b) is cooled to about 60 °C.6763018663 3267224-55839023. The process according to claim 16, wherein the amount of water added in step c) is about 2 volumes.

24. The process according to claim 16, wherein step b) further comprises adding a seed crystal to the mixture formed in step a).

25. The process according to claim 16, wherein the wet milling in step d) is performed at approximately 23 m / s tip speed for 20 turnovers.

26. The process according to claim 16, wherein the amount of water added in step e) is about 3 volumes.

27. The process according to claim 16, wherein the mixture formed in step e) is reduced in step f) by about 5 volumes.

28. The process according to claim 16, wherein the amount of water added in step g) is about 5 volumes.

29. The process according to claim 16, wherein the slurry in step h) is cooled from about 60 °C to about 25 °C.

30. The process according to any one of claims 1-29, further comprising producing Compound 2, or a salt thereof, with high optical purity from Compound 2-racN H N NH2Compound 2-racthe process comprising contacting Compound 2-rac with an optically active acid in the presence of a solvent, and isolating the resulting Compound 2 acid addition salt.

31. The process according to claim 30, wherein the optically active acid is selected from L-mandelic acid, L-pyroglutamic acid, N-Acetyl-L-leucine, (+)-Camphanic acid, and (2R, 3R)-tartranilic acid.6863018663 3267224-55839032. The process according to claim 31, wherein the optically active acid is L-mandelic acid.

33. The process according to claim 30, wherein the solvent is a polar organic solvent.

34. The process according to claim 33, wherein the solvent is selected from methanol, acetone, dimethyl sulfoxide, ethyl acetate, acetonitrile, methylene chloride, dimethylformamide, diethyl ether, acetic acid, isopropanol, methyl ethyl ketone, methyl acetate, dimethylacetamide, and isopropyl acetate, or any combination thereof.

35. The process according to claim 34, wherein the solvent is acetonitrile, dimethylformamide, or a combination thereof.

36. The process according to claim 30, further comprising exchanging the optically active anion of the Compound 2 acid addition salt for chloride by contacting the Compound 2 acid addition salt with hydrochloric acid in the presence of an aprotic solvent, and isolating the Compound 2-HC1 salt.

37. The process according to claim 36, wherein the aprotic solvent is selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof.

38. The process according to claim 37, wherein the aprotic solvent is THF.

39. The process according to any one of claims 1-38, further comprising reducing CompoundN I HN' NH₂Compound 3in the presence of a reducing agent to provide Compound 2-rac.

40. The process of claim 39, wherein the reduction is performed in the presence of an acid and a solvent.6963018663 3267224-55839041. The process according to claim 40, wherein the solvent is selected from 1 -methyl-2-pyrrolidone, 2,5,7,10-tetraoxaundecane (TOU), Elcosol DM, and 1,3-dioxolane.

42. The process according to claim 41, wherein the solvent is l-methyl-2-pyrrolidone.

43. The process according to claim 40, wherein the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

44. The process according to claim 43, wherein the acid is methanesulfonic acid.

45. The process according to any one of claims 39-44, wherein the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

46. The process according to claim 45, wherein the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

47. The process according to claim 45, wherein the catalyst is selected from Pd / C, Pd / AkCh, Pt / C, Pt / AhCh, Rh / C, Rh / AICCh, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

48. The process according to claim 45, wherein the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

49. The process according to any one of claims 1-48, further comprising reducing CompoundN I HN^NH2Compound 3in the presence of a first reducing agent to provide Compound 87063018663 3267224-558390Compound 8and then reducing Compound 8 in the presence of a second reducing agent to provide Compound 2-rac.

50. The process according to claim 49, wherein the first reduction is performed in the presence of a first solvent, and the second reduction is performed in the presence of a second solvent.

51. The process according to claim 49, wherein the first and second reducing agents are the same or different and are selected from dimethyl sulfide borane, dimethyl sulfide dichloroborane, dimethyl sulfide chloroborane, tetrahydrofuran borane, catechol borane, 9-borabicyclo[3.3.1]nonane, sodium triacetoxyborohydride, sodium borohydride, dissopinocampheylborane, trimethylamine borane, 2-methylpyridine borane, / c / v-butylamine borane, pyridine borane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with triphenylborane, trichlorosilane, dichlorosilane, phenylsilane, chlorophenylsilane, dichlorophenylsilane, diphenyl silane, triphenylsilane, 2,4,6, 8-tetramethylcyclotetrasiloxane, triethoxysilane, polymethylhydrosiloxane (PMHS), 1,1,3,3-tetramethyldisiloxane, and pentamethyldisiloxane.

52. The process according to claim 51, wherein the first and second reducing agents are the same or different and further comprise an acid.

53. The process according to claim 52, wherein the acid is selected from hydrochloride acid, pyridinium hydrochloride, and trifluoro acetic acid.

54. The process according to any one of claims 49-53, wherein the first and second reducing agents are both trichlorosilane.

55. The process according to any one of claims 49-54 wherein the first reducing agent is trichlorosilane and the second reducing agent is catechol borane.7163018663 3267224-55839056. The process according to any one of claims 49-55, wherein the first solvent is acetonitrile and the second solvent is di chloromethane or 1,4-di oxane.

57. The process according to any one of claims 49-56, wherein the trichlorosilane is reacted in the presence of a base.

58. The process according to claim 57, wherein the base is N-hexyl imidazole.

59. The process according to any one of claims 1-58, further comprising reacting Compound 4NH12Compound 4with (2-fluoro-5-methylphenyl)boronic acid to provide Compound 3.

60. The process of claim 59, wherein the reaction is performed in the presence of a catalyst and / or ligand, a base, and a solvent.

61. The process according to claim 60, wherein the catalyst comprises palladium or nickel.

62. The process according to claim 61, wherein the catalyst is selected from Pd(PPh3)4, PdCl2(PPh3)2, Ni(PPh3)2(naph)Cl, Ni(o-Tol)(Cl)(PPh3)2, andNi(o-Tol)(Cl)(TMEDA).

63. The process according to claim 60, wherein the catalyst or ligand is selected from Pd(OAc)2, [Pd(crotyl)Cl]2, SPhos-Pd-G3, XPhos-Pd(crotyl)Cl, XPhos-Pd-G3, PPh3, CPhos, CyJohnPhos, XPhos, SPhos, PPt Cy, P(p-F-Ph)3, and P(p-Anis)3.

64. The process according to any one of claims 60-63, wherein the base is selected from Na2CO3, K2CO3, DBU, KOH, NaOH, TEA, DIPEA, NaH, Na3PO4, and K3PO4.

65. The process according to claim 64, wherein the base is K3PO4.7263018663 3267224-55839066. The process according to any one of claims 60-65, wherein the solvent is selected from MeTHF, iPAc, MeOH, and THF.

67. The process according to claim 66, wherein the solvent is THF.

68. The process according to any one of claims 1-67, further comprising aminating Compound 5Compound 5with an aminating agent having the formula NH2R, to provide a compound of Formula AFormula Awherein R is hydrogen or an amine protecting group.

69. The process of claim 68, wherein the amination is performed in the presence of Cui, a base, and a solvent.

70. The process according to any one of claims 68-69, wherein the process further comprises the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO), N, N'-bis(2-phenylphenyl) oxalamide (BPPO), or N, N'-bis-phenyl oxalamide (BPO).

71. The process according to claim 70, wherein the process further comprises the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO).

72. The process according to any one of claims 69-71, wherein the base is selected from a cesium, sodium or potassium salt of methoxide, ethoxide, zc / 7-butoxide, CO32’, PO43’, H’, or OH’.

73. The process according to claim 72, wherein the base is potassium terZ-butoxide or K3PO43’.7363018663 3267224-55839074. The process according to any one of claims 69-73, wherein the solvent is selected from THF, diethylether, acetonitrile, NMP, dioxane, DMA, DMF, DMSO, and water, or a combination thereof.

75. The process according to claim 74, wherein the solvent is THF.

76. The process according to claim 74, wherein the solvent is a combination of THF and water.

77. The process according to claim 76, wherein the THF and water are present in a ratio of about 1:1.

78. The process according to any one of claims 69-77, wherein the Cui is present in from about 5 mol% to about 30 mol%.

79. The process according to any one of claims 68-78, wherein R is hydrogen, and the compound of Formula A is Compound 4.

80. The process according to any one of claims 68-78, wherein R is an amine protecting group, and the process further comprises deprotecting the compound of Formula A to produce Compound 4.

81. The process according to claim 80, wherein R is an amine protecting group selected from carbobenzyl oxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), / c' / 7-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-m ethoxyphenyl (PMP) group, tosyl (Ts), trichloroethyl chloroformate (TROC), and 2,4-dimethoxybenzyl.

82. The process according to claim 81, wherein R is 2,4-dimethoxybenzyl and the compound of Formula A is Compound 77463018663 3267224-558390Compound 783. The process according to claim 82, wherein the 2,4-dimethoxybenzyl protecting group is removed by contacting the compound of Formula A with a strong acid in the presence of an organic solvent.

84. The process according to claim 83, wherein the 2,4-dimethoxybenzyl protecting group is removed by contacting the compound of Formula A with methanesulfonic acid in acetonitrile.

85. The process according to claim 84, further comprising isolating the methanesulfonic acid salt of Compound 4, and deprotonating the salt with a base to produce Compound 4.

86. The process according to any one of claims 1-85, further comprising coupling Compound 6Compound 6with 4-aminotetrahydropyran, or a salt thereof, in the presence of a coupling reagent, a base, and a solvent, to provide Compound 5.

87. The process according to claim 86, wherein the 4-aminotetrahydropyran is present as the hydrochloride salt.

88. The process according to claim 86, wherein the coupling agent is selected from BOP, COMU, HATU, HBTU, HCTU, PyBOP, PyAOP, PyOxim, TSTU, and CDI.

89. The process according to claim 88, wherein the coupling reagent is CDI.7563018663 3267224-55839090. The process according to claim 86, wherein the solvent is DMF, DMA, or NMP.

91. The process according to claim 86, wherein the solvent is DMF.

92. The process according to claim 86, wherein the base is triethylamine or DIPEA.

93. The process according to any one of claims 1-92, further comprising chlorinating Compound 6OCI^I\F <3lCompound 6with a chlorinating reagent, optionally in the presence of a solvent, to provide Compound 8OFXX CI^N CklciCompound 8and contacting Compound 8 with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base and a solvent to produce Compound 5.

94. The process according to claim 93, wherein the 4-aminotetrahydropyran is present as the hydrochloride salt.

95. The process according to claim 93, wherein the chlorinating reagent is selected from thionyl chloride, oxalyl chloride, PCh, PCls, POCI3, PhPO(Cl)2, phosgene, and Cyanuric chloride.

96. The process according to claim 93, wherein Compound 8 is contacted with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base selected from triethylamine, DIPEA, DBU, and pyridine, and a solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof, to produce Compound 5.7663018663 3267224-55839097. A process for producing Compound 1, comprisinga) contacting Compound 6Compound 6with 4-aminotetrahydropyran, or a salt thereof, in the presence of a base selected from triethylamine and DIPEA, a coupling reagent selected from BOP, COMU, HATU, HBTU, HCTU, PyBOP, PyAOP, PyOxim, TSTU, and CDI, and a solvent selected from DMF, DMA, and NMP, to provide Compound 5;b) aminating Compound 5Compound 5with NH3 in the presence of Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, ter / -butoxide, COs2', PO43', H’, or OH', and a solvent selected from THF, diethylether, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 4, orcontacting Compound 5 with 2,4-dimethoxybenzyl amine in the presence of (2,6-dimethylphenyl)carbamoyl]formic acid (DMPAO) or N, N'-bis(2-phenylphenyl) oxalamide (BPPO), Cui, a base selected from a cesium, sodium or potassium salt of methoxide, ethoxide, / c / 7-butoxide, COs2', PO43', H', or OH', and a solvent selected from THF, diethylether, NMP, dioxane, DMA, acetonitrile, DMF, DMSO, and water, or a combination thereof, to provide Compound 77763018663 3267224-558390Compound 7and treating Compound 7 with methanesulfonic acid in a polar aprotic solvent, followed by a neutralizing base to produce Compound 4;c) reacting Compound 4Compound 4with (2-fluoro-5-methylphenyl)boronic acid in the presence of PdC12(PPh3)2, a base selected from Na2CO3, K2CO3, DBU, KOH, NaOH, TEA, DIPEA, NaH, Na3PO4, and K3PO4, and a solvent selected from MeTHF, iPAc, MeOH, and THF, to provide Compound 3;d) reducing Compound 3Compound 3in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water, an acid selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and acetic acid, and a solvent that is 1 -methyl-2-pyrrolidone, to provide Compound 2-rac.e) contacting Compound 2-racCompound 2-racwith L-mandelic acid in acetonitrile and optionally dimethylformamide, and isolating Compound 2-MAf) exchanging the L-mandelate anion in Compound 2-MA7863018663 3267224-558390Compound 2-MAfor chloride by contacting the Compound 2-MA with hydrochloric acid in the presence of an aprotic solvent selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, di methyl acetamide, and acetonitrile, or any combination thereof, and isolating Compound 2-HC1; andg) contacting Compound 2-HC1Compound 2-HC1with carbonyldiimidazole in the presence of THF and a base selected from tri ethylamine and DIPEA to provide Compound 198. The process according to claim 97, wherein the 2,4-dimethoxybenzyl protecting group is removed in step b) by contacting Compound 7 with methanesulfonic acid in acetonitrile.

99. The process according to claim 97, wherein the acid in step d) is methanesulfonic acid.

100. The process according to claim 97, wherein the solvent in step f) is THF.

101. The process according to claim 97, further comprising producing crystalline Form B of Compound 1, characterized by an X-ray powder diffraction pattern, obtained by irradiation with7963018663 3267224-558390Cu-Ka at room temperature, comprising peaks at 5.5, 7.1, 9.3, and 19.0 °20 ± 0.2 °20, the process comprising:h) heating a mixture of solid Compound 1 in a solvent that is a mixture of tetrahydrofuran, ethanol, and water to about 72 °C to dissolve the solid Compound 1;i) cooling the mixture formed in step a) to about 60 °C and adding a seed crystal of crystalline Form B of Compound 1 to the mixture to create a slurry;j) adding water to the mixture formed in step b);k) wet milling the slurry formed in step c) at approximately 23 m / s tip speed for 20 turnovers;l) adding water to the slurry formed in step d);m) reducing the amount of solvent in the slurry formed in step e) by about 5 volumes by distillation at reduced pressure;n) adding water to the slurry formed in step f);o) cooling the slurry formed in step g) from about 60 °C to about 25 °C; and p) isolating the solid Form B of Compound 1.

102. The process according to claim 101, wherein the volume ratio of tetrahydrofuran to ethanol to water in the solvent in step h) is about 2.5: 10:3.5.

103. The process according to claim 101, wherein the volume of the solvent in step h) is about 17 volumes.

104. The process according to claim 101, wherein the amount of water added in step j) is about 2 volumes.

105. The process according to claim 101, wherein the amount of water added in step 1) is about 3 volumes.

106. The process according to claim 101, wherein the amount of water added in step n) is about 5 volumes.

107. A compound, or salt thereof, selected from the group consisting of8063018663 3267224-558390oN1 1 H II J H NT N H2NH2Compound 2 Compound 3o oYYW II J H II j n CI / X'N^NH2CI^N^ LICompound 4 Compound 5O r^OoII jhCI^^N^NH II II H ^^N^NH2|l 1 HOandCompound 8 Compound 7108. The salt according to claim 107, wherein the salt is an acid addition salt of Compound 2.

109. The salt according to claim 108, wherein the acid addition salt is selected from the group consisting of Compound 2-HC1, Compound 2-L-mandelic acid, Compound 2-L-pyroglutamic acid, Compound 2-N-Acetyl-L-leucine, Compound 2-(+)-Camphanic acid, and Compound 2-(2R, 3R)-tartranilic acid.

110. The salt according to claim 108, wherein the acid addition salt is produced from an optically active acid.

111. The salt according to claim 110, wherein the acid addition salt is selected from the group consisting of Compound 2-L-mandelic acid, Compound 2-L-pyroglutamic acid, Compound 2-N-Acetyl-L-leucine, Compound 2-(+)-Camphanic acid, and Compound 2-(2R,3R)-tartranilic acid.

112. The salt according to claim 111, wherein the acid addition salt is Compound 2 -MA.8163018663 3267224-558390113. The salt according to claim 112, wherein the Compound 2-MA is characterized by an15N INEPT NMR spectrum, using a 71 MHz NMR spectrometer in DMSO- e at 25°C, having peaks at about 133.41 ppm, about 126.72 ppm, about 118.18 ppm, about 117.95 ppm, about 113.45 ppm, and about 111.14 ppm.

114. The salt according to claim 113, wherein the Compound 2-MA is characterized as solid Form 1.

115. The salt according to claim 114, wherein the Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 17.3, 18.1, and 19.2 °29 ± 0.2 °29.

116. The salt according to claim 115, wherein the Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, and 19.2 °29 ± 0.2 °29.

117. The salt according to claim 116, wherein the Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, 19.2, 20.6, and 21.1 °29 ± 0.2 °29.

118. The salt according to claim 117, wherein the Compound 2-MA, Form 1 is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Ka at room temperature, comprising peaks at 5.8, 8.8, 11.5, 13.7, 17.3, 18.1, 19.2, 20.6, 21.1, 24.2, and 24.9 °29 ± 0.2 °29.

119. The salt according to claim 118, wherein the Compound 2-MA, Form 1 is characterized by a13C ssNMR spectrum having peaks at 178.86 ± 0.2, 168.71 ± 0.2, 165.14 ± 0.2, 160.65 ± 0.2, 158.68 ± 0.2, 142.34 ± 0.2, 136.34 ± 0.2, 131.07 ± 0.2, 129.42 ± 0.2, 128.50 ± 0.2, 126.78 ± 0.2, 122.11 ± 0.2, 115.46 ± 0.2, 84.35 ± 0.2, 83.09 ± 0.2, 73.11 ± 0.2, 67.36 ± 0.2, 50.84 ± 0.2, 46.81 ± 0.2, 45.77 ± 0.2, 32.92 ± 0.2, 31.73 ± 0.2, 25.88 ± 0.2, and 18.42 ± 0.2 ppm120. A process for producing Compound 2,8263018663 3267224-558390Compound 2or a salt thereof, with high optical purity from Compound 2-racCompound 2-racthe process comprising contacting Compound 2-rac with an optically active acid in the presence of a solvent, and isolating the resulting Compound 2 acid addition salt.

121. The process according to claim 120, wherein the optically active acid is selected from L-mandelic acid, L-pyroglutamic acid, N-Acetyl-L-leucine, (+)-Camphanic acid, and (2R, 3R)-tartranilic acid.

122. The process according to claim 121, wherein the optically active acid is L-mandelic acid.

123. The process according to claim 121, wherein the solvent is a polar organic solvent.

124. The process according to claim 123, wherein the solvent is selected from methanol, acetone, dimethyl sulfoxide, ethyl acetate, acetonitrile, methylene chloride, dimethylformamide, diethyl ether, acetic acid, isopropanol, methyl ethyl ketone, methyl acetate, dimethylacetamide, and isopropyl acetate, or any combination thereof.

125. The process according to claim 124, wherein the solvent is acetonitrile, dimethylformamide, or a combination thereof.

126. The process according to claim 121, further comprising exchanging the optically active anion of the Compound 2 acid addition salt for chloride by contacting the Compound 2 acid 8363018663 3267224-558390addition salt with hydrochloric acid in the presence of an aprotic solvent, and isolating the Compound 2-HC1 salt.

127. The process according to claim 126, wherein the aprotic solvent is selected from DCM, chloroform, THF, acetone, ethyl acetate, toluene, DMF, dimethylacetamide, and acetonitrile, or any combination thereof.

128. The process according to claim 127, wherein the aprotic solvent is THF.

129. A process for producing Compound 1N N N H HFCompound 1or a salt thereof, the process comprising contacting Compound 2-MAHi AI HN^NH2PhCompound 2-MAOwith a compound having the structurex2, in the presence of a solvent and a trifluoromethanesulfonate salt, wherein Xi and X2 are the same or different and are selected from halogen, CI3CO-, F3CO-, (optionally substituted C1-6 alkyl)-C(O)O-, (optionally substitutedphenyl)-C(O)O-, (optionally substituted phenyl)-O-, imidazole,or O8463018663 3267224-558390130. The process according to claim 129, wherein Xi and X2 are each independently selected from chloro, bromo, CI3CO-, F3CO-, imidazole, 4-nitrophenoxy, pentafluorophenoxy, orO131. The process according to claim 130, wherein Xi and X2 are both imidazole.

132. The process according to any one of claims 129-131, wherein the reaction is performed in the presence of an organic solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, sulfolane, tetrahydrofuran, toluene, DCM, and hexane, cyclohexane, and heptane, or any combination thereof.

133. The process according to claim 132, wherein the organic solvent is THF.

134. The process according to any one of claims 129-133, wherein the reaction is performed in the presence of a trifluoromethanesulfonate salt selected from Ca(OTf)2, Mg(OTf)2, and NaOTf.

135. The process according to any one of claims 129-134, wherein the reaction is performed in the presence of Ca(OTf)2.

136. A process for producing Compound 2-rac:I HN^NH2Compound 2-racthe process comprising reducing Compound 38563018663 3267224-558390N^NH2FCompound 3in the presence of a reducing agent to provide Compound 2-rac.

137. The process of claim 136, wherein the reduction is performed in the presence of an acid and a solvent.

138. The process according to claim 137, wherein the solvent is selected from l-methyl-2-pyrrolidone, 2,5,7, 10-tetraoxaundecane (TOU), Elcosol DM, and 1,3 -di oxolane.

139. The process according to claim 137, wherein the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

140. The process according to claim 139, wherein the acid is methanesulfonic acid.

141. The process according to any one of claims 136-140, wherein the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

142. The process according to claim 141, wherein the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

143. The process according to claim 141, wherein the catalyst is selected from Pd / C, Pd / AhCh, Pt / C, Pt / AbCh, Rh / C, Rh / AICCh, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

144. The process according to any one of claims 136-143, wherein the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt % water.8663018663 3267224-558390145. A process for producing a compound of Formula IFormula Ior a salt thereof, comprising reducing a compound of Formula IIor a salt thereof, in the presence of a reducing agent, whereinwherein Ring A and Ring B are each independently selected from phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from R’, OH, halo, CN, NH2, NHR’, N(R’)2, OR’, C(O)H, C(O)R’, C(O)OR’, C(O)NH2, C(O)NHR’, and C(O)N(R’)2, wherein each R’ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halo, OH, oxo, and OC1-6 alkyl;each R is independently selected from OH, halo, CN, C1-6 alkyl, C1-6 haloalkyl, OC1-6 alkyl, C(O)H, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, C(O)NH2, C(O)NHCI-6alkyl, and C(O)N(CI-6 alkyl)2; andeach p is 0, 1, or 2.

146. The process of claim 145, wherein Ring A is selected from optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl.

147. The process of claim 145 or claim 146, wherein Ring A is selected from phenyl and 5-6 membered heteroaryl, wherein Ring A is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.8763018663 3267224-558390148. The process of any one of claims 145-147, wherein Ring A is phenyl, optionally substituted with one or more substituents selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2-6 alkynyl.

149. The process of any one of claims 145-148, wherein Ring B is selected from optionally substituted 3-6 membered cycloalkyl, and optionally substituted 3-6 membered heterocycloalkyl.

150. The process of any one of claims 145-149, wherein Ring B is selected from 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.

151. The process of any one of claims 145-150, wherein Ring B is 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from O and N, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, C1-6 haloalkyl, and OC1-6 alkyl.

152. The process of any one of claims 145-151, wherein Ring B is an unsubstituted tetrahydropy an-4-yl.

153. The process of any one of claims 145-152, wherein each R is independently selected from OH, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and OC1-6 alkyl.

154. The process of any one of claims 145-153, wherein each R is independently selected from OH, halo, and C1-6 alkyl.

155. The process of any one of claims 145-154, wherein p is 1.

156. The process of any one of claims 145-155, wherein p is 1 and R is halo.

157. The process of any one of claims 145-156, wherein the reduction is performed in the presence of an acid and a solvent.

158. The process according to claim 157, wherein the solvent is selected from l-methyl-2-pyrrolidone, 2,5,7, 10-tetraoxaundecane (TOU), Elcosol DM, and 1,3-dioxolane.8863018663 3267224-558390159. The process according to claim 157, wherein the acid is selected from HC1, HBr, toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, R / S-camphor sulfonic acid, chloroacetic acid, di chloroacetic acid, oxalic acid, phosphoric acid, and acetic acid.

160. The process according to claim 159, wherein the acid is methanesulfonic acid.

161. The process according to claim 157, wherein the reducing agent is molecular hydrogen in the presence of a metal catalyst, which further comprises one or more transition metals.

162. The process according to claim 161, wherein the transition metal is selected from iridium, nickel, palladium, platinum, rhodium, and ruthenium, or a combination thereof.

163. The process according to claim 162, wherein the catalyst is selected from Pd / C, Pd / AhCh, Pt / C, P AI2O3, Rh / C, RI1 / AICO3, Pd(OH)2 / C, and a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

164. The process according to claim 163, wherein the reducing agent is hydrogen in the presence of a catalyst comprising 4.5 wt% Pd and 0.5 wt% Rh on carbon, and 50 wt% water.

165. A process for producing a compound of Formula Ior a salt thereof, comprising reducing a compound of Formula 11Formula IIor a salt thereof, in the presence of a first reducing agent to provide a compound of Formula III8963018663 3267224-558390Formula IIIor a salt thereof, and then reducing the compound of Formula III in the presence of a second reducing agent to provide a compound of Formula I,wherein Ring A and Ring B are each independently selected from phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from R’, OH, halo, CN, NH2, NHR’, N(R’)2, OR’, C(O)H, C(O)R’, C(O)OR’, C(O)NH2, C(O)NHR’, and C(O)N(R’)2, wherein each R’ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halo, OH, oxo, and OC1-6 alkyl;each R is independently selected from OH, halo, CN, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl, C(O)H, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, C(O)NH2, C(O)NHCi-6 alkyl, and C(O)N(CI-6 alkyl)2; andeach p is 0, 1, or 2.

166. The process of claim 165, wherein Ring A is selected from optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl.

167. The process of claim 165 or claim 166, wherein Ring A is selected from phenyl and 5-6 membered heteroaryl, wherein Ring A is optionally substituted with one or more substituents selected from Ci-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OCi 6 alkyl.

168. The process of any one of claims 165-167, wherein Ring A is phenyl, optionally substituted with one or more substituents selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkynyl.

169. The process of any one of claims 165-168, wherein Ring B is selected from optionally substituted 3-6 membered cycloalkyl, and optionally substituted 3-6 membered heterocycloalkyl.9063018663 3267224-558390170. The process of any one of claims 165-169, wherein Ring B is selected from 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein Ring B is optionally substituted with one or more substituents selected from Ci-6 alkyl, OH, halo, CN, NH2, C1-6 haloalkyl, and OC1-6 alkyl.

171. The process of any one of claims 165-170, wherein Ring B is 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from O and N, wherein Ring B is optionally substituted with one or more substituents selected from C1-6 alkyl, OH, halo, C1-6 haloalkyl, and OC1-6 alkyl.

172. The process of any one of claims 165-171, wherein Ring B is an unsubstituted tetrahydropyan-4-yl.

173. The process of any one of claims 165-172, wherein each R is independently selected from OH, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and OC1-6 alkyl.

174. The process of any one of claims 165-173, wherein each R is independently selected from OH, halo, and C1-6 alkyl.

175. The process of any one of claims 165-174, wherein p is 1.

176. The process of any one of claims 165-175, wherein p is 1 and R is halo.

177. The process according to any one of claims 165-176, wherein the first reduction is performed in the presence of a first solvent, and the second reduction is performed in the presence of a second solvent.

178. The process according to any one of claims 165-177, wherein the first and second reducing agents are the same or different and are selected from dimethyl sulfide borane, dimethyl sulfide di chloroborane, dimethyl sulfide chloroborane, tetrahydrofuran borane, catechol borane, 9-borabicyclo[3.3.1]nonane, sodium triacetoxyborohydride, sodium borohydride, dissopinocampheylborane, trimethylamine borane, 2-methylpyridine borane, tert-butylamine borane, pyridine borane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with triphenylborane, trichlorosilane, dichlorosilane, phenyl silane, chlorophenylsilane, dichlorophenyl silane,9163018663 3267224-558390diphenylsilane, triphenyl silane, 2,4,6,8-tetramethylcyclotetrasiloxane, tri ethoxy silane, polymethylhydrosiloxane (PMHS), 1,1,3,3-tetramethyldisiloxane, and pentamethyldisiloxane.

179. The process according to claim 178, wherein the first and second reducing agents are the same or different further and further comprise an acid selected from hydrochloride acid, pyridinium hydrochloride, and trifluoro acetic acid.

180. The process according to any one of claims 165-179, wherein the first and second reducing agents are both trichlorosilane.

181. The process according to any one of claims 165-180, wherein the first solvent is acetonitrile.

182. The process according to any one of claims 165-181, wherein the second solvent is dichloromethane.

183. The process according to any one of claims 165-182, wherein Compound 3 is reduced to Compound 8 in the presence of N-hexyl imidazole.

184. The process according to any one of claims 165-183, wherein Compound 8 is reduced to Compound 2-rac in the presence of N-hexyl imidazole and (S)-2-pyrrolidone-5-carboxylic acid t-butyl ester.

185. A process for producing Compound 1,N N N H HFCompound 1or a salt thereof, the process comprising:(1) contacting Compound 6 with a tetrahydro-2H-pyran-4-amine to form Compound 5,9263018663 3267224-558390Compound 6 Compound 5(2) aminating Compound 5 with NH3 to form Compound 4,NH3Compound 5 Compound 4 (3) coupling Compound 4 with (2-fluoro-5-methylphenyl)boronic acid to form Compound 3,OHiCompound 4 Compound 3(4) reducing Compound 3 with H2 to form Compound 2-rac,Compound 3 Compound 2-rac (5) contacting Compound 2-rac with (Z)-Mandelic acid to form Compound 2-MA,9363018663 3267224-558390(L)-Mandelic acidCompound 2-rac Compound 2-MA(6) contacting Compound 2-MA with N, N’ -carbonyldiimidazole to form Compound 1Compound 2-MA186. The process according to claim 185, wherein the reaction contacting Compound 6 with a tetrahydro-2H-pyran-4-amine further comprises the presence of CDI in dimethylformamide as a solvent.

187. The process according to claim 185 or 186, wherein the reaction aminating Compound 5 with NH3 further comprises the presence of copper(I) iodide and potassium phosphate in tetrahydrofuran as a solvent.

188. The process according to any one of claims 185-187, wherein the reaction coupling Compound 4 with (2-fluoro-5-methylphenyl)boronic acid further comprises the presence of potassium phosphate in a mixture of tetrahydrofuran and water as a solvent.

189. The process according to any one of claims 185-188, wherein the reaction reducing Compound 3 with H2 further comprises the presence of a palladium / rhodium catalyst and methane sulfonic acid in N-methyl-2-pyrrolidone as a solvent.9463018663 3267224-558390190. The process according to any one of claims 185-189, wherein the reaction contacting Compound 2 -A with (L)-mandelic acid further comprises a mixture of acetonitrile and dimethylformamide as a solvent.

191. The process according to any one of claims 185-190, wherein the reaction contacting Compound 2 -MA with N, N’ -carbonyl diimidazole further comprises the presence of calcium triflate in tetrahydrofuran as a solvent.9563018663 3

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