Methods of manufacturing danicamtiv

Abstract

The present disclosure provides novel methods of chemical synthesis useful for the manufacturing of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (referred to herein as a compound of Formula ( I )), also known as danicamtiv, and a polymorphic form thereof. Danicamtiv is useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and / or right ventricular systolic dysfunction or systolic reserve.

Description

METHODS OF MANUFACTURING DANICAMTIVCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional application no. 63 / 649,622, filed May 20, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] Heart failure (HF) is a global pandemic affecting about 26 million people worldwide. It is the most rapidly growing cardiovascular condition globally, with substantial morbidity, mortality, and cost burden to healthcare systems (Ponikowski et al., ESC Heart Fail. (2014) l(l):4-25; Savarese and Lund, Card Fail Rev. (2017) 3(1):7-11). HF is the most common cause of hospitalization in patients older than 65 years (Ponikowski, supra; Savarese and Lund, supra; and Shah et al., J Am Coll Cardiol. (2017) 70(20):2476-86). The five-year mortality rate after HF hospitalization is about 42%, comparable to many cancers (Benjamin et al.. Circulation (2019) 139:e56-e528).

[0003] In the United States alone, there are about 2.6 million heart failure with reduced ejection fraction (HFrEF) patients, corresponding to about 40% of the U.S. HF population (Bloom et al., Nat Rev Dis Primers. (2017) 3: 17058). HFrEF may develop from an ischemic origin (primarily attributed to coronary artery disease) or a non-ischemic origin (attributed to a disease of the myocardium from non-coronary causes). Coronary artery disease (coronary heart disease) is a disease in which there is a narrowing of the passageway of the coronary arteries, and when severe, the narrowing causes inadequate blood supply to the heart muscle and may lead to the death of heart muscle cells (infarction).

[0004] Non-ischemic HFrEF is sometimes referred to as dilated cardiomyopathy (DCM). Despite the nomenclature, dilated (enlarged) heart chambers can be found in both nonischemic and ischemic HFrEF patients. Dilated cardiomyopathy (DCM) includes a group of myocardial disorders that lead to left ventricular dilatation and systolic dysfunction (abnormality of contraction). DCM can be subdivided into ischemic (attributed due to coronary artery' disease) or non-ischemic (primary' diseases of the myocardium). Hereafter, DCM refers to non-ischemic primary diseases of the myocardium. DCM can be assigned a clinical diagnosis of “idiopathic"’ DCM if no identifiable cause (except genetic) can be found. Idiopathic DCM can be further subcategorized based upon whether a genetic cause can be identified. Mutations in over 30 genes, including sarcomere genes, perturb a diverse set of myocardial proteins to cause a DCM phenotype. Some of the genetic links to DCM arediscussed in Hershberger, et al., Nature Reviews (2013) 10(9): 531-47. Epidemiologic data indicate that approximately 1 in 2.500 individuals in the general population have idiopathic DCM.

[0005] Medical therapy remains the mainstay in patients with DCM and heart failure. Betablocker, ACE inhibitor or ARB, mineralcorticoid receptor blocker, and loop diuretics continue to be standard options for the treatment of heart failure symptoms and reduction of risk for cardiovascular death and heart failure hospitalization. Implantable cardioverter defibrillators (ICD) for patients with left ventricular ejection fraction of less than 30% can reduce sudden arrhythmic death. Additionally, cardiac resynchronization therapy (CRT) has been shown to improve heart failure-free survival in select patients. Despite these interventions, morbidity and mortality for heart failure remain high, and hospitalization for heart failure remains the most common reason for hospitalization in the elderly. The present disclosure provides therapeutic agents and methods to make such that remedy the unmet need for improved treatment of systolic dysfunction, DCM, HFrEF, and related cardiac disorders. In particular, the present disclosure provides improved methods for making such compounds in high yields, high purity, and / or at increased scale.BRIEF SUMMARY OF THE INVENTION

[0006] The present disclosure provides a method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a chiral acid salt of Formula (IX)with a compound of Formula (III)or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted C1-8alkyl or a substituted or unsubstituted aryl, in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0007] In some implementations, the base of step (a) comprises N,N-diisopropylethylamine (DIPEA), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2). barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH), or any combination thereof. In some implementations, the base of step (a) is DIPEA. In some implementations, step (a) takes place in the presence of a solvent. In some implementations, the solvent of step (a) is acetonitrile (MeCN). And, in some implementations. R1is unsubstituted aryl.

[0008] In some implementations, the method further comprises:(b) recrystallizing the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0009] In some implementations, step (b) comprises:(b-1) heating the compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first solvent to a temperature of about 55 °C to about 75 °C to form a first heated mixture.

[0010] In some implementations, the solvent first comprises acetonitrile (MeCN).

[0011] In some implementations, wherein step (b) further comprises:(b-2) adding a second solvent to the first heated mixture to form a second mixture.

[0012] In some implementations, the second solvent comprises water, methyl tert-butyl ether (MTBE), or any combination thereof.

[0013] In some implementations, step (b) further comprises:(b-3) reducing the temperature of the second mixture by about 5 °C to about 15 °C.

[0014] In some implementations, step (b) further comprises:(b-4) seeding the second mixture with seed crystals of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In some implementations, the method further comprises:(c) contacting a compound of F ormula (II-R-A)or a pharmaceutically acceptable salt thereof, with ( / <)- mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

[0016] In some implementations, the solvent of step (c) comprises 2-propanol. In some implementations, step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and (R)- mandelic acid with seed crystals of the chiral acid salt of Formula (IX).

[0017] In some implementations, the method further comprises:(d) recrystallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

[0018] In some implementations, the solvent of step (d) comprises water, 2-propanol, or any combination thereof. And, in some implementations, the solvent of step (d) comprises about 25% 2-propanol and about 75% water.

[0019] In some implementations, the method further comprises:(e) contacting a compound of F ormula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form the compound of Formula (II-R-A). or a pharmaceutically acceptable salt thereof.

[0020] In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxycarbonyl (BOC); 9- fluorenylmethyloxy carbonyl (FMOC); acetyd (Ac); benzoyl (Bz); benzyl (Bn); p- methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM): p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate. And, in some implementations, R2is a BOC protecting group.

[0021] In some implementations, the strong acid of step (e) is hydrochloric acid or trifluoroacetic acid. In some implementations, the strong acid of step (e) is hydrochloric acid. In some implementations, the solvent of step (e) comprises water, 2-propanol, or anycombination thereof. And, in some implementations, the solvent of step (e) comprises water and 2-propanol.

[0022] In another aspect, the present disclosure also provides a method of preparing a compound of Formula (XI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising two ordered reactions comprising:(g-1) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) to form a fluorinated compound or a pharmaceutically acceptable salt thereof; and(g-2) contacting the fluorinated compound or pharmaceutically acceptable salt thereof with an oxidizing reagent to form the compound of Formula (XI) or a pharmaceutically acceptable salt thereof.

[0023] In some implementations, the method takes place in the absence of N- fluorobenzensulfonimide (NFSI). In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxy carbonyl (BOC); 9-fluorenylmethyl oxy carbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p- methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate. And, in some implementations, R2is a BOC protecting group.

[0024] In some implementations, the fluorinating reagent of step (g-1) comprises 1- (chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate; 1- fluoro-2, 4, 6-trimethyl pyridinium triflate; 1 -fluoropyridinium tritiate; or any combination thereof. In some implementations, the fluorinating reagent of step (g-1) is l-(chloromethyl)- 4-fluoro-1.4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate. In someimplementations, the oxidizing reagent of step (g-2) comprises hydrogen peroxide / sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalic acid dehydrate / hydrogen peroxide, metachloroperoxybenzoic acid, urea-hydrogen peroxide adduct, pennanganate / manganese dioxide, ruthenium chloride hydrate / sodium periodate, oxone, or any combination thereof. And, in some implementations, the oxidizing reagent of step (g-2) is ruthenium chloride hydrate / sodium periodate.

[0025] In some implementations, the fluorinated compound or pharmaceutically acceptable salt thereof of step (g-1) is a compound of Formula (XII)or a pharmaceutically acceptable salt thereof.

[0026] In some implementations, step (g-1) takes place in the presence of a base and a solvent. In some implementations, the base of step (g-1) comprises triethylamine (TEA); 1,4- diazabicyclo[2.2.2]octane (DABCO); N-methyl morpholine; N,N-diisopropylethylamine (DIPEA); quinuclidine; pyridine; 2-methylpyridine; 2,6-dimethylpyridine; 2,6-di-tert- butylpyridine; or any combination thereof. In some implementations, the base of step (g-1) comprises TEA, DABCO, N-methyl morpholine, DIPEA, diisopropylethylamine, or any combination thereof. In some implementations, the base of step (g-1) is TEA. In some implementations, the solvent of step (g-1) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof. And, in some implementations, the solvent of step (g-1) is MeCN.

[0027] In some implementations, step (g-2) takes place in the presence of a solvent. In some implementations, the solvent of step (g-2) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof. And, in some implementations, the solvent of step (g-2) is MeCN.

[0028] In a further aspect, the present disclosure provides a method of preparing a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising:(f) contacting a compound of Formula (XI)or a pharmaceutically acceptable salt thereof, with a methylating reagent to form a compound of Formula (IV) or a pharmaceutically acceptable salt thereof.

[0029] In some implementations, the methylating reagent of step (f) is CH I. In some implementations, step (f) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS). In some implementations, step (I) takes place in the presence of toluene. And, in some implementations, the compound of Formula (XI) or a pharmaceutically acceptable salt thereof is prepared according to a method described herein.

[0030] In one aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(e- 1 ) contacting a compound of F ormula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form a reaction mixture; and(e-2) contacting the reaction mixture of step (e-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

[0031] In some implementations, the solvent of step (e-1) comprises 2-propanol, water, or any combination thereof. In some implementations, the strong acid of step (e-1) is hydrochloric acid (HC1). And, in some implementations, the solvent of step (e-2) comprises isopropyl acetate.

[0032] In some implementations, the method further comprises:(e-1 a) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e- la) to form a second reaction mixture.

[0033] In some implementations, the method further comprises:(e-3) adding water to the second reaction mixture of step (e-2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-4) separating the organic layer from the aqueous layer; and(e-5) concentrating the separated organic layer.

[0034] In some implementations, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is prepared according to a method described herein.

[0035] In another aspect, the present disclosure provides a method of preparing a chiral acid salt of Formula (IX) comprising:(c) contacting a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, with (R)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

[0036] In some implementations, the solvent of step (c) comprises 2-propanol. And, in some implementations, step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and ( / bimandelic acid with seed crystals of the chiral acid salt of Formula (IX).

[0037] In some implementations, the method further comprises:(d) recrystallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

[0038] In some implementations, the solvent of step (d) comprises water, 2-propanol, or any combination thereof. In some implementations, the solvent of step (d) comprises about 25% 2-propanol and about 75% water. And, in some implementations, the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof is prepared according to a method described herein.

[0039] In a further aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(g-la) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form the compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-1-1) contacting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof with a strong acid in the presence of a solvent to form a reaction mixture; and(e-1-2) contacting the reaction mixture of step (e-1-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A).

[0040] In some implementations, step (e) further comprises:(e-1-1 a) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-l-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e-l-la) to form a second reaction mixture.

[0041] In some implementations, the method further comprises:(e-1-3) adding water to the second reaction mixture of step (e-l-2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-1-4) separating the organic layer from the aqueous layer; and(e-1-5) concentrating the separated organic layer.

[0042] In some implementations, the method further comprises:(h-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is with Compound1.5aor a pharmaceutically acceptable salt thereof, in the presence of a palladium catalyst, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0043] In some implementations, the method further comprises:(i-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc i, with Compound1.5bor a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, a base, and a solvent, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0044] In some implementations, the copper catalyst of step (i-1) is selected from the group consisting of copper iodide, copper bromide, and copper chloride. In some implementations, the copper catalyst of step (i-1) is copper iodide. In some implementations, the base of step (i-1) is selected from the group consisting of sodium carbonate, potassium carbonate, and cesium carbonate. In some implementations, the base of step (i-1) is sodium carbonate. In some implementations, the solvent of step (i-1) is a protic solvent. In some implementations,the protic solvent is selected from a group consisting of IP A, n-BuOH, and ethanol. And, in some implementations, the protic solvent is n-BuOH.

[0045] In some implementations, the method further comprises:(j ) contacting a compound of F ormula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is withpotassium thioacetate to form the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof.

[0046] In some implementations, the method further comprises:(k) contacting a compound of F ormula (XVI)or a pharmaceutically acceptable salt thereof, with tosyl chloride to form the compound of Formula (XV) or a pharmaceutically acceptable salt thereof.

[0047] In some implementations, step (k) takes place in the presence of dichloromethane (DCM), 4-dimethylaminopyridine (DMAP). and triethylamine (TEA).

[0048] In some implementations, the fluorinating reagent of step (g-1) comprises 1- (chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-I,4-diium ditetrafluoroborate, 1- fluoro-2,4,6-trimethyl pyridinium triflate, 1 -fluoropyridinium tritiate, or any combination thereof. In some implementations, the fluorinating reagent of step (g-1) is l-(chloromethyl)- 4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate. And, in some implementations, the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof is converted to the compound of Formula (XI) or a pharmaceutically acceptable salt thereof without isolating the compound of Formula (XII) or a pharmaceutically acceptable salt thereof.

[0049] In some implementations, the oxidizing reagent of step (g-2) comprises sodium periodate. And, in some implementations, the oxidizing reagent of step (g-1) further comprises ruthenium chloride hydrate.

[0050] In some implementations, the methylating reagent of step (I) is CEEI. In some implementations, step (f) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS). And, in some implementations, step (I) takes place in the presence of toluene.

[0051] In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxycarbonyl (BOC); 9- fluorenylmethyloxy carbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p- methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate. And, in some implementations, R2is a BOC protecting group.

[0052] In one aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(k) contacting a compound of F ormula (XVI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with tosyl chloride to form a compound of Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is(j) contacting the compound of Formula (XV) or a pharmaceutically acceptable salt thereof with potassium thioacetate to form a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is(i) contacting the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5bor a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, to form a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof;(g-la) contacting the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof; and(e-x) deprotecting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, the present disclosure provides a method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprising:(g- 1 ) contacting a compound of F ormula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-x) deprotecting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof;(c) contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with (A)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX) and(a) contacting a chiral acid salt of Formula (IX) with a compound of Formulawherein R1is substituted or unsubstituted C1-8alkyl or a substituted or unsubstituted aryl, in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof

[0054] In a further aspect, the present disclosure provides a chiral acid salt of Formula (IX):

[0055] In one aspect, the present disclosure provides a cry stalline form of a chiral acid salt of Formula (IX):

[0056] In some implementations, the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13. 10 ± 0.2, 14.81 ± 0.2. and 15.42 ± 0.2 in an X-ray powder diffraction pattern. And. in some implementations, the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern.

[0057] The details of certain aspects of the invention are set forth in the Detailed Description, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The following figures are presented as examples and are not intended to limit the scope of the invention.

[0059] FIG. 1 shows an X-ray powder diffraction pattern of a crystalline form (Form B) of a compound of Formula (I) recorded at room temperature.

[0060] FIG. 2 shows a differential scanning calorimetry' (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of the crystalline form (Form B) of a compound of Formula (I).

[0061] FIG. 3 shows a simulated powder diffraction pattern from the crystalline form (Form B) of a compound of Formula (I) at copper wavelength. The numerical labels of the peaks in FIG. 3 are expressed in 1 -theta degree, which corresponds to one half of the X-axis values of the peaks expressed in 2-theta degrees.

[0062] FIG. 4 shows an X-ray powder diffraction pattern of a chiral acid salt of Formula (IX) at room temperature.

[0063] FIG. 5 shows a DSC thermogram and a TGA thermogram of the chiral acid salt of Formula (IX).

[0064] FIG. 6 shows liquid chromatography-mass spectrometry (LCMS) data for the chiral acid salt of Formula (IX).

[0065] FIG. 7 shows a 1H NMR spectrum for the chiral acid salt of Formula (IX).DETAILED DESCRIPTION

[0066] I. DEFINITIONS

[0067] As used herein, “a compound of Formula (I)” refers to the compound having the formula (or structure):The compound of Formula (I) is also referenced as (A)-4-(l-((3-(difluoromethyl)-l-methyl- lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l -carboxamide, danicamtiv, and 1-491. The compound of Formula (I) has been demonstrated to be useful in the treatment of systolic dysfunction, dilated cardiomyopathy, HFrEF, and related cardiac disorders. The compound of Formula (I) was described in U.S. Patent No. 9,925,177 and PCT Application Publication No. WO 2016 / 118774, each of which are incorporated by reference in their entirety herein. The present disclosure provides methods of chemical synthesis useful for the manufacturing of the compound of Formula (I) and a crystalline form (Form B) of the compound of Formula (I). The methods described herein are advantageous due to one or more factors including scalability, efficiency, ease of operation, cost benefits, safety, reduced manufacturing burden, particle size, and the like.

[0068] As used herein, “protecting group’’ refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Wuts and Greene: “Greene's Protective Groups in Organic Synthesis” 4th Ed, Wuts. P. G. M. and Greene, T. W.. Wiley-Interscience, New York: 2006. In some embodiments and implementations described herein, a protecting group may be selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyl oxy carbonyl (BOC); 9- fluorenylmethyloxycarbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzy l (Bn); p-methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate.

[0069] As used herein, the term '‘salt” refers to an acid or base salt of a compound of the invention. Pharmaceutically acceptable salts can be derived, for example, from mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acids (acetic acid, propionic acid, glutamic acid, citric acid and the like), and quaternary ammonium ions. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0070] The neutral form of a compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0071] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 20 of, e.g., between 20° and 70°, inclusive, using CuKa radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 20 of between 20° and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.

[0072] The term “poly morphs” or “polymorphic form” refers to a cry stalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form todominate. Various polymorphs of a compound can be prepared by cry stallization under different conditions.

[0073] The term '‘crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, ty pically first order (melting point). The term "cry stalline” or "crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a cry stalline form includes one or more sharply defined peaks.

[0074] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g , separate enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, it is meant to refer to the compound in which one of the isomers is present and is substantially free of the other isomer. “Substantially free of’ another isomer indicates at least a 70 / 30 ratio of the two isomers at the stereochemical center shown, more preferably 80 / 20, 90 / 10, or 95 / 5 or more. In some implementations, one of the isomers will be present in an amount of at least -99%.

[0075] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as tritium (3H), iodine-125 (125I) or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon- 13 (13C). Such isotopic variations can provide additional utilities to those described elseyvhere yvithin this application. For instance, isotopic variants of the compounds of the invention may find additional utility', including but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics, which can contribute to enhanced safety', tolerability' or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. When specifically referred to, suchas, C1-C4 deuteroalkyl - the term refers to an alkyl group with the indicated number of carbon atoms and having hydrogen atoms replaced by deuterium in a number of from one to a perdeutero form, wherein the deuterium replacement is greater than the natural abundance of deuterium - typically 50%, 60%, 70%, 80%, 90%, 95% or more deuterium replacement. Examples of C1-C4 deuteroalkyl are -CD3, -CH2CD3, -CD2CD3, -CH2CH2CH2D, and the like.

[0076] As used herein, the term “pharmaceutically acceptable” refers to a substance that is compatible with a compound of the invention, as well as with any other ingredients with which the compound is formulated. Furthermore, a pharmaceutically acceptable substance is not deleterious to the recipient of the substance. The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

[0077] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N IC 1 4 alky 1)4’ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0078] As used herein, the term “pharmaceutical composition” refers to a product including a compound of the invention, an excipient as defined herein, and other optional ingredients in specified amounts, as well as any product which results directly or indirectly from combination of the specified ingredients in the specified amounts.

[0079] As used herein, the term “excipient” refers to a substance that aids the administration of an active agent to a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One skilled in the art will recognize that other excipients can be useful in the present invention.

[0080] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some implementations, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other implementations, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g. , in light of a history of symptoms and / or in light of exposure to a pathogen) to delay or prevent disease occurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. As used herein, the terms “treat,” “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of a pathology7, injury7, condition, or symptom related to systolic dysfunction. DCM, HFrEF, or other cardiac disorders, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms; making the pathology, injury', condition, or symptom more tolerable to the patient; decreasing the frequency or duration of the pathology, injury7, condition, or symptom; or, in some situations, preventing the onset of the pathology, injury7, condition, or symptom. Treatment or amelioration can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0081] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g, infant, child, or adolescent) or adult subject (e.g , young adult, middle-aged adult, or senior adult)) or non-human animal. A “patient” refers to a human subject in need of treatment of a disease.

[0082] The terms "condition." “disease,” and “disorder” are used interchangeably.

[0083] An “effective amount” of a compound or polymorphic form described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of the compound of Formula (I) described herein may vary' depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound or polymorphic form, the condition being treated, the mode of administration, and the age and health of the subject. In certain implementations, an effective amount is a therapeutically effective amount. In certain implementations, an effective amount is the amount of the compound of Formula (I) described herein in a single dose. In certain implementations, an effective amount is the combined amounts multiple doses.

[0084] A “therapeutically effective amount” of the compound of Formula (I) described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically' effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0085] 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% (i.e., ± 10%) or within 5% (i.e., ± 5%)of a stated value or of a stated limit of a range.

[0086] II. METHODS OF PREPARATION

[0087] The present disclosure provides methods of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of preparing compounds useful in the preparation of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0088] In one aspect, the present disclosure provides methods of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof.

[0089] In some implementations, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is prepared by a method comprising contacting a compound of Formula (II-A)or a pharmaceutically acceptable salt thereof, with a compound of Formula (III)or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted C1-8alkyl or substituted or unsubstituted aryl.

[0090] In some implementations, the compound of Formula (II-A) or pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt. In some implementations, the compound of Formula (II-A) or pharmaceutically acceptable salt thereof is a salt of a chiral reagent. In some implementations, the compound of Formula (II-A) or pharmaceutically acceptable salt thereof is a salt of a chiral acid. In some implementations, the chiral acid is selected from the group consisting of (+)-camphoric acid, (-)-camphoric acid, (+)- camphorsulfonic acid, (-)-camphorsulfonic acid, (+)-dibenzoyltartaric acid. (-)- dibenzoyltartaric acid, (+)-malic acid, (-)-malic acid, (+)-mandelic acid, (-)-mandelic acid (also referred to herein is (7?)-mandelic acid), (+)-tartaric acid, and (-)-tartaric acid. In some implementations, the compound of Formula (II-A) or pharmaceutically acceptable salt thereof is a salt of mandelic acid. And, in some implementations, the compound of Formula (II-A) or pharmaceutically acceptable salt thereof is a salt of (R)-mandelic acid salt.

[0091] In some implementations, the method of preparing the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises contacting a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof w ith a compound of Formula (III) or apharmaceutically acceptable salt thereof in the presence of a base. In some implementations, the base is a strong base. In some implementations, the base is an alkali metal base. In some implementations, the base is an amine base. In some implementations, the base comprises N,N-diisopropylethylamine (DIPEA), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hy droxide (CsOH), magnesium hydroxide (Mg(0H)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH). or any combination thereof. In some implementations, the base is selected from the group consisting of diisopropylethylamine, KOH, NaOH, LiOH, RbOH, CsOH, Mg(0H)2, Ca(OH)2, Sr(OH)2. Ba(OH)2, and NH4OH.

[0092] In some implementations, the step of contacting a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof with a compound of Formula (III) or a pharmaceutically acceptable salt thereof is carried out in a solvent. In some implementations, the solvent is polar. In some implementations, the solvent is aprotic. In some implementations, the solvent is acetonitrile (MeCN).

[0093] In some implementations, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is prepared by a method including contacting a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof with a solution of a compound of Formula (III), diisopropylethylamine, and acetonitrile.

[0094] In some implementations, a method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprises:(a) contacting a chiral acid salt of Formula (IX)with a compound of Formula (HI)or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted C1-8alkyl (e.g., unsubstituted Ci-6 alkyl) or a substituted or unsubstituted aryl (e.g., unsubstituted aryl), in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0095] In some implementations, the base of step (a) comprises N,N-diisopropylethylamine (DIPEA), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide(LiOH), rubidium hydroxide (RbOH). cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH), or any combination thereof. In some implementations, the base of step (a) comprises DIPEA. In some implementations, the base of step (a) comprises KOH. In some implementations, the base of step (a) comprises NaOH. In some implementations, the base of step (a) comprises LiOH. In some implementations, the base of step (a) comprises RbOH. In some implementations, the base of step (a) comprises CsOH. In some implementations, the base of step (a) comprises Mg(OH)2. In some implementations, the base of step (a) comprises Ca(OH)2. In some implementations, the base of step (a) comprises Sr(OH)2. In some implementations, the base of step (a) comprises Ba(OH)2. In some implementations, the base of step (a) comprises NH4OH. And, in some implementations, the base of step (a) is DIPEA.

[0096] In some implementations, step (a) takes place in the presence of a solvent. In some implementations, the solvent of step (a) comprises a polar organic solvent. In some implementations, the solvent of step (a) comprises a protic organic solvent. In some implementations, the solvent of step (a) comprises acetonitrile (MeCN). In some implementations, the solvent of step (a) is acetonitrile (MeCN).

[0097] In some implementations of the methods of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, R1is substituted or unsubstituted C1-8alkyl. In some implementations, R1is substituted C1-8alkyl. In some implementations, R1is unsubstituted C1-8alkyl. In some implementations, R1is substituted or unsubstituted aryl. In some implementations, R1is substituted aryl. In some implementations, R1is unsubstituted aryl. In some implementations, R1is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and phenyl. And, in some implementations, R1is phenyl.

[0098] In some implementations of the methods of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the methods comprise:(b) recrystallizing the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0099] In some implementations, step (b) comprises:(b-1) heating the compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first solvent to a temperature of about 55 °C to about 75 °C to form a first heated mixture.

[0100] In some implementations, step (b-1) comprises heating the compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first solvent to a temperature of about 60 °C to about 70 °C to form a first heated mixture. In some implementations, step (b-1) comprises heating the compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first solvent to a temperature of about 65 °C to form a first heated mixture. In some implementations, the solvent first comprises acetonitrile (MeCN).

[0101] In some implementations, step (b) further comprises:(b-2) adding a second solvent to the first heated mixture to form a second mixture.

[0102] In some implementations, the second solvent comprises water, methyl tert-butyl ether (MTBE), or any combination thereof. In some implementations, the second solvent comprises water. In some implementations, the second solvent comprises MTBE. In some implementations, the second solvent comprises water and MTBE. And, in some implementations, step (b-2) is performed at about the same temperature as step (b-1) (e.g., about 55 °C to about 75 °C, about 60 °C to about 70 °C, or about 65 °C).

[0103] In some implementations, step (b) further comprises:(b-3) reducing the temperature of the second mixture by about 5 °C to about 15 °C.

[0104] In some implementations, step (b-3) comprises reducing the temperature of the second mixture by about 7.5 °C to about 12.5 °C. And, in some implementations, step (b-3) comprises reducing the temperature of the second mixture by about 10 °C.

[0105] In some implementations, the temperature of the second mixture after step (b-2) is about 30 °C to about 60 °C. In some implementations, the temperature of the second mixture after step (b-2) is about 40 °C to about 60 °C. In some implementations, the temperature of the second mixture after step (b-2) is about 50 °C to about 60 °C. And, in some implementations, the temperature of the second mixture after step (b-2) is about 55 °C.

[0106] In some implementations, step (b) further comprises:(b-4) seeding the second mixture with seed cry stals of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0107] In some implementations, the seed crystals of step (b-4) comprise a crystalline form (Form B) of the compound of Formula (I). In some implementations, a mass of the crystalline form (Form B) of the compound of Formula (I) seeded in step (b-4) is about 3 wt.% to about 5 wt.% of a mass of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to be recrystallized. In some implementations, a mass of the crystalline form (Form B) of the compound of Formula (I) seeded in step (b-4) is about 3 wt.% of a mass of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to be recrystallized. In some implementations, a mass of the cry stalline form (Form B) of the compound of Formula (I) seeded in step (b-4) is about 5 wt.% of a mass of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to be recrystallized.

[0108] In some implementations, the crystalline form (Form B) of the compound of Formula (I) is added to the second mixture as a seed suspension comprising the cry stalline form (Form B) of the compound of Formula (I) and water. In some implementations, the crystalline form (Form B) of the compound of Formula (I) is added to the second mixture as a seed suspension comprising the crystalline form (Form B) of the compound of Formula (I) and methyl tert-butyl ether (MTBE). In some implementations, the seed suspension has a concentration of the crystalline form (Form B) of the compound of Formula (I) of about 60 g / L. In some implementations, the seed suspension has a concentration of the crystalline form (Form B) of the compound of Formula (I) of about 80 g / L. And, in some implementations, the seed suspension has a concentration of the crystalline form (Form B) of the compound of Formula (I) of about 100 g / L.

[0109] In some implementations the seed suspension is wet grinded prior to adding the seed suspension to the second mixture. In some implementations, the wet grinding of the seed suspension is performed at about 10 °C. In some implementations, the wet grinding is performed at a rotational speed of about 13,000 revolutions per minute (rpm) to about 17,000 rpm (e.g., about 16,000 rpm). In some implementations, the crystalline form (Form B) of the compound of Formula (I) has a particle size of about 20 pm or less for at least 50% of the population. And, in some implementations, the crystalline form (Form B) of the compound of Formula (I) has a particle size of about 16 pm or less for at least about 50% of the population.

[0110] In some implementations, a concentration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof after step (b-4) is about 50 g / L to about 120 g / L (e.g., about 50 g / L, about 60 g / L, about 100 g / L, or about 120 g / L). In some implementations, the concentration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof after step (b-4) is about 100 g / L.[OHl] In some implementations, step (b) further comprises:(b-5) maintaining the second mixture at about 5 °C to about 15 °C for about 6 hours after step (b-4).

[0112] In some implementations, step (b-5) comprises maintaining the second mixture at about 7.5 °C to about 12.5 °C for about 6 hours after step (b-4). In some implementations, step (b-5) comprises maintaining the second mixture at about 10 °C for about 6 hours after step (b-4).

[0113] In some implementations, step (b) further comprises:(b-6) wet grinding the second mixture.

[0114] In some implementations, the wet grinding is not one pass and instead the second mixture is recirculated through a closed system comprising a grinding chamber comprising grinders. In some implementations, the second mixture is recirculated at least 6 times (e.g., 6 times, 10 times, 15 times, 20 times, 25 times, or 30 times) through the grinding chamber comprising grinders. And. in some implementations, the second mixture is recirculated such that at least 6 times the reaction volume passes through the grinding chamber comprising grinders.

[0115] In some implementations, the second mixture is wet grinded for at least about 24 minutes (e.g., about 30 minutes). In some implementations, step (b-6) is performed at about 10 °C.

[0116] In some implementations, step (b) further comprises:(b-7) filtering the second mixture to isolate the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0117] In some implementations, step (b-7) is performed with an agitated filter dryer. In some implementations, the isolated compound of Formula (I) or a pharmaceutically acceptable salt thereof is rinsed with water. In some implementations, the isolated compound of Formula (I) or a pharmaceutically acceptable salt thereof is further rinsed with methyl tertbutyl ether (MTBE).

[0118] In some implementations, step (b) further comprises:(b-8) drying the isolated compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0119] In some implementations, step (b-8) is performed under reduced pressure. In some implementations, step (b-8) is performed at about 30 °C to about 60 °C. In some implementations, step (b-8) is performed at about 40 °C to about 50 °C. And, in some implementations, step (b-8) is performed at about 45 °C.

[0120] In some implementations of the methods of preparing a compound of Formula (1) or a pharmaceutically acceptable salt thereof, step (b) provides a crystalline form (Form B) of the compound of Formula (I) after recry stallization.

[0121] In some implementations of the methods of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the methods yield a crystalline form (Form B) of the compound of Formula (I) that is pure. In some implementations, 50% of the population of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the crystalline form (Form B) of the compound of Formula (I)) has a particle size of about 15 pm or less. And, in some implementations, 50% of the population of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the crystalline form (Form B) of the compound of Formula (I)) has a particle size of about 11 pm or less.

[0122] In another aspect, the present disclosure provides a method of preparing a chiral acid salt of a compound of Formula (II-A)the method comprising contacting a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, with a chiral acid to form a chiral acid salt of the compound of Formula (II-R-A).

[0123] In some implementations, the chiral acid is selected from the group consisting of (+)- camphoric acid, (-)-camphoric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, (+)- dibenzoyltartaric acid, (-)-dibenzoyltartaric acid, (+)-malic acid, (-)-malic acid, (+)-mandelicacid, (-)-mandelic acid (also referred to herein as (R)-mandelic acid), (+)-tartaric acid, and (-)-tartaric acid. In some implementations, the chiral acid is (+)-camphoric acid. In some implementations, the chiral acid is (-)-camphoric acid. In some implementations, the chiral acid is (+)-camphorsulfonic acid. In some implementations, the chiral acid (-)- camphorsulfonic acid. In some implementations, the chiral acid is (+)-dibenzoyltartaric acid. In some implementations, the chiral acid is (-)-dibenzoyltartaric acid. In some implementations, the chiral acid is (+)-malic acid. In some implementations, the chiral acid is (-)-malic acid. In some implementations, the chiral acid is (-)-malic acid. In some implementations, the chiral acid is (+)-mandelic acid. In some implementations, the chiral acid (-)-mandelic acid. In some implementations, the chiral acid is (+)-tartaric acid. And, in some implementations, the chiral acid is (-)-tartaric acid.

[0124] In some implementations, contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with the chiral acid takes place in the presence of a solvent. In some implementations, the solvent is a protic solvent. In some implementations, the protic solvent is an alcohol solvent. In some implementations, the solvent is a Ci-Ce alcohol. In some implementations, the solvent comprises methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, isobutanol, tert-butanol, or any combination thereof. In some implementations, the solvent is selected from the group consisting of methanol, ethanol, 1- propanol, 2-propanol, 1 -butanol. 2-butanol, isobutanol, and tert-butanol. In some implementations, the solvent is propanol. In some implementations, the solvent is 2-propanol.

[0125] In some implementations, the chiral acid (e g., (J?)-mandelic acid) is introduced as a solution. In some implementations, the chiral acid is introduced as a solution in 2-propanol and water. In some implementations, contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with a chiral acid solution is carried out at elevated temperature (e.g., about 45 °C to about 70 °C). In some implementations, the method further comprises cooling after contacting the chiral acid salt and the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof. In some implementations, the method further comprises adding a seed suspension comprising greater than about 99% of the chiral acid salt of Formula (IX) in an alcohol. In some implementations, the particle size of the chiral acid salt of Formula (IX) is less than about 20 pm for 50% of the population, which is obtained via wet grinding. In some implementations, the alcohol is 2-propanol. In some implementations, after addition of the seed suspension, the mixture of the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof, the chiral acid, and the seedsuspension is maintained at elevated temperature (e.g., about 28 °C to about 40 °C (e.g., about 35 °C)) for about 6 hours. In some implementations, the method further comprises cooling the mixture of the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof, the chiral acid, and the seed suspension to below room temperature (e.g., about 5 °C to about 15 °C (e.g., about 10 °C)). In some implementations, the temperature below room temperature is maintained for at least about 6 hours. In some implementations, the mixture of the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof, the chiral acid, and the seed suspension is filtered, rinsed, and dried to obtain the chiral acid salt of the compound of Formula (II-R-A).

[0126] In some implementations, contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with the chiral acid further comprises recrystallizing the chiral acid salt. In some implementations, the recrystallization is carried out in water and 2-propanol. In some implementations, the recrystallization is carried out in about 25% 2- propanol and about 75% water.

[0127] In a further aspect, the present disclosure provides a method of preparing a chiral acid salt of Formula (IX) the method comprising:(c) contacting a compound of F ormula (II-R-A)(II-R-A), or a pharmaceutically acceptable salt thereof, with (7?)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

[0128] In some implementations, the solvent of step (c) comprises a polar organic solvent. In some implementations, the solvent of step (c) comprises a protic organic solvent. In some implementations, the solvent of step (c) comprises an alcohol. In some implementations, the solvent of step (c) comprises a Ci-6 alcohol. In some implementations, the solvent of step (c) comprises methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, isobutanol, tert-butanol, or any combination thereof. In some implementations, the solvent of step (c) is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol. 1-butanol, 2-butanol, isobutanol, and tert-butanol. In some implementations, the solvent of step (c) is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, and tert-butanol. In some implementations, the solvent of step (c) is methanol. In some implementations, the solvent of step (c) is ethanol. In some implementations, the solvent of step (c) is 1-propanol. In some implementations, the solvent of step (c) is 2-propanol. In some implementations, the solvent of step (c) is 1-butanol. In some implementations, the solvent of step (c) is 2-butanol. And, in some implementations, the solvent of step (c) is isobutanol. In some implementations, the solvent of step (c) is tert-butanol.

[0129] In some implementations, step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and (7?)-mandelic acid with seed crystals of the chiral acid salt of Formula (IX). In some implementations, the seed crystals are seeded as a seed suspension comprising greater than about 99% of the chiral acid salt of Formula (IX) in an alcohol. In some implementations, the particle size of the chiral acid salt of Formula (IX) in the seed suspension is less than about 20 pm for 50% of the population, which is obtained via wet grinding.

[0130] In some implementations, step (c) is performed at a temperature of about 45 °C to about 70 °C. In some implementations, step (c) comprises contacting a compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with a solution comprising (7?)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX). In some implementations, the solution comprises (7?)-mandelic acid and 2-propanol. In some implementations, the solution comprises (7?)-mandelic acid and water. And, in some implementations, the solution comprises (J?)-mandelic acid. 2-propanol, and water.

[0131] In some implementations, step (c) further comprises:(c-1) contacting a compound of Formula (II-R-A) or a pharmaceutically acceptable45 °C to about 70 °C to form a mixture; and(c-2) cooling the mixture of step (c-1).

[0132] In some implementations, step (c) further comprises:(c-3) seeding the mixture of step (c-1) with seed cry stals of the chiral acid salt of Formula (IX) to form a seeded mixture.

[0133] In some implementations, the seeded mixture of step (c-3) is maintained at about 28 °C to about 40 °C for about 6 hours. In some implementations, the seeded mixture of step (c-3) is maintained at about 35 °C for about 6 hours.

[0134] In some implementations, step (c) further comprises:(c-4) cooling the seeded mixture of (c-3) to about 5 °C to about 15 °C.

[0135] In some implementations, step (c-4) comprises cooling the seeded mixture of step (c- 3) to about 10 °C. In some implementations, step (c-4) compnses cooling the seeded mixture of step (c-3) to about 5 °C to about 15 °C for about 6 hours. In some implementations, step (c-4) comprises cooling the seeded mixture of step (c-3) to about 10 °C for about 6 hours.

[0136] In some implementations, step (c) further comprises:(c-5) filtering, rinsing, and drying the seeded mixture of step (c-3) to obtain the chiral acid salt of Formula (IX).

[0137] In some implementations of the methods of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the methods comprise:(d) recrystallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

[0138] In some implementations, the solvent of step (d) comprises water, 2-propanol, or any combination thereof. In some implementations, the solvent of step (d) comprises water. In some implementations, the solvent of step (d) comprises 2-propanol. In some implementations, the solvent of step (d) comprises water and 2-propanol. And, in some implementations, the solvent of step (d) comprises about 25% 2-propanol and about 75% water.

[0139] In some implementations, the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt. In some implementations, the pharmaceutically acceptable salt is an acid salt. In some implementations, the acid salt is a hydrochloride (HC1) salt.

[0140] When the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof is an acid salt, the methods of preparing a chiral acid salt (e g., a chiral acid salt of Formula (IX)) may further comprise neutralizing the acid salt prior to contacting with a chiral acid (e.g., prior to step (c)). In some implementations the acid salt of the compound of Formula (II-R-A) is neutralized with a base. In some implementations, the base is a strong base. In some implementations, the base is selected from the group consisting of potassium hy droxide (KOH), sodium hy droxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2). calciumhydroxide (Ca(0H)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(0H)2), ammonium hydroxide (NH4OH), sodium carbonate (Na2COs), and potassium carbonate (K2CO3). In some implementations, the neutralization is performed in a mixture of water and an aprotic solvent. In some implementations, the aprotic solvent is an ether. In some implementations, the aprotic solvent comprises tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-MeTHF), diethyl ether, methyl tert-buty l ether (MTBE), or any combination thereof. In some implementations, the aprotic solvent is selected from the group consisting of THF, 2-MeTHF, diethyl ether, and MTBE. In some implementations, the acid salt of the compound of Formula (II-R-A) is a HC1 salt and the methods of preparing a chiral acid salt comprise neutralizing the acid salt of the compound of Formula (II-R-A) in 2- MeTHF with a solution of NaOH in water.

[0141] In one aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, the method comprising:(e-x) deprotecting a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

[0142] In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxycarbonyl (BOC); 9- fluorenylmethyloxy carbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p- methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate. In some implementations, R2is a MeOZ protecting group. In some implementations. R2is a BOC protecting group. In some implementations, R2is a FMOC protecting group. In some implementations, R2is a Ac protecting group. In some implementations, R2is a Bzprotecting group. In some implementations. R2is a Bn protecting group. In some implementations, R2is a PMB protecting group. In some implementations, R2is a DMPM protecting group. In some implementations, R2is a PMP protecting group. In some implementations, R2is a Ts protecting group. In some implementations, R2is a troc protecting group. In some implementations, R2is a sulfonamide protecting group. In some implementations, R2is a carbamate protecting group. And, in some implementations, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is a compound of Formula (IV-A):or a pharmaceutically acceptable salt thereof.

[0143] In some implementations, step (e-x) is carried out in the presence of one or more of hydrogen (H2), an acid, and a base. In some implementations, step (e-x) is earned out in the presence of hydrogen (H2).

[0144] In some implementations, step (e-x) is carried out in the presence of an acid. In some implementations, the acid of step (e-x) is selected from the group consisting of hydrochloric acid (HC1). hydrobromic acid (HBr), hydroiodic acid (HI), hydrofluonc acid (HF), nitric acid (HNO3), chloric acid (HCIO3), perchloric acid (HCIO4), sulfuric acid (H2SO4), acetic acid, and trifluroacetic acid. In some implementations, the acid of step (e-x) is HC1. In some implementations, the acid of step (e-x) is HBr. In some implementations, the acid of step (e- x) is HI. In some implementations, the acid of step (e-x) is HF. In some implementations, the acid of step (e-x) is HNO3. In some implementations, the acid of step (e-x) is HCIO3. In some implementations, the acid of step (e-x) is HCIO4. In some implementations, the acid of step (e-x) is H2SO4. In some implementations, the acid of step (e-x) is acetic acid. And, in some implementations, the acid of step (e-x) is trifluroacetic acid.

[0145] In some implementations, step (e-x) is carried out in the presence of a base. In some implementations, the base of step (e-x) is selected from the group consisting of piperidine, pyridine, methylamine, trimethylamine, triethylamine, diisopropylethylamine, KOH, NaOH, LiOH, RbOH, CsOH, Mg(OH)2. Ca(OH)2, Sr(OH)2, Ba(OH)2, NH4OH, Na2CO3. K2CO3, and ammonia (NH3). In some implementations, the base of step (e-x) is piperidine. In some implementations, the base of step (e-x) is pyridine. In some implementations, the base of step(e-x) is methylamine. In some implementations, the base of step (e-x) is trimethylamine. In some implementations, the base of step (e-x) is triethylamine. In some implementations, the base of step (e-x) is diisopropylethylamine. In some implementations, the base of step (e-x) is KOH. In some implementations, the base of step (e-x) is NaOH. In some implementations, the base of step (e-x) is LiOH. In some implementations, the base of step (e-x) is RbOH. In some implementations, the base of step (e-x) is CsOH. In some implementations, the base of step (e-x) is Mg(OH)2. In some implementations, the base of step (e-x) is Ca(OH)2. In some implementations, the base of step (e-x) is Sr(OH)2. In some implementations, the base of step (e-x) is Ba(OH)2. In some implementations, the base of step (e-x) is NH4OH. In some implementations, the base of step (e-x) is Na2CCh. In some implementations, the base is K2CO3. And, in some implementations, the base of step (e-x) is NH3.

[0146] In some implementations, step (e-x) is performed at about 50 °C to about 60 °C, about 60 °C to about 70 °C, about 70 °C to about 80 °C, about 80 °C to about 90 °C, or about 90 °C to about 100 °C. In some implementations, step (e-x) is performed at about 50 °C to about 60 °C. In some implementations, step (e-x) is performed at about 60 °C to about 70 °C. In some implementations, step (e-x) is performed at about 70 °C to about 80 °C. In some implementations, step (e-x) is performed at about 80 °C to about 90 °C. And, in some implementations, step (e-x) is performed at about 90 °C to about 100 °C.

[0147] In some implementations, step (e-x) takes place in the presence of a polar solvent. In some implementations, the polar solvent of step (e-x) is a polar aprotic solvent. In some implementations, the solvent of step (e-x) comprises dichloromethane (DCM), THF, ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), MeCN, dimethyl sulfoxide (DMSO), or any combination thereof. In some implementations, the solvent of step (e-x) is selected from the group consisting of DCM, THF, EtOAc, DMF, acetonitrile, and DMSO. In some implementations, the solvent of step (e-x) is DCM. In some implementations, the solvent of step (e-x) is THF. In some implementations, the solvent of step (e-x) is EtOAc. In some implementations, the solvent of step (e-x) is DMF. In some implementations, the solvent of step (e-x) is acetonitrile. And, in some implementations, the solvent of step (e-x) is DMSO.

[0148] In some implementations, step (e-x) takes place in the presence of an ether. In some implementations, the ether is selected from the group consisting of THF, 2-MeTHF, diethyl ether. MTBE, and cyclopentyl methyl ether. In some implementations, the ether is THF. In some implementations, the ether is 2-MeTHF. In some implementations, the ether is diethylether. In some implementations, the ether is MTBE. In some implementations, the ether is cyclopentyl methyl ether. And, in some implementations, step (e-x) takes place in the presence of the solvent (e.g., the polar aprotic solvent) and the ether.

[0149] In some implementations of the methods of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the methods comprise:(e) contacting a compound of F ormula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form the compound of Formula (II-R-A), or a pharmaceutically acceptable salt thereof.

[0150] In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC; Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations, R2is a MeOZ protecting group. In some implementations, R2is a BOC protecting group. In some implementations, R2is a FMOC protecting group. In some implementations, R2is a Ac protecting group. In some implementations, R2is a Bz protecting group. In some implementations. R2is a Bn protecting group. In some implementations, R2is a PMB protecting group. In some implementations, R2is a DMPM protecting group. In some implementations, R2is a PMP protecting group. In some implementations. R2is a Ts protecting group. In some implementations, R2is a troc protecting group. In some implementations, R2is a sulfonamide protecting group. In some implementations, R2is a carbamate protecting group. And, in some implementations, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is a compound of Formula (IV-A):or a pharmaceutically acceptable salt thereof.

[0151] In some implementations, the strong acid of step (e) is selected from the group consisting of HC1, HBr, HI, HF, HNO3, HCIO3, HCIO4, H2SO4, acetic acid, and trifluroaceticacid. In some implementations, the strong acid of step (e) is HC1 or trifluoroacetic acid. In some implementations, the strong acid of step (e) is HC1. And, in some implementations, the strong acid of step (e) is trifluoroacetic acid.

[0152] In some implementations, the solvent of step (e) comprises water, 2-propanol, or any combination thereof. And, in some implementations, the solvent of step (e) comprises water and 2-propanol.

[0153] In one aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A):or a pharmaceutically acceptable salt thereof, comprising:(e-1) contacting a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form a reaction mixture; and(e-2) contacting the reaction mixture of step (e-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

[0154] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC: Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations. R2is a BOC protecting group.

[0155] In some implementations, the solvent of step (e-1) comprises 2-propanol, water, or any combination thereof. In some implementations, the solvent of step (e-1) comprises 2- propanol. In some implementations, the solvent of step (e-1) comprises water. And. in some implementations, the solvent of step (e-1) comprises 2-propanol and water.

[0156] In some implementations, the strong acid of step (e-1) is selected from the group consisting of HC1, HBr, HI, HF, HNO3, HCIO3, HCIO4. H2SO4, acetic acid, and trifluroacetic acid. In some implementations, the strong acid of step (e-1) is HC1 or trifluoroacetic acid. In some implementations, the strong acid of step (e-1) is HC1. And, in some implementations, the strong acid of step (e-1) is trifluoroacetic acid.

[0157] In some implementations, the solvent of step (e-2) comprises isopropyl acetate.

[0158] In some implementations, the method of preparing a compound of Formula (Il-R-A) or a pharmaceutically acceptable salt thereof further comprises:(e-1 a) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e- la) to form a second reaction mixture.

[0159] In some implementations, the method of preparing a compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof further comprises:(e-3) adding water to the second reaction mixture of step (e-2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-4) separating the organic layer from the aqueous layer; and (e-5) concentrating the separated organic layer.

[0160] In another aspect, the present disclosure provides a method of preparing a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising:(I) contacting a compound of F ormula (XI)or a pharmaceutically acceptable salt thereof, with a methylating reagent to form a compound of Formula (IV) or a pharmaceutically acceptable salt thereof.

[0161] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC; Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations, R2is a BOC protecting group.

[0162] In some implementations, the methylating reagent of step (1) is a methyl halide. In some implementations, the methylating reagent of step (f) is selected from the group consisting of methyl iodide (CH3I), methyl bromide (CHsBr), and methyl chloride (CH3CI). In some implementations, the methylating reagent of step (f) is CH3I. In some implementations, the methylating reagent of step (f) is CFFBr. And, in some implementations, the methylating reagent of step (f) is CH3CI.

[0163] In some implementations, step (1) takes place in the presence of a base. In some implementations, the base of step (f) is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS). sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), sodium diisopropylamide (NaDA), and lithium tetramethylpiperidide (LiTMP). In some implementations, the base of step (f) is selected from the group consisting of LiHMDS and NaHMDS. In some implementations, the base of step (f) is LiHMDS. In some implementations, the base of step (f) is NaHMDS. In some implementations, the base of step (f) is KHMDS. In some implementations, the base of step (I) is LDA. In some implementations, the base of step (f) is NaDA. And, in some implementations, the base of step (f) is LiTMP.

[0164] In some implementations, step (I) further comprises:(f-1) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with the base to form a mixture; and(f-2) contacting the mixture of step (f-1) with the methylating reagent to form the compound of Formula (IV) or a pharmaceutically acceptable salt thereof.

[0165] In some implementations, step (I) further comprises quenching with acetic acid and THF. In some implementations, the quenching is performed at about -80 °C to about -60 °C.

[0166] In some implementations, step (f) takes place in the presence of a solvent. In some implementations, the solvent of step (f) comprises toluene, THF, 2-methyl-THF, or a combination thereof. In some implementations, the solvent of step (I) comprises toluene. Insome implementations, the solvent of step (f) comprises THF. In some implementations, the solvent of step (I) comprises 2-MeTHF. And. in some implementations, the solvent of step (I) comprises toluene and 2-MeTHF

[0167] In some implementations, a method of preparing a compound of Formula (IV) or a pharmaceutically acceptable salt thereof further comprises recrystallizing the compound of Formula (IV) or a pharmaceutically acceptable salt thereof. In some implementations, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is recrystallized in ethanol and water.

[0168] In another aspect, the present disclosure provides a method of preparing a compound of Formula (XI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising two ordered reactions comprising:(g-1) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) to form a fluorinated compound or a pharmaceutically acceptable salt thereof: and(g-2) contacting the fluorinated compound or pharmaceutically acceptable salt thereof with an oxidizing reagent to form the compound of Formula (XI) or a pharmaceutically acceptable salt thereof.

[0169] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC; Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations, R2is a BOC protecting group.

[0170] In some implementations, the method takes place in the absence of N- fluorobenzensulfonimide (NFSI).

[0171] In some implementations, the fluorinating reagent of step (g-I) comprises 1- (chloromethyl)-4-fluoro-1.4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate; 1- fluoro-2, 4, 6-trimethyl pyridinium triflate; 1 -fluoropyridinium triflate; or any combination thereof. In some implementations, the fluorinating reagent of step (g-1) is l-(chloromethyl)- 4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate. In some implementations, the fluorinating reagent of step (g-1) is l-fluoro-2, 4, 6-trimethyl pyridinium triflate. And, in some implementations, the fluorinating reagent of step (g-I) is 1- fluoropyridinium triflate.

[0172] In some implementations, the oxidizing reagent of step (g-2) comprises hydrogen peroxide / sodium tungstate, peracetic acid, benzy l hydroperoxide, ethylbenzene hydroperoxide, cumy l hydroperoxide, sodium hypochlorite, oxalic acid dehydrate / hydrogen peroxide, meta-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct, permanganate / manganese dioxide, ruthenium chloride hydrate / sodium periodate, oxone, or any combination thereof. In some implementations, the oxidizing reagent of step (g-2) is hydrogen peroxide / sodium tungstate. In some implementations, the oxidizing reagent of step (g-2) is peracetic acid. In some implementations, the oxidizing reagent of step (g-2) is benzyl hydroperoxide, In some implementations, the oxidizing reagent of step (g-2) is ethylbenzene hydroperoxide, In some implementations, the oxidizing reagent of step (g-2) is cumyl hydroperoxide. In some implementations, the oxidizing reagent of step (g-2) is sodium hypochlorite. In some implementations, the oxidizing reagent of step (g-2) is oxalic acid dehydrate / hydrogen peroxide. In some implementations, the oxidizing reagent of step (g-2) is meta-chloroperoxybenzoic acid. In some implementations, the oxidizing reagent of step (g-2) is urea-hydrogen peroxide adduct. In some implementations, the oxidizing reagent of step (g-2) is permanganate / manganese dioxide. In some implementations, the oxidizing reagent of step (g-2) is ruthenium chloride hydrate / sodium periodate. And, in some implementations, the oxidizing reagent of step (g-2) is oxone.

[0173] In some implementations, the fluorinated compound or pharmaceutically acceptable salt thereof of step (g-I) is a compound of Formula (XII)or a pharmaceutically acceptable salt thereof.

[0174] In some implementations, the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof is converted to the compound of Formula (XI) or a pharmaceutically acceptable salt thereof without isolating the compound of Formula (XII) or a pharmaceutically acceptable salt thereof.

[0175] In some implementations, step (g-1) takes place in the presence of a base and a solvent. In some implementations, the base of step (g-1) comprises triethylamine (TEA); 1,4- diazabicyclo[2.2.2]octane (DABCO); N-methyl morpholine; N.N-diisopropylethylamine (DIPEA); quinuclidine; pyridine; 2-methylpyridine; 2,6-dimethylpyridine; 2,6-di-tert- butylpyridine; or any combination thereof. In some implementations, the base of step (g-1) comprises TEA. In some implementations, the base of step (g-1) comprises DABCO. In some implementations, the base of step (g-1) comprises N-methyl morpholine. In some implementations, the base of step (g-1) comprises DIPEA. In some implementations, the base of step (g-1) comprises quinuclidine. In some implementations, the base of step (g-1) comprises pyridine. In some implementations, the base of step (g-1) comprises 2- methylpyridine. In some implementations, the base of step (g-1) comprises 2,6- dimethylpyridine. In some implementations, the base of step (g-1) comprises 2,6-di-tert- butylpyridine. In some implementations, the base of step (g-1) comprises diisopropylethylamine, quinuclidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6- du-tert-butylpyridine, or any combination thereof. In some implementations, the base of step (g-1) comprises TEA, DABCO, N-methyl morpholine, DIPEA. diisopropylethylamine, or any combination thereof. In some implementations, the base of step (g-1) is TEA. In some implementations, the base of step (g-1) comprises TEA and 2,6-dimethylpyridine.

[0176] In some implementations, the solvent of step (g-1) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof. In some implementations, the solvent of step (g-1) is MeCN. In some implementations, the solvent of step (g-1) is DCM. In some implementations, the solvent of step (g-1) is THF. In some implementations, the solvent of step (g-1) is EtOAc. In some implementations, the solvent of step (g-1) is toluene.

[0177] In some implementations, step (g-2) takes place in the presence of a solvent. In some implementations, the solvent of step (g-2) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof. In some implementations, the solvent of step (g-2) is MeCN. In some implementations, the solvent of step (g-2) is DCM. In some implementations, the solvent of step (g-2) is THF. Insome implementations, the solvent of step (g-2) is EtOAc. And, in some implementations, the solvent of step (g-2) is toluene.

[0178] In a further aspect, the present disclosure provides a method of preparing a compound Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising:(h) contacting a compound of F ormula (VIII) ,or a pharmaceutically acceptable salt thereof, wherein SAc is, with Compound1.5aor a pharmaceutically acceptable salt thereof, in the presence of a catalyst, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0179] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC: Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations. R2is a BOC protecting group. In some implementations, the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof may be a compound of Formula (VIII-A)or a pharmaceutically acceptable salt thereof.

[0180] In some implementations, the catalyst of step (h) is a palladium catalyst. In some implementations, the palladium catalyst is generated in situ from a palladium source and aligand. In some implementations, the palladium source is selected from the group consisting of bis(dibenzyhdeneacetone)palladium(0) (Pd(dba)2); tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3); tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (Pd2(dba)s • CHCI3); tetrakis(acetonitrile)palladium(II) tetrafluoroborate (PdCCHsCNXBF^); tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4); palladium(II) acetyl acetonate (Pd(acac)2); allylpalladium(ll) chloride dimer ([Pd(allyl)Cl]2); bis(acetonitrile)palladium di chloride (Pd(MeCN)2C12); palladium(II) trifluoroacetate (Pd(TFA)2); palladium(II) acetate (Pd(OAc)2); dichlorobis(tricyclohexylphosphine)palladium(II) (Pd(Pcy3)2Ch); and bis(triphenylphosphine)palladium(II) dichloride (PdfPPh^C'b). In some implementations, the palladium source is Pd2(dba)3 CHCh.

[0181] In some implementations, the ligand is a phosphorous based ligand. In some implementations, the ligand comprises a phosphine. In some implementations, the ligand is a Josiphos ligand. And, in some implementations, the Josiphos ligand is CyPF-tBu:

[0182] In some implementations, the ligand is a Buchwald ligand. In some implementations, the ligand is a Xantphos-based ligand, wherein the Xantphos-based ligand is selected from the group consisting of Xantphos, N-Xantphos, tBu-Xantphos, and P.P'-(9,9-Dimethyl-9H- xanthene-4,5-diyl)bis[N,N,N',N'-tetraethyl-phosphonous diamide]. And, in some implementations, the Xantphos-based ligand is Xantphos:

[0183] In some implementations, the palladium catalyst is generated from a precatalyst. In some implementations, the precatalyst is selected from the group consisting of:

[0184] In some implementations, the palladium source is Pd2(dba)3*CHC13, and the ligand is CyPF-tBu. In some implementations, the palladium source is Pd2(dba)3, and the ligand is Xantphos. And, in some implementations, the palladium source is Pd2(dba)s, and the ligand is Davephos.

[0185] In some implementations, step (h) takes place in the presence of a base. In some implementations, the base of step (h) is a carbonate base. In some implementations, the base of step (h) is a phosphate base. In some implementations, the base of step (h) is selected from the group consisting of potassium carbonate (K2CO3), potassium tert-butoxide (KOtBu), cesium carbonate (CS2CO3), tripotassium phosphate (K3PO4), sodium hydroxide (NaOH), tri ethylamine (TEA), potassium hydroxide (KOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH), sodium carbonate (Na2CO3), ammonia (NH3), pyridine, methylamine, trimethylamine, and diisopropylethylamine (DIPEA). In some implementations, the base of step (h) is K2CO3. In some implementations, the base of step (h) is K3PO4. And, in some implementations, the base of step (h) is CS2CO3.

[0186] In some implementations, step (h) takes please in the presence of a solvent. In some implementations, the solvent of step (h) is selected from the group consisting of toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dioxane. In some implementations, the solvent of step (h) is toluene. In some implementations, the solvent of step (h) is THF. In some implementations, the solvent of step (h) is DMF. In some implementations, the solvent of step (h) is dioxane.

[0187] In some implementations, step (h) is performed at about 60 °C. about 70 °C. about 80 °C, about 90 °C, about 100 °C, about 1 10 °C, or about 120 °C. In some implementations.step (h) is performed at about 60 °C to about 65 °C. In some implementations, step (h) is performed at about 110 °C to about 115 °C.

[0188] In some implementations, step (h) takes place in the presence of an additive. In some implementations, the additive of step (h) is a salt. In some implementations, the additive of step (h) is selected form the group consisting of potassium iodide (KI), sodium iodide (Nal), lithium iodide (Lil), cesium iodide (CsI), magnesium iodide (Mgh) calcium iodide (Cab) potassium fluoride (KF), sodium fluoride (NaF), cesium fluoride (CsF), BU2NF, and Bu2NBr. In some implementations, the additive of step (h) is KI.

[0189] In some implementations, step (h) comprises contacting a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5a or a pharmaceutically acceptable salt thereof in the presence of Pd2(dba)3eCHC13. a carbonate base, KI, and either Xantphos or Davephos in toluene or dioxane at from about 1 10 °C to about 115 °C to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0190] In some implementations, step (h) comprises contacting a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5a or a pharmaceutically acceptable salt thereof in the presence of Pd2(dba)3*CHC13, either a carbonate base or phosphate base, KI, and Xantphos in toluene at from about 110 °C to about 115 °C.

[0191] In some implementations, step (h) comprises contacting a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5a or a pharmaceutically acceptable salt thereof in the presence of Pd2(dba)3*CHC13, CS2CO3, KI, and Xantphos in toluene at from about 110 °C to about 115 °C.

[0192] In some implementations, step (h) comprises contacting a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5a or a pharmaceutically acceptable salt thereof in the presence oftoluene at from about 110 °C to about 115 °C.

[0193] In a further aspect, the present disclosure provides a method of preparing a compound Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising:(i) contacting a compound of F ormula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is , with Compound1.5bor a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0194] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC; Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations, R2is a BOC protecting group. In some implementations, the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof may be a compound of Formula (VIII-A)or a pharmaceutically acceptable salt thereof.

[0195] In some implementations, the copper catalyst of step (i) is a copper halide. In some implementations, the copper catalyst of step (i) is selected from the group consisting of copper iodide, copper bromide, and copper chloride. In some implementations, the copper catalyst of step (i) is copper iodide. In some implementations, the copper catalyst of step (i)is copper bromide. And, in some implementations, the copper catalyst of step (i) is copper chloride.

[0196] In some implementations, step (i) takes place in the presence of a base. In some implementations, the base of step (i) is selected from the group consisting of sodium carbonate, potassium carbonate, and cesium carbonate. In some implementations, the base of step (i) is sodium carbonate. In some implementations, the base of step (i) is potassium carbonate. And. in some implementations, the base of step (i) is cesium carbonate.

[0197] In some implementations, step (i) takes place in the presence of a solvent. In some implementations, the solvent of step (i) is a protic solvent. In some implementations, the solvent of step (i) is selected from a group consisting of isopropyl alcohol (IP A), n-butanol (n-BuOH). and ethanol. In some implementations, the solvent of step (i) is IP A. In some implementations, the solvent of step (i) is n-BuOH. In some implementations, the solvent of step (i) is ethanol.

[0198] In one aspect, the present disclosure provides a method of preparing a compound Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is, and wherein R2is a protecting group, the method comprising:(j ) contacting a compound of F ormula (XV) or a pharmaceutically acceptablesalt thereof, wherein OTs is potassium thioacetate to form the compound of Formula (VTII) or a pharmaceutically acceptable salt thereof.

[0199] R2may be any protecting group described herein. In some implementations, R2is a protecting group selected from the group consisting of MeOZ; BOC; FMOC: Ac; Bz; Bn; PMB; DMPM; PMP; Ts; troc; a sulfonamide; and a carbamate. In some implementations, R2is a BOC protecting group.

[0200] In some implementations, step (j) is performed in the presence of a solvent. In some implementations, the solvent of step (j) is N,N-dimethylformamide (DMF). In someimplementations, step (j) contacting a compound of Formula (XV) or a pharmaceutically acceptable salt thereof with potassium thioacetate at about 30 °C to about 60 °C (e.g., about 40 °C to about 50 °C). In some implementations, step (j) is performed for about 3 hours.

[0201] In another aspect, the present disclosure provides a method of preparing a compound Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs, wherein R2is a protecting group, and wherein the method comprises:(k) contacting a compound of F ormula (XVI)or a pharmaceutically acceptable salt thereof, with tosyl chloride to form the compound of Formula (XV) or a pharmaceutically acceptable salt thereof.

[0202] In some implementations, step (k) takes place in the presence of a solvent. In some implementations, the solvent of step (k) is dichloromethane (DCM). In some implementations, step (k) takes place in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine (TEA). And, in some implementations, step (k) takes place in the presence DCM, DMAP, and TEA.

[0203] In a further aspect, the present disclosure provides a method of preparing Compound1.5aor a pharmaceutically acceptable salt thereof, the method comprising:(1) contacting 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid(Compound 1.4)or a pharmaceutically acceptable salt thereof, with a bromine source to form Compound 1.5a or a pharmaceutically acceptable salt thereof.

[0204] In some implementations, step (1) takes place in the presence of a base or an amphoteric compound. In some implementations, step (1) takes place in the presence of a base. And, in some implementations, step (1) takes place in the presence of an amphoteric compound.

[0205] In some implementations, the base of step (1) is a strong base. In some implementations, the base of step (1) is an alkali metal base. In some implementations, the base of step (1) is selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH), sodium bicarbonate (NaHCO3). and sodium acetate (NaOAc). In some implementations the base of step (1) is NaHCO3. And, in some implementations, the base of step (1) is NaOH.

[0206] In some implementations, the bromine source of step (1) is N-bromosuccinimide (NBS) or bromine (Bn). In some implementations, the bromine source of step (1) is NBS. And, in some implementations, the bromine source of step (1) is Bn.

[0207] In some implementations, step (1) takes place in the presence of a solvent. In some implementations, the solvent of step (1) is water or N,N-dimethylformamide (DMF). In some implementations, the solvent of step (1) is water. And, in some implementations, the solvent of step (1) is DMF.

[0208] In some implementations, step (1) is performed at about 10 °C to about 15 °C. And, in some implementations, step (1) is performed at about 25 °C to about 30 °C, about 50 °C to about 55 °C, or about 75 °C to about 80 °C.

[0209] In some implementations, step (1) comprises contacting Compound 1.4 or a pharmaceutically acceptable salt thereof with Br2 in the presence of NaOH in H2O at about 10 °C to about 15 °C to form Compound 1.5a or a pharmaceutically acceptable salt thereof. In some implementations, step (1) comprises contacting Compound 1.4 or apharmaceutically acceptable salt thereof with NBS in the presence of NaHCCh and DMF at from about 25 °C to about 30 °C, about 50 °C to about 55 °C. or about 75 °C to about 80 °C, to form Compound 1.5a or a pharmaceutically acceptable salt thereof.

[0210] In one aspect, the present disclosure provides a method of preparing Compound 1.5(b)or a pharmaceutically acceptable salt thereof, the method comprising:(m) contacting 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid(Compound 1.4)or a pharmaceutically acceptable salt thereof, with an iodine source to form Compound 1.5b or a pharmaceutically acceptable salt thereof.

[0211] In some implementations, the iodine source of step (m) is N-iodosuccinimide (NIS) or iodine (h). In some implementations, the iodine source of step (m) is NIS. And, in some implementations, the iodine source of step (m) is I2.

[0212] In some implementations, step (m) takes place in the presence of a base. In some implementations, the base of step (m) is selected from the group consisting of tripotassium phosphate (K3PO4); sodium bicarbonate (NaHCCh); potassium carbonate (K2CO3); cesium carbonate (CS2CO3); 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU); 4-(dimethylamino)pyridine (DMAP), and pyridine. In some implementations, the base of step (m) is NaHCCh.

[0213] In some implementations, step (m) takes place in the presence of a solvent. In some implementations, the solvent of step (m) comprises acetonitrile (MeCN), N,N- dimethylformamide (DMF), dioxane, or any combination thereof. In some implementations, the solvent of step (m) is selected from the group consisting of MeCN, DMF, and dioxane. In some implementations, the solvent of step (m) is MeCN. In some implementations, the solvent of step (m) is DMF. And, in some implementations, the solvent of step (m) is dioxane.

[0214] In some implementations, step (m) takes place in the absence of sulfuric acid. In some implementations, step (m) takes place in the presence of a radical initiator. In some implementations, step (m) takes place in the absence of a radical initiator. In some implementations, step (m) takes place in the presence of sodium periodate (NaIO4).

[0215] In some implementations, step (m) takes place in the presence of a phase transfer catalyst. In some implementations, the phase transfer catalyst of step (m) is tetrabutylammonium hydrogensulfate (NBU4HSO4) or tetrabutylammonium periodate (NBU4IO4). In some implementations, the phase transfer catalyst of step (m) is NBU4HSO4. And, in some implementations, the phase transfer catalyst of step (m) is NBU4IO4.

[0216] In another aspect, the present disclosure provides a method of preparing 3- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid (Compound 1.4)or a pharmaceutically acceptable salt thereof, the method comprising(n) contacting ethyl 3-(difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylate(Compound 1.3)or a pharmaceutically acceptable salt thereof, with a base to form Compound 1.4 or a pharmaceutically acceptable salt thereof.

[0217] In some implementations, the base of step (n) is a strong base. In some implementations, the base of step (n) is an alkali metal base. In some implementations, the base of step (n) is selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH). cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), and barium hydroxide (Ba(OH)2) In some implementations, the base of step (n) is LiOH. And, in some implementations, step (n) comprises contactingCompound 1.3 or a pharmaceutically acceptable salt thereof with LiOH in THF / H2O at about 75 °C.

[0218] In a further aspect, the present disclosure provides a method of preparing ethyl 3-(difluoromethyl)-l-methyl-IH-pyrazole-4-carboxylate (Compound 1.3)or a pharmaceutically acceptable salt thereof, the method comprising(0) contacting ethyl 4,4-difluoro-3-oxobutanoateor a pharmaceutically acceptable salt thereof, with triethyl orthoformate and methylhydrazine to form Compound 1.3 or a pharmaceutically acceptable salt thereof.

[0219] In some implementations, step (0) takes place in the presence of acetic anhydride. In some implementations , step (0) is performed at about 110 °C. And, in some implementations, step (o) further comprises:(o-l) contacting ethyl 4,4-difluoro-3-oxobutanoate with triethyl orthoformate in the presence of acetic anhydride at about 110 °C to form a mixture: and(o-2) adding methylhydrazine and toluene to the mixture of step (o-l) at about 0 °C to about 5 °C to form Compound 1.3 or a pharmaceutically acceptable salt thereof.

[0220] In one aspect, the present disclosure provides a method of preparing a compound of Formula (III)or a pharmaceutically acceptable salt thereof, the method comprising:(p) contacting 3-aminoisoxazole with R1OC(=O)X1, wherein R1issubstituted or unsubstituted C1-8alkyl or substituted or unsubstituted aryl and X1is a halogen(e.g., Cl, Br, F, etc.) to form the compound of Formula (III) or a pharmaceutically acceptable salt thereof.

[0221] In some implementations, R1is unsubstituted C1-8alkyl. In some implementations, R1is unsubstituted Ci-4 alkyl. In some implementations R1is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. In some implementations, R1is unsubstituted aryl. And, in some implementations, R1is phenyl.

[0222] In some implementations, X1is Cl, Br. or F. In some implementations. X1is Cl. In some implementations, X1is Br. And, in some implementations, X1is F.

[0223] In some implementations, step (p) takes place in the presence of a base. In some implementations, the base of step (p) is a strong base. In some implementations, the base of step (p) is an alkali metal base. In some implementations, the base of step (p) is an amine base. In some implementations, the base of step (p) is a carbonate base. In some implementations, the base of step (p) is selected from the group consisting of pyridine, trimethylamine, triethylamine, diisopropylethylamine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH). cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(OH)2), ammonium hydroxide (NH4OH), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and ammonia (NH3). In some implementations, the base of step (p) is pyridine.

[0224] In some implementations, step (p) takes place in the presence of a solvent. In some implementations, the solvent of step (p) is polar. In some implementations, the solvent of step (p) is aprotic. In some implementations, the solvent of step (p) is acetonitrile (MeCN). And, in some implementations, step (p) comprises contacting 3-aminoisoxazole with phenyl chloroformate (PhOC(=O)Cl) in acetonitrile in the presence of pyridine to form the compound of Formula (III) or a pharmaceutically acceptable salt thereof.

[0225] In another aspect, the present disclosure provides a method of preparing a chiral acid salt of Formula (IX)comprising:(c) contacting a compound of F ormula (II-R-A)or a pharmaceutically acceptable salt thereof, with ( / <)- mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

[0226] In some implementations, the solvent of step (c) comprises water, isopropyl acetate, or any combination thereof. And, in some implementations, step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and (A)-mandelic acid with seed crystals of the chiral acid salt of Formula (IX).

[0227] In some implementations, the method further comprises:(d) recry stallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

[0228] In some implementations, the solvent of step (d) comprises water. 2-propanol, or any combination thereof. In some implementations, the solvent of step (d) comprises about 25% 2-propanol and about 75% water. And, in some implementations, the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof is prepared according to a method described herein.

[0229] In a further aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(g-la) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form the compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-1-1) contacting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof with a strong acid in the presence of a solvent to form a reaction mixture; and(e-1-2) contacting the reaction mixture of step (e-1-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A).

[0230] In some implementations, step (e) further comprises:(e-l-la) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-l-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e-l-la) to form a second reaction mixture.

[0231] In some implementations, the method further comprises:(e-1-3) adding water to the second reaction mixture of step (e-1 -2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-1-4) separating the organic layer from the aqueous layer; and (e-1-5) concentrating the separated organic layer.

[0232] In some implementations, the method further comprises:(h-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc iswith Compound1.5bor a pharmaceutically acceptable salt thereof, in the presence of a palladium catalyst, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0233] In some implementations, the method further comprises:(i-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is with Compound1.5bor a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, a base, and a solvent, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

[0234] In some implementations, the copper catalyst of step (i-1) is selected from the group consisting of copper iodide, copper bromide, and copper chloride. In some implementations, the copper catalyst of step (i-1) is copper iodide. In some implementations, the base of step(i-1) is selected from the group consisting of sodium carbonate, potassium carbonate, and cesium carbonate. In some implementations, the base of step (i-1) is sodium carbonate. In some implementations, the solvent of step (i-1) is a protic solvent. In some implementations, the protic solvent is selected from a group consisting of IP A, n-BuOH, and ethanol. And, in some implementations, the protic solvent is n-BuOH.

[0235] In some implementations, the method further comprises:(j) contacting a compound of Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is withpotassium thioacetate to form the compound of Formula (VTII) or a pharmaceutically acceptable salt thereof.

[0236] In some implementations, the method further comprises:(k) contacting a compound of Formula (XVI)or a pharmaceutically acceptable salt thereof, with tosyl chloride to form the compound of Formula (XV) or a pharmaceutically acceptable salt thereof.

[0237] In some implementations, step (k) takes place in the presence of dichloromethane (DCM), 4-dimethylaminopyridine (DMAP). and triethylamine (TEA).

[0238] In some implementations, the fluorinating reagent of step (g-1) comprises 1- (chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate, 1- fluoro-2,4,6-trimethyl pyridinium triflate, 1 -fluoropyridinium triflate, or any combination thereof. In some implementations, the fluorinating reagent of step (g-1) is l-(chloromethyl)- 4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate. And, in some implementations, the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof is converted to the compound of Formula (XI) or a pharmaceutically acceptable salt thereof without isolating the compound of Formula (XII) or a pharmaceutically acceptable salt thereof.

[0239] In some implementations, the oxidizing reagent of step (g-2) comprises sodium periodate. And, in some implementations, the oxidizing reagent of step (g-1) further comprises ruthenium chloride hydrate.

[0240] In some implementations, the methylating reagent of step (f) is CH3I. In some implementations, step (f) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS). And, in some implementations, step (f) takes place in the presence of toluene.

[0241] In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-buty loxy carbonyl (BOC); 9- fluorenylmethyloxycarbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p- methoxybenzyl (PMB); 3.4-dimethoxy benzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate. And, in some implementations, R2is a BOC protecting group.

[0242] In one aspect, the present disclosure provides a method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(k) contacting a compound of F ormula (XVI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with tosyl chloride to form a compound of Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is(j) contacting the compound of Formula (XV) or a pharmaceutically acceptable salt thereof with potassium thioacetate to form a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is(i) contacting the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5bor a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, to form a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof;(g-la) contacting the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof; and(e-x) deprotecting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

[0243] In another aspect, the present disclosure provides a method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprising:(g- 1 ) contacting a compound of F ormula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-x) deprotecting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof;(c) contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with ( / ?)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX)(a) contacting a chiral acid salt of Formula (IX) with a compound of Formula(HI)wherein R1is substituted or unsubstituted C1-8alkyl or a substituted or unsubstituted aryl, in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0244] In a further aspect, the present disclosure provides a method of making a compound of Formula (I):or a pharmaceutically acceptable salt thereof, the method including: reacting a chiral acid salt of a compound of Formula (II -A)with a compound of Formula (III)or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted C1-8alky l or substituted or unsubstituted ary l.

[0245] In some implementations of this method, R1is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and phenyl. In some implementations, R1is phenyl.

[0246] In some implementations of the method, the chiral acid salt of the compound of Formula (II-A) is a chiral acid salt of Formula (IX):

[0247] In some implementations, the reaction is carried out in the presence of a base. In some implementations, the base is selected from the group consisting ofdiisopropylethylamine (DIPEA), KOH, NaOH, LiOH, RbOH, CsOH, Mg(OH)2, Ca(OH)2, Sr(OH)2, Ba(OH)2. and NH4OH. In some implementations, the base is DIPEA.

[0248] In some implementations, the reaction is carried out in the presence of a solvent. In some implementations, the solvent is acetonitrile.

[0249] In some implementations, the method further includes adding sodium hydroxide, sodium chloride, and water in dichloromethane.

[0250] In some implementations, the method further includes seeding the reaction mixture of the compound of Formula (III) and the chiral acid salt of the compound of Formula (II-A) with seed crystals of a crystalline form (Form B) of the compound of Formula (I).

[0251] In some implementations, the method further includes wet-milling the compound of Formula (I) to reduce particle size.

[0252] In some implementations, the method further includes: separating the enantiomers of a compound of Formula (II-R-A):or a pharmaceutically acceptable salt thereof, by contacting a compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with a chiral acid (e.g., (A’)-mandelic acid); and isolating the chiral acid salt of the compound of Formula (II-A).

[0253] In one aspect, the present disclosure provides a method of making a compound of Formula (I):or a pharmaceutically acceptable salt thereof, the method comprising:(Z-i) contacting a compound of F ormula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc i and wherein R2is aprotecting group, with Compound 1.5bor a pharmaceutically acceptable salt thereof to form a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof;(Z-ii) fluorinating the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof with a fluorinating reagent in the presence of D AST to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(Z-iii) oxidizing the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(Z-iv) methylating the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(Z-v) deprotecting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof;(Z-vi) reacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with (7?)-mandelic acid to form a chiral acid salt of Formula (IX) and(Z-vii) reacting the chiral acid salt of Formula (IX) with Compound 1.14p or a pharmaceutically acceptable salt thereof to form the compound of Formula (I).

[0254] In some implementations, step (Z-vii) further includes recry stallizing the compound of Formula (I) to produce a crystalline form (Form B) of the compound of Formula (I).

[0255] In some implementations, step (Z-vi) further includes recrystallizing the chiral acid salt of Formula (IX).

[0256] In some implementations, the method further includes iodinating Compound 1.4 or a pharmaceutically acceptable salt thereof with an iodinating reagent to form Compound 1.5b or a pharmaceutically acceptable salt thereof.

[0257] In some implementations, the iodinating comprises: contacting Compound 1.4 or a pharmaceutically acceptable salt thereof with iodine (I2) and sodium bicarbonate to form a reaction mixture; andcontacting the reaction mixture with sodium periodate

[0258] In some implementations, the reaction of step (Z-i) takes place in the presence of a copper catalyst. In some implementations, the copper catalyst is copper halide. In some implementations, the copper halide is copper iodide (Cui).

[0259] In some implementations, the fluorinating reagent of step (Z-ii) is selected from the group consisting of l-Fluoro-2,4,6-trimethyl pyridinium triflate, 1 -Fluoropyridinium triflate, and l-(Chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate. In some implementations, the fluorinating reagent is l-(Chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate (Select-Fluor).

[0260] In some implementations, the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof is converted to the compound of Formula (XI) without isolation, i.e., the product of step (Z-ii) is not isolated.

[0261] In some implementations, the oxidizing reagent of step (Z-iii) comprises sodium periodate. In some implementations, the oxidizing reagent of step (Z-iii) further comprises ruthenium chloride hydrate.

[0262] In some implementations, the methylating reagent of step (Z-iv) is methyl iodide (CH3I). In some implementations, the methylating reagent step (Z-iv) is methyl bromide (CHsBr) or methyl chloride (CH3CI). In some implementations, the methylating of step (Z- iv) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS). In some implementations, the methylating of step (Z-iv) takes place in the present of toluene. In some implementations, deprotecting of step (Z-v) includes contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with hydrochloric acid (HC1), follow ed by sodium hydroxide (NaOH). In some implementations, a HC1 salt of the compound of Formula (II-R-A) is not isolated in step (Z-v).

[0263] In some implementations, the method further includes reacting a compound of Formula (XV) or a pharmaceutically acceptable salt thereof with potassium thioacetate(KSAc) to form the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof.

[0264] In some implementations, the method further includes reacting a compound of Formula (XVI) or a pharmaceutically acceptable salt thereof with tosyl chloride (TsCl) to form the compound of Formula (XV) or a pharmaceutically acceptable salt thereof.

[0265] In some implementations, the reaction with tosyl chloride takes place in the presence of dichloromethane (DCM), 4-Dimethylaminopyridine (DMAP), and triethylamine (TEA).

[0266] In some implementations, R2is a protecting group selected from the group consisting of p-methoxybenzyl carbonyl (MeOZ), tert-butyloxy carbonyl (BOC), 9- fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- methoxybenzyl (PMB) , 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trichloroethyl chloroformate (troc), a sulfonamide, and a carbamate. In some implementations, R2is a BOC protecting group.

[0267] III. CHIRAL ACID SALTS

[0268] The present disclosure provides a chiral acid salt of a compound of Formula (II-A):

[0269] In some embodiments, the chiral acid salt is selected from the group consisting of a (+)-camphoric acid salt, a (-)-camphoric acid salt, a (+)-camphorsulfonic acid salt, a (-)- camphorsulfonic acid salt, a (+)-dibenzoyltartaric acid salt, a (-)-dibenzoyltartaric acid salt, a (+)-malic acid salt, a (-)-malic acid salt, a (+)-mandelic acid salt, a (-)-mandelic acid salt (i.e., ( / ?)-mandelic acid) salt, a (+)-tartaric acid salt, and a (-)-tartaric acid salt.

[0270] In another aspect, the present disclosure provides a chiral acid salt of Formula (IX):

[0271] IV. CRYSTALLINE FORMS

[0272] A. A Chiral Acid Salt of Formula (IX)

[0273] The present disclosure provides a crystalline form of a chiral acid salt of Formula (IX)

[0274] In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 4. In some embodiments, the cry stalline form of the chiral acid salt of Formula (IX) is characterized by a melting onset temperature of about 108 °C. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by a peak melting temperature of about 131 °C. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 5. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG. 5.

[0275] In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2. and 15.42 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by two or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2. 13.10 ± 0.2, 14.81 ± 0.2. and 15.42 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by three or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13. 10 ± 0.2, 14.81 ± 0.2, and 15.42 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized byfour or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, and 15.42 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by five or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, and 15.42 ± 0.2 in an X-ray powder diffraction pattern. And, in some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 1 1.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, and 15.42 ± 0.2 in an X-ray powder diffraction pattern.

[0276] In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by two or more peaks corresponding to 2- theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2. 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by three or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by four or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2. 10.21 ± 0.2, 11.01 ± 0.2. 13.10 ± 0.2, 14.81 ± 0.2. 15.42 ± 0.2, 17. 12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by five or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2. 11.01 ± 0.2,13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by seven or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2. 20.54 ± 0.2, 23.05 ± 0.2. 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by eight or more peaks corresponding to 2- theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2. 11.01 ± 0.2, 13.10 ± 0.2. 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by nine or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. In some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by ten or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2. 25.47 ± 0.2, 26.65 ± 0.2. 27.09 ± 0.2, 27.76 ± 0.2. 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern. And, in some embodiments, the crystalline form of the chiral acid salt of Formula (IX) is characterized by peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2. 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2. 18.33 ± 0.2, 18.87 ± 0.2. 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern.

[0277] B. Form B of a Compound of Formula (I)

[0278] It is well known that a crystalline polymorph form of a particular drug is often an important determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation, and in vivo pharmacology. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and thermodynamic stabilities specific to a particular polymorph form. In cases where two or more polymorph substances can be produced, it is desirable to prepare each of the polymorphs in pure form and determine the properties of each polymorph. Based on the desired features, properties, and stabilities, a preferred polymorph may be selected. In certain aspects, ease of preparation or stability are deemed to be especially important and present a preferred polymorph. In other situations, a different polymorph may be preferred for greater solubility and / or superior pharmacokinetics. Because improved drug formulations, with better bioavailability or better stability for example, are consistently sought, there is an ongoing need for new or purer polymorphic forms of existing drug molecules.

[0279] A crystalline form (Form B) of a compound of Formula (I)was described in U.S. Patent Application Publication No. 2021 / 0053939 and PCT Application Publication No. WO 2021 / 01 1586, each of which are incorporated by reference in their entirety herein. Form B was identified as having superior stability compared to other polymorphic forms of the Compound of Formula (I) (e.g., Form A, Form C, Form D).

[0280] The present disclosure provides the crystalline form (Form B) of the compound of Formula (I). In some embodiments, Form B is characterized by at least one of(a) a X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having two or more peaks expressed in degrees 2-theta ± 0.2° and selected from about 7.32, 7.88, 10.20, 10.88, 13.40. 14.68, 15.24. 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98. 22.94, 23.16. 23.86, 24.24. 24.78, 25.38, 26.40. 26.88, and 28.74 degrees; and(b) a differential scanning calorimetry (DSC) thermogram showing an endotherm at from about 170 °C to about 185 °C.

[0281] In some embodiments, Form B is characterized by a X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having each of the peaks expressed in degrees 2-theta ±0.2° and selected from about 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48. 19.02, 20.18. 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24. 24.78, 25.38. 26.40, 26.88, and 28.74 degrees. In some embodiments. Form B is characterized by 4 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks expressed in degrees 2- theta ± 0.2° and selected from about 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02. 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78. 25.38, 26.40. 26.88, and 28.74 degrees.

[0282] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having peaks expressed in degrees 2-theta ± 0.2° at each of about 7.88, 10.20, 20.70, and 26.88 degrees. In some embodiments, Form B is characterized by 3 peaks or 2 peaks expressed in degrees 2-theta ± 0.2° at each of about 7.88, 10.20, 20.70, and 26.88 degrees.

[0283] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having peaks expressed in degrees 2-theta ± 0.2° at each of about 7.32, 7.88, 10.20, and 18.48 degrees. In some embodiments, Form B is characterized by 2 or more, or 3 or more peaks selected from 7.32, 7.88, 10.20, and 18.48 degrees.

[0284] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having peaks expressed in degrees 2-theta ± 0.2° at each of about 7.32, 16.28. and 26.88 degrees. In some embodiments, Form B is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected from 7.32, 16.28, and 26.88 degrees.

[0285] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka having peaks expressed in degrees 2-theta ± 0.2° at each of about 7.88, 15.42, 17.70, and 21.56 degrees. In some embodiments, Form B is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected from 7.88, 15.42, 17.70, and 21.56 degrees.

[0286] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern essentially the same as shown in FIG. 1. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern essentially the same as shown in FIG. 3.

[0287] In some embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka lacking peaks expressed in degrees 2- theta ± 0.05° at each of about 0 to 6.80 and 8. 10 to 9.00 degrees. In some embodiments.there are no peaks expressed in degrees 2-theta ± 0.05° at each of about 0 to 6.80 and 8. 10 to 9.00 degrees. In some embodiments, there are no peaks expressed in degrees 2-theta ± 0.05° in at least 1 of the ranges consisting of 0 to 6.80 and 8.10 to 9.00 degrees. In some embodiments, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at each of about 0 to 6.80 and 8. 10 to 9.00 degrees. In some embodiments, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° in at least 1 of the ranges consisting of 0 to 6.80 and 8. 10 to 9.00. In some embodiments, there are only peaks that are equal than or less than 1 / 20 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at each of about 0 to 6.80 and 8. 10 to 9.00 degrees. In some embodiments, there are only peaks that are equal to or less than 1 / 20 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at least 1 of the ranges consisting of 0 to 6.80 and 8. 10 to 9.00. In some embodiments, there are only peaks that are equal than or less than 1 / 10 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at each of about 0 to 6.80 and 8. 10 to 9.00 degrees. In some embodiments, there are only peaks that are equal than or less than 1 / 10 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at least 1 of the ranges consisting of 0 to 6.80 and 8.10 to 9.00.

[0288] In some embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka lacking peaks expressed in degrees 2- theta ± 0.05° at about 0 to 6.80 degree. In some embodiments, there are no peaks expressed in degrees 2-theta ± 0.05° at about 0 to 6.80 degrees. In some embodiments, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at about 0 to 6.80 degrees. In some embodiments, there are only peaks that are equal than or less than 1 / 20 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at about 0 to 6.80 degrees. In some embodiments, there are only peaks that are equal than or less than 1 / 10 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at about 0 to 6.80 degrees.

[0289] In some embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka lacking peaks expressed in degrees 2- theta ± 0.05° at each of about 8. 10 to 9.00 degrees. In some embodiments, there are no peaks expressed in degrees 2-theta ± 0.05° at about 8. 10 to 9.00 degrees. In some embodiments, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at about 8.10 to 9.00 degrees. In some embodiments, there are only peaks that are equal than or less than 1 / 20 the height of the most intense peak expressed in degrees 2-theta ± 0.05° at about 8.10 to 9.00 degrees. In some embodiments, there are only peaks that are equal than or less than 1 / 10 theheight of the most intense peak expressed in degrees 2-theta ± 0.05° at about 8.10 to 9.00 degrees.

[0290] In some embodiments, Form B has is characterized by a DSC thermogram and / or a TGA thermogram essentially the same as shown in FIG. 2. In some embodiments, Form B is characterized by a DSC thermogram showing an endotherm at from about 170 °C to about 185 °C. In some embodiments, Form B is characterized by a melt onset of about 170 °C. In some embodiments, Form B is characterized by a melting point of 178 °C ± 2 °C. In some embodiments, Form B is characterized by a DSC thermogram showing a second endotherm at from about 185 °C to about 200 °C. In some embodiments, Form B is characterized by a second melting point of 192.7 °C ± 2 °C.

[0293] In another aspect, provided herein is a composition comprising Form B. In some embodiments, the composition comprises greater than or equal to 99.5% by weight Form B. In another aspect, provided herein is a composition, wherein the ratio of the amount of the Form B to the sum of the amounts of other polymorphic forms is equal to or greater than 80:20. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 90: 10. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 95:5. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 97:3. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 98:2. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 99: 1. In another aspect, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 99.5:0.5.

[0294] Also provided herein is a composition comprising Form B that is essentially solvent free. In some embodiments, the composition has less than 6 wt. % of solvent. In some embodiments, the composition has less than 3 wt. % of solvent. In some embodiments, the composition has less than 1 wt. % of solvent. In some embodiments, the composition has less than 0.7 wt. % of solvent. In some embodiments, the solvent is a mixture of water and methanol. In some embodiments, the solvent is a mixture of water and ethanol. In some embodiments, the solvent is a mixture of water and acetonitrile. In some embodiments, the solvent is water.

[0295] V. PHARMACEUTICAL COMPOSITIONS

[0296] In another aspect, provided herein is a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a crystalline form (Form B) of the compound of Formula (I)) and a pharmaceutically acceptable excipient. The pharmaceutical compositions are useful for treating cardiac disorders associated with systolic dysfunction including dilated cardiomyopathy and HFrEF in humans and other subjects.

[0297] The pharmaceutical compositions for the administration of the polymorphs or their pharmaceutically acceptable salts provided herein may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary', shaping the product into the desired formulation. In the pharmaceutical composition, the active agent is generally included in an amount sufficient to increase myocardial contractility (i.e. , to improve the systolic dysfunction in DCM or HFrEF) and to improve or not worsen left ventricular relaxation in diastole. Such improved relaxation can alleviate symptoms in dilated cardiomyopathy and other etiologies of diastolic dysfunction, such as heart failure with preserved ejection fraction (HFpEF). It can also ameliorate the effects of diastolic dysfunction causing impairment of coronary blood flow, improving the latter as an adjunctive agent in angina pectoris and ischemic heart disease. It can also confer benefits on salutary' left ventricular remodeling in DCM and other causes of left ventricular dysfunction due to ischemic heart disease or chronic volume or pressure overload from, e.g.. myocardial infarction, valvular heart disease or systemic hypertension

[0298] In another aspect, provided herein is a pharmaceutical composition comprising the crystalline form (Form B) of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In some embodiments, provided herein is a pharmaceutical composition, wherein the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 80:20. In some embodiments, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 90: 10. In some embodiments, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 95:5. In some embodiments, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 97:3. In some embodiments, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 98:2. In some embodiments, the ratio of the amount of the Form B to the sum of the amounts of other forms is equal to or greater than 99: 1.

[0299] In some embodiments, the pharmaceutical composition comprising Form B further comprises an additional agent. Exemplary’ non-limiting additional agents include agents that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), P-blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contractility (e g., positive inotropic agents, such as the 0-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). In some embodiments, the additional agent in the pharmaceutical composition is a cardiovascular medication.

[0300] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example PVP. cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for controlled release.

[0301] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.

[0302] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0303] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0304] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0305] The pharmaceutical compositions provided herein may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soybean, lecithin, and esters or partial esters derived from fatty' acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0306] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[0307] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents yvhich have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are yvater, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0308] The polymorphs or their pharmaceutically acceptable salts provided herein may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary’ temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery' of the subject compounds can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds or their pharmaceutically acceptable salts provided herein are employed. As used herein, topical application also includes applications via the use of mouth washes and gargles.

[0309] The polymorphs of this invention may also be coupled to a carrier that is a suitable polymer for targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenoL polyhydroxyethyl-aspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the polymorphs or their pharmaceutically acceptable salts provided herein may be coupled to a carrier that is a biodegradable polymer useful in achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polygly colic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, poly dihydropyrans, poly cyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

[0310] Pharmaceutical Composition Comprising Form B

[0311] In certain aspects of the disclosure, provided herein is pharmaceutical composition comprising Form B and a diluent. In some embodiments, the pharmaceutical composition further comprises a disintegrant. In some embodiments, the pharmaceutical composition further comprises a binder. In some embodiments, the pharmaceutical composition further comprises a lubricant.

[0312] In some embodiments, the pharmaceutical composition comprises Form B and a diluent selected from the group consisting of calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodiumphosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures of any of the foregoing diluents. In some embodiments, the pharmaceutical composition further comprises a disintegrant is selected from the group consisting of agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any of the foregoing disintegrants. In some embodiments, the pharmaceutical composition further comprises a binder is selected from the group consisting of starch (e.g., cornstarch and starch paste), gelatin, sugars (e g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, pan war gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures of any of the foregoing binders. In some embodiments, the pharmaceutical composition further comprises a lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

[0313] In some embodiments, the pharmaceutical composition comprises Form B, at least one diluent, at least one disintegrant, at least one binder, and at least one lubricant. In some embodiments, Form B makes up about 1-55% of the mass of the composition. In some embodiments. Form B makes up about 1-20% of the mass of the composition. In some embodiments, the one or more diluents makes up about 30-95% of the mass of the composition. In some embodiments, the one or more diluents makes up about 40-95% of the mass of the composition. In some embodiments, the one or more diluents makes up about 75-95% of the mass of the composition. In some embodiments, the one or more disintegrants make up about 0-10% of the mass of the composition. In some embodiments, the one or more disintegrants make up about 0-5% of the mass of the composition. In some embodiments, the one or more binders make up about 0-10% of the mass of the composition. In some embodiments, the one or more binders make up about 0-5% of the mass of thecomposition. In some embodiments, the one or more lubricants make up about 0-10% of the mass of the composition. In some embodiments, the one or more lubricants make up about 0- 5% of the mass of the composition

[0314] In some embodiments, the pharmaceutical composition comprises Form B in about 2.5%, 12.5 %, or 50% by weight, at least one diluent in about 42%, 79.5 %, or 89.5% byweight. at least one disintegrant at about 4% by weight, at least one binder 3 by weight, and at least one lubricant at about 1% by weight. In some embodiments, the pharmaceutical composition comprises Form B in about 2.5%, 12.5 %, or 50% by weight, two diluents in about 42%, 79.5 %, or 89.5% total by weight, at least one disintegrant at about 4% by weight, at least one binder 3 by weight, and at least one lubricant at about 1% by weight.

[0315] In some embodiments, provided herein is a pharmaceutical composition comprising Form B, lactose, cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate. In some embodiments, the pharmaceutical composition comprises, Form B, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate.

[0316] Methods of Treating Cardiac Disorders

[0317] The invention provides a method of treating systolic dysfunction. Further provided are methods of treating DCM. Provided herein are methods of treating HFrEF. The disclosure also provides methods of treating dilated cardiomyopathy (DCM) or a cardiac disorder having one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve. The method includes administering to a subject in need thereof an effective amount of a polymorph or composition provided herein.

[0318] Particularly, the invention provides a method of treating systolic dysfunction by administering to a subject in need thereof with an effective amount of a compound of Formula (I) (e.g., a crystalline form (Form B) of the compound of Formula (I)). Further provided are methods of treating DCM by administering to a subject in need thereof an effective amount of a compound of Formula (I) (e.g., a cry stalline form (Form B) of the compound of Formula (I)). Also provided herein are methods of treating HFrEF by administering to a subject in need thereof an effective amount of a compound of Formula (I) (e.g., a crystalline form (Form B) of the compound of Formula (I)). The disclosure also provides methods of treating dilated cardiomyopathy (DCM) or a cardiac disorder having one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve by administering to a subject in need thereof aneffective amount of a compound of Formula (I) (e.g., a crystalline form (Form B) of the compound of Formula (I)).

[0319] The compounds of the invention or their pharmaceutically acceptable salts can alter the natural history of DCM and other diseases rather than merely palliating symptoms. The mechanisms conferring clinical benefit to DCM patients can extend to patients with other forms of heart disease sharing similar pathophysiology, with or without demonstrable genetic influence. For example, an effective treatment for DCM. by improving ventricular contraction, can also be effective in a broader population characterized by systolic dysfunction. The compounds of the invention or their pharmaceutically acceptable salts can specifically target the root causes of the conditions or act upon other downstream pathways. Accordingly, the compounds of the invention or their pharmaceutically acceptable salts can also confer benefit to patients suffering from heart failure with reduced ejection fraction (HFrEF), HFpEF, chronic congestive heart failure, acute heart failure, right-sided (or right ventricular) heart failure, cardiogenic shock and inotropic support after cardiac surgery. Compounds of the invention or their pharmaceutically acceptable salts can potentially improve cardiac function in the following patient segments: idiopathic dilated cardiomyopathy, genetically defined or familial dilated cardiomyopathy, ischemic or postinfarction cardiomyopathy, viral cardiomyopathy or myocarditis, toxic cardiomyopathies (e.g., post-anthracy cline anticancer therapy), metabolic cardiomyopathies (in conjunction with enzyme replacement therapy), diastolic heart failure (with diminished systolic reserve), right heart failure due to pulmonary hypertension, and ventricular dysfunction due to on- bypass cardiovascular surgery. Compounds of the invention or their pharmaceutically acceptable salts can also promote salutary ventricular reverse remodeling of left ventricular dysfunction due to ischemia or volume or pressure overload; e.g.. myocardial infarctions, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. By reducing left ventricular filling pressures the compounds could improve the symptom of dyspnea and reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation, and with it reduce the attendant risk of arterial thromboembolic complications including but not limited to cerebral arterial embolic stroke. The compounds or their pharmaceutically acceptable salts may reduce the severity' of the chronic ischemic state associated with DCM and thereby reduce the risk of Sudden Cardiac Death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators(frequent and / or repeated ICD discharges) and / or the need for potentially toxic antiarrhythmic medications. The compounds or their pharmaceutically acceptable salts could be valuable in reducing or eliminating the need for concomitant medications with their attendant potential toxicities, drug-drug interactions, and / or side effects. The compounds or their pharmaceutically acceptable salts may reduce interstitial myocardial fibrosis and / or slow the progression, arrest, or reverse left ventricular stiffness and diastolic dysfunction.

[0320] Depending on the disease to be treated and the subject’s condition, the compounds or their pharmaceutically acceptable salts provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by implantation (e.g., as when the compound is coupled to a stent device), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0321] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary' characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition for the subject undergoing therapy.

[0322] Compounds and compositions provided herein may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds and compositions provided herein are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound or composition provided herein. When a compound or composition provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition provided herein is preferred. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition provided herein. Suitable additional active agents include, for example: therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs). (3-blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents, such as the 0-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The compounds or their pharmaceutically acceptable salts may be used in combination with a beta-blocker (a drug class with known side-effects due to negative inotropic effect) to confer unique tolerability' of beta-blocker titration to target doses. The compounds or their pharmaceutically acceptable salts may be used in combination with a lusitropic agent for the treatment of diastolic heart failure (or HFpEF. a disorder with diastolic dysfunction and reduced systolic reserve). The weight ratio of the compound provided herein to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

[0323] VI. EXAMPLES

[0324] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0325] General Materials and Methods

[0326] Abbreviations used herein are set forth in Table 1.

[0327] Table 1: Abbreviations.

[0328] Example 1. First Exemplary Preparation of Form B of Danicamtiv: (R)-4-(l-((3- (difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3- yl)piperidine- 1-carboxamide (1-491).

[0329] Compound 1.1. tert-butyl 4-((tosyloxy)methyl)piperidine-l-carboxylate (Method 1)

[0330] To a solution of 4-dimethylaminopyridine (DMAP; 90 g, 0.05 eq.), triethylamine (TEA; 3.0 kg, 2.13 eq ), and tert-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (30. kg, 1.0 eq.) in dichloromethane (DCM; 30 L, 10 vol.), was added tosyl chloride (TsCI; 2.92 kg, 1.1 eq.) in DCM (6 L, 2 vol.) dropwise with stirring at from about 15 °C to about 25 °C. After 3 h, cold water (H2O; 30 L, 10 vol.) was added at from about 15 °C to about 25 °C with stirring. The organic layer was washed with aq. hydrochloric acid (HC1; 0.5 M, 15 L, 5 vol.) twice and then washed with H2O (15 L, 5 vol.). The organic layer was concentrated (~2.5 vol. to 3 vol.) under reduced pressure. Heptane (45 L) was added to the organic layer and concentrated (~6.5 vol. to 7.0 vol.) under reduced pressure. The mixture was cooled to about 5 °C to about 10 °C and stirred for 2 h. After 2 h, the mixture was filtered and the solid was washed with heptane (18 L). The solid was dried at from about 40 °C to about 45 °C under reduced pressure to obtain 13.4 kg of tert-butyl 4-((tosyloxy)methyl)piperidine-l -carboxylate (Compound 1.1) as an off-white color solid with 99.5% purity by HPLC.

[0331] Compound 1.1. tert-butyl 4-((tosyloxy)methyl)piperidine-l-carboxylate (Method 2)

[0332] To a solution of 4-dimethylaminopyridine (90 g, 0.05 eq.), triethylamine (3.0 kg, 2.13 eq.), and tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (30. kg. 1.0 eq.) in dichloromethane (30 L, 10 v), was added tosyl chloride (TsCl: 2.92 kg, 1.1 eq.) in DCM (6 L, 2 v) dropwise with stirring at about 15 °C to about 25 °C. After 3 hours, cold H2O (30 L, 10 v) was added at about 15 °C to about 25 °C with stirring. The organic layer was washed with aq. HC1 (0.5 M, 15 L, 5 v) twice and then washed with H2O (15 L, 5 vol.). The organic layer was concentrated (-2.5-3 vol.) under reduced pressure. Heptane (45 L) was added to the organic layer and concentrated (-6.5-7.0 vol.) under reduced pressure. The mixture was cooled to about 5 °C to about 10 °C and stirred for 2 h. After 2 h, the mixture was filtered and the solid washed with heptane (18 L). The solid was dried at about 40 °C to about 45 °C under reduced pressure to obtain 13.4 kg of tert-butyl 4-((tosyloxy)methyl)piperidine-l- carboxylate (Compound 1.1) as an off-white color solid with 99.5% purity by HPLC.

[0333] Compound 1.2. tert-butyl 4-((acetylthio)methyl)piperidine-l-carboxylate

[0334] A solution of potassium thioacetate (KSAc; 1.32 kg, 1.3 eq.) and tert-butyl 4- ((tosyloxy)methyl)piperidine-l -carboxylate (Compound 1.1: 3.3 kg. 1.0 eq.) in N.N- dimethylformamide (DMF: 23.1 L, 7 vol.) was heated to from 40 °C to 50 °C with stirring for 3 h. The reaction was cooled to from about 20 °C to about 25 °C and H2O (16.5 L, 5 vol.) was added. After stirring at room temperature for 1 h, the solution was extracted with methyl tert-butyl ether (MTBE; 16.5 L, 5 vol.) twice. The combined organic layer was washed with H2O (16.5 L, 5 vol.) three times. The organic layer was slurried with an active charcoal suspension (660 g in MTBE (3.3 L, 1 vol.)) for 1 h at about 30 °C. The mixture was filtered and the solid was washed with MTBE (3.3 L, 1 vol.). The filtrate was concentrated under reduced pressure at from about 30 °C to about 40 °C and chilled to from about 5 °C to about 15 °C overnight to give 4.51 kg of tert-butyl 4-((acetylthio)methyl)piperidine-l-carboxylate (Compound 1.2) as a white solid with 97.7% purity by HPLC.

[0335] Compound 1.3. ethyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate

[0336] Ethyl 4,4-difluoro-3-oxobutanoate (100 g, 602 mmol) was placed in a 1,000 mL 3- necked flask at room temperature. Triethylorthoformate (HC(OEt)s; 178 g, 1204 mmol) and acetic anhydride (184 g, 1806 mmol) were added to the reaction mixture. The reaction mixture was heated to about 110 °C for 3.5 h. The reaction mass was cooled to room temperature, and then the solution was concentrated at about 60 °C under reduced pressure to remove the solvent and give an intermediate compound (148 g).

[0337] Toluene (650 mL) was placed in a 2.000 mL 3-necked flask at room temperature and 40% methylhydrazine (NH?NHMe: 72.9 g) was added. The mixture was cooled to about 0 °C with ice-water. A solution of the intermediate compound in toluene (100 mL) was added dropwise to the solution while maintaining a temperature below about 5 °C. After the addition was completed, the reaction mixture was stirred at from about 0 °C to about 5 °C for 3 h. H2O (600 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was further extracted with ethyl acetate (750 mL). The combined organic layers were washed with brine (600 mL). The organic layer was then concentrated to approximately 2.0 vol. under reduced pressure. Heptane (600 mL, 6.0 vol.) was added to the concentrated organic layer and then concentrated to approximately 2.0 vol. under reduced pressure. Heptane (100 mL, 1.0 vol.) was added to the concentrated organic layer and stirred at from about 5 °C to about 10 °C for 3 h. The mixture was filtered, washed with heptane twice (300 mL, 3.0 vol. each wash), and dried at about 35 °C under reduced pressure to obtain ethyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate (Compound 1.3: 102.2 g) as a yellow solid.

[0338] Compound 1.4. 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid

[0339] To a solution of ethyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate (Compound 1.3; 50 g, 244.8 mmol) in tetrahydrofuran (THF; 150 mL, 3.0 vol.) was added a solution of lithium hydroxide (LiOH; 35.1 g, 1469.1 mmol) in H2O (150 mL. 3.0 vol.). After the addition was completed, the reaction mixture was heated to about 75 °C for 3 h and then concentrated under reduced pressure at from about 40 °C to about 45 °C. The aqueous layer w as acidified to a pH of from 3 to 4 with a concentrated HC1 solution. The precipitate w as filtered and w ashed with heptane twice (100 mL, 2.0 vol. each wash). The solid was dried toafford 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (Compound 1.4; 41.2 g) as a light yellow solid.

[0340] Compound 1.5a. 4-bromo-3-(difluoromethyl)-l-methyl-lH-pyrazole

[0341] To a solution of sodium hydroxide (NaOH; 87.5 g, 1.1 eq) in H2O (2800 mL. 8.0 vol.) in an ice bath (—20 °C to 30 °C) was added 3 -(difluoromethyl)- 1 -methyl- lH-pyrazole-4- carboxylic acid (350 g, 1.0 eq). The reaction mixture was stirred below about 15 °C for 1 h. Bromine (Br2; 317.8 g. 1.0 eq) was added dropwise to the reaction mixture below about 15 °C. The reaction mixture was stirred below about 15 °C for 0.5 h. Ethyl acetate (EtOAc; 1750 mL, 5.0 vol.) was added to the reaction mixture and the layers were separated. The aqueous layer was further extracted with EtOAc (1750 mL, 5.0 vol.). The combined organic layers were w ashed with saturated sodium bicarbonate in H2O (1750 mL, 5.0 vol.), saturated sodium sulfite in H2O (1750 mL, 5.0 vol.), and brine (1750 mL, 5.0 vol.). The organic layer was concentrated at about 45 °C under reduced pressure to afford 4-bromo-3- (difluoromethyl)-l-methyl-lH-pyrazole (Compound 1.5a) as yellow^ oil (368 g , Yield = 87.8% , Purity = 98.4%).

[0342] Compound 1.6. tert-butyl 4-(((3-(difhioromethyl)-l-methyl-lH-pyrazol-4- yl)thio)methyl)piperidine-l-carboxylate

[0343] A solution of 4-bromo-3-(difluoromethyl)-l-methyl-lH-pyrazole (Compound 1.5a; 5.0 g. 1.0 eq), Pd2(dba)3*CHCl3(1.2 g, 0.05 eq). Xantphos (CAS No. 161265-03-8; 1.4 g, 0.10 eq.), cesium carbonate (CS2CO3; 19.3 g, 2.5 eq.), potassium iodide (KI; 0.6 g, 0.16 eq.) and tert-butyl 4-((acetylthio)methyl)piperidine-l -carboxylate (Compound 1.2; 7.8 g, 1.2 eq) under nitrogen (N2) was heated to from about 110 °C to about 115 °C for 15 h with stirring, tert-butyl 4-((acetylthio)methyl)piperidine-l -carboxylate (Compound 1.2; 1.3 g. 0.2 eq) was subsequently added under N2and the mixture was heated to from about 110 °C to about115 °C for 7 h with stirring. The reaction mixture was cooled to from about 20 °C to about 30 °C. The mixture was filtered and washed with toluene (50 mL, 10 vol.) twice. The organic layer was washed with H2O (100 mL, 20 vol.) twice and concentrated at about 45 °C under reduced pressure. The crude product was then purified by column chromatography (silica gel, 1 : 15-1:4 ethyl acetate:petroleum ether) to give a brown oil. The oil was dissolved in EtOAc (20 mL, 4.0 vol.) and concentrated (-1.0 vol.) under reduced pressure. Heptane (50 mL, 10.0 vol.) was added, and the mixture was stirred at about 0 °C to about 5 °C for 1 h and then filtered. The solid was dried under reduced pressure at about 40 °C to about 45 °C to obtain tert-butyl 4-(((3-(difluoromethyl)- 1 -methyl- lH-pyrazol-4-yl)thio)methyl)piperidine- 1 - carboxylate (Compound 1.6) as a yellow solid (Purity' = 98.9%).

[0344] Compound 1.7. tert-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol- 4-yl)thio)methyl)piperidine-l-carboxylate

[0345] A solution of tert-butyl 4-(((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)thio)methyl)piperidine-l -carboxylate (Compound 1.6; 25.25 kg, 1.0 eq.) in THF (179.20 kg, 8 vol.) was cooled to a temperature of about -85 °C to about -75 °C under N2. n- butyllithium (n-BuLi; 21.10 kg, 1.1 eq.) was added dropwise to the solution over 40 min and the mixture was stirred for 1.5 h while maintaining a temperature between about -85 °C to about -75 °C. A solution of C2CI6 in THF (8.25 kg. 0.5 eq. / 22.40 kg. 1.0 vol.) was added dropwise to the mixture over 1.5 h while maintaining a temperature between about -85 °C to about -75 °C. A saturated ammonium chloride (NH4CI) solution (105.05 kg, 3.3 vol.) was added to the reaction mixture resulting in a final temperature of about 15 °C to about 5 °C. H2O (25.20 kg. 1.0 vol.) was subsequently added to the reaction mixture ending with a final temperature of about 25 °C. The organic layer was concentrated (~2.0 vol. to 2.5 vol.) under vacuum at a temperature below about 50 °C. The mixture was cooled to between 10 °C to 30 °C and charged with MTBE (95.35 kg, 5.0 vol.) and H2O (76.70 kg, 3.0 vol.). The organic layer was concentrated (~2.0 vol. to 2.5 vol.) under vacuum at a temperature below about 50 °C. n-Heptane (85.05 kg, 5.0 vol.) was added to the mixture and then the organic layer was concentrated to about 3.0 vol. to 3.5 vol. under vacuum at a temperature belowabout 50 °C. The mixture was cooled to about 15 °C to about 20 °C and stirred for 2 h. The mixture was further cooled to about 0 °C to about 5 °C and stirred for 3.5 h. The resulting slurry was centrifuged and the solid was rinsed with n-heptane (40.75 kg, 2.0 vol.). The solid was dried at about 45 °C to about 55 °C to obtain 25.29 kg of tert-butyl 4-(((5-chloro-3- (difluoromethyl)- 1 -methyl- lH-pyrazol-4-yl)thio)methyl)piperi dine- 1 -carboxylate (Compound 1.7) as a yellow solid material (Purity = 98.5%; Yield = 91%).

[0346] Compound 1.8. tert-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol- 4-yl)sulfonyl)methyl)piperidine-l-carboxyIate

[0347] A solution of tert-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)thio)methyl)piperidine-l -carboxylate (Compound 1.7; 25.20 kg, 1.0 eq.) and ruthenium(III) chloride trihydrate (RuCh’Sf^O; 0.025kg, 1% w / w) in THF (333.95 kg, 15.0 vol.) was cooled to about -5 °C to about 5 °C. Then, an additional 23.80 kg of THF (1.0 vol.) was added. A solution of sodium periodate (NaICU; 33.82 kg, 2.5 eq.) in H2O (378.00 kg, 15 vol.) was added dropwise to the solution over 8.5 h while maintaining a temperature of about -5 °C to about 5 °C. The mixture was warmed to about 15 °C to about 25 °C and stirred for 3 h. The reaction mixture was cooled to about -5 °C to about 5 °C and a solution of aqueous sodium sulfite (Na2SOs; 10% w / w, 280.65 kg. 10.0 vol.) was added dropwise to the mixture over 3 h, and then stirred for an additional 1 h at about -5 °C to about 5 °C. EtOAc (113.00 kg, 5.0 vol.) was added and the mixture was stirred for 2 h at about 0 °C to about 30 °C. The solution was filtered and the aqueous layer was extracted with EtOAc (222.20 kg, 10.0 vol.). The organic layers were combined, washed with brine (168.35 kg, 5.0 vol.) twice, and concentrated under vacuum below about 50 °C. n-Heptane (85.20 kg, 5.0 vol.) was added at about 35 °C to about 45 °C, the mixture was cooled to about 0 °C to about 5 °C and stirred for 1 h. The mixture was filtered and the solid was collected. H2O (251.65 kg, 10.0 vol.) was added to the solid and the resultant mixture was heated to about 35 °C to about 45 °C and stirred for 2 h before being cooled to about 20 °C to about 30 °C and stirred for an additional 2 h. The mixture was filtered, rinsed with H2O (51.20 kg, 2.0 vol.), and dried under vacuum at about 45 °C to about 55 °C to obtain 25.2 kg of terf-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)methyl)piperidine-l-carboxylate (Compound 1.8) as an off-white solid (Purity = 98.7%; Yield = 93%).

[0348] Compound 1.9. tert-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol- 4-yl)sulfonyl)fluoromethyl)piperidine-l-carboxylate

[0349] A solution of tert-butyl 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)methyl)piperidine-l-carboxylate (Compound 1.8; 25.10 kg, 1.0 eq.) in THF (155.85 kg, 7.0 vol.) under N2 was cooled to about -88 °C to about -78 °C. A solution of lithium diisopropylamide (LDA; 2 M in THF, 32.25 kg. 1.4 eq.) was added dropwise over about 80 min at about -88 °C to about -78 °C. The reaction mixture was stirred at about -88 °C to about -78 °C for 10 min. Next, the solution was added to a solution of NFSI (20.25 kg, 1.1 eq.) in THF (209.50 kg, 9.0 vol.) under N2 at about -88 °C to about -78 °C. After 30 min of stirring at about -88 °C to about -78 °C, H2O (25.00 kg, 1.0 vol.) was added to the mixture over 20 min. The mixture was warmed to about -15 °C to about -5 °C and stirred for 1 h. Saturated NH4CI (347.80 kg, 10.0 vol.) was added, and the mixture was warmed to room temperature with stirring for 30 min. The organic layer was diluted with EtOAc (352.25 kg, 16.0 vol.), washed with 5% NaCl (263.50 kg, 10.0 vol.) three times, and concentrated under vacuum at about 40 °C to about 50 °C. Ethanol (EtOH; 97.60 kg, 5.0 vol.) was added and the solution was concentrated under vacuum at about 40 °C to about 50 °C, repeating the addition and concentration a second time. The mixture was stirred for 2 h at about 0 °C to about 5 °C, filtered, rinsed with EtOH (10.20 kg, 0.5 vol.), and dried at about 40 °C to about 50 °C under vacuum to afford 17.64 kg of / er / -butyl 4-(((5-chloro-3-(difluoromethyl)-l- methyl-lH-pyrazol-4-yl)sulfonyl)fluoromethyl)piperidine-l-carboxylate (Compound 1.9) as an off-white solid (Purity = 93.7%; Yield = 67%).

[0350] Compound 1.10. tert-butyl 4-(l-((5-chloro-3-(difluoromethyl)-l-methyl-lH- pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine-l-carboxylate

[0351] A solution of te / 7-butyl 4-(((5 -chi oro-3 -(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)fluoromethyl)piperidine-l -carboxylate (Compound 1.9; 17.57 Kg. 1.0 eq.) and methyl iodide (CH3I; 7.27 kg, 1.3 eq.) in THF (158.00 kg, 10.0 vol.) were cooled to about -88 °C to about -78 °C. A solution of potassium tert-butoxide (t-BuOK; 8.80 kg, 2.0 eq.) in THF (47.40 kg, 3 vol.) was added dropwise over 2.5 h and stirred for 0.5 h at about -88 °C to about -78 °C. Saturated NH4CI (23.35 kg, 1.0 vol.) was added, and the mixture was warmed to about -10 °C to about 0 °C. Then, saturated NH4CI (91.80 kg, 4.0 vol.) was added at about -10 °C to about 20 °C, and the mixture was warmed to about 10 °C to about 30 °C and stirred for 30 min. The organic layer was concentrated under reduced pressure at about 40 °C to 45 °C, diluted with MTBE (65.70 kg, 5.0 vol.), washed with 10% aq. sodium sulfite (Na2SOs) solution (58.39 kg. 3 vol.), washed with aq. 10% sodium chloride (NaCl) solution (59.00 kg.3 vol.) twice, and the organic layer was concentrated under vacuum at about 40 °C to about 45 °C. n-Heptane (11.85 kg, 1.0 vol.) was added to the residue at about 20 °C to about 30 °C and the mixture was stirred for 30 min. A seed cry stal of tert-butyl 4-(l-((5-chloro-3- (difluoromethy 1)- 1 -methyl- lH-pyrazol-4-yl)sulfonyl)-l -fluoroethyl)piperi dine- 1 -carboxylate (Compound 1.10) was added at about 20 °C to about 30 °C and the solution was stirred for 1 h at about 20 °C to about 30 °C. n-Heptane (36.00 kg, 3.0 vol.) was added at about 10 °C to about 30 °C and cooled to 10 °C to 20 °C and stirred for 2.5 h. The mixture was filtered and rinsed with n-heptane (6.05 kg, 0.5 vol.). The solid was suspended in EIOH / H2O (3 / 2 v / v, 123.35 kg, 8.0 vol.) and heated to about 60 °C to about 80 °C with stirring to obtain a clear solution. The solution was cooled to about 50 °C to about 55 °C and a seed (0. 19 kg) was added to the solution at about 50 °C to about 55 °C and stirred for 1 h. The solution was further cooled to about 40 °C to about 45 °C and stirred for 2 h, about 30 °C to about 35 °C and stirred for 1 h, about 20 °C to about 25 °C and stirred for 1 h. about 10 °C to about 15 °C and stirred for 1 h, and about 0 °C to about 5 °C and stirred for 1 h. The mixture was filtered, rinsed with EtOH / H2O (1 / 1 v / v, 15.85 kg, 1 vol.), and the resultant solid was dried at about45 °C to about 55 °C to afford 15.21 kg of tert-butyl 4-(l-((5-chloro-3-(difluoromethyl)-l- methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine-l -carboxylate (Compound 1.10) as an off-white solid (Purity = 98.5%; Yield = 83%).

[0352] Compound 1.11. tert-butyl 4-(l-((3-(difluoromethyl)-l,l-dimethyl-lH-114- pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine-l-carboxylate

[0353] A solution of tert-butyl 4-(l-((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)piperidine-l -carboxylate (Compound 1.10; 23.40 kg, 1.0 eq.) in EtOH (147.90 kg, 8 vol.) under N2 was heated to 45 °C ± 5 °C and stirred for about 30 min. The solution was transferred to an autoclave under N2, rinsed with EtOH (27.40 kg, 1 vol.), and sodium acetate (NaOAc; 6.32 kg, 1.5 eq.) was added. The headspace of the autoclave was purged with N2 (five times), charged wi th Pd / C (10%, wet) (4.68 kg, 20% w / w), and rinsed with EtOH (27.95 kg, 1 vol ). The autoclave atmosphere was further purged with N2 (ten times). The autoclave was heated to about 40 °C to about 45 °C. before hydrogen (0.7 ± 0.2 MPa) was introduced. The reaction was stirred for about 22 h at about 40 °C to about 45 °C under 0.7 MPa H2 to 0.9 MPaH2. The reaction was cooled to about 30 °C to about 35 °C, filtered, rinsed with EtOH (27.40 kg, 1 vol.), and filtered through a Millipore filter. The filtrate was concentrated, cooled to about 10 °C to about 15 °C, and H2O (128.80 kg, 5.5 vol.) was added dropwise slowly over 7 h at about 10 °C to about 15 °C followed by stirring for an additional 30 min at about 10 °C to about 15 °C. The resultant mixture was centrifuged, washed with EtOH / EEO (1 / 1, 41.9 kg, 2 vol.), centrifuged, and the solid was dried at about 45 °C to about 55 °C to give 19.37 kg tert-butyl 4-(l-((3-(difluoromethyl)-l,l- dimethyl-lH-114-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine-l-carboxylate (Compound 1.11) as a white solid material (Purity = 99.8%; Yield = 89%).

[0354] Salt 1.12a. 4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l- fluoroethyl)piperidine»HCl

[0355] A solution of te / 7-butyl 4-(l-((3-(difluoromethyl)-l,l-dimethyl-lH-ll4-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)piperidine-l -carboxylate (Compound 1.11) in acetonitrile was mixed with a solution of HC1 in cyclopentyl methyl ether (CPME). After completion of the reaction and dilution with cyclopentyl methyl ether, 4-(l-((3-(difluoromethyl)-l-methyl-lH- pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine • HC1 (Salt 1.12a) was isolated by filtration, washed with tert-butyl methyl ether, and dried.

[0356] Salt 1.13. ( / ?)-4-(l-((3-(difluoromethyl)-l-inethyl-lH-pyrazol-4-yl)sulfonyl)-l- fluoroethyl)piperidine (7?)-mandelic acid (Method 1)4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine • HC1 (Salt 1.12a) was mixed with a solution of sodium hydroxide in H2O and 2-methyl tetrahydrofuran (2-MeTHF). The organic layer was recovered, and the 2-MeTHF was distilled off and replaced by 2-propanol to obtain a 2-propanol solution of 4-(l-((3- (difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine. The solution was mixed with (A)-mandelic acid in H2O and heated to result in full dissolution. After cooling, the solid was isolated by filtration. (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH- pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine • (7?)-mandclic acid (Salt 1.13; also referred to herein as a chiral acid salt of Formula (IX)) was washed with 2-propanol, dried, mixed with 2-propanol and H2O, and heated to result in complete dissolution. After cooling, the resultant solid was filtered, washed with 2-propanol, and dried to give (7?)-4-(l-((3- (difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine • (7?)-mandelic acid (Salt 1.13).

[0358] 4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l- fluoroethyl)piperidine • HC1 (Salt 1.12a; 1.00 kg) was mixed with 0.5 L (5 vol.) of 2-MeTHF and 2.50 L (2.5 vol.) of H2O. To the reaction mixture, 2.76 L of 2 M NaOH (5.53 mol, 2 eq.) was added. An additional 0.5 L of H2O were added. The reaction mixture was stirred at 15 min at 20 °C ± 5 °C (pH ~ 14). The organic and aqueous layers were separated, and 3 L (3 vol.) of 2-MeTHF was added to the aqueous layer. The mixture was stirred for 15 min before the organic and aqueous layers were separated. The organic layers were combined, and 2 L of H2O was added. After stirring for 15 min, the layers were separated, and the organic layer was concentrated under vacuum to 2 vol. 2-propanol (5 vol.) was added and the resultant mixture was stirred, before concentrating under vacuum to 0.875 vol. and adding H2O (1 vol ). The mixture was stirred and heated to about 60 °C. In a separate vessel, 0.421 kg of fR)-mandelic acid was mixed with 0.22 L of 2-propanol and 0.645 L of H2O. and the mixture was heated to about 50 °C. The mandelic acid solution at a temperature of about 45 °C to about 50 °C was added to the reaction mixture heated to a temperature of about 60 °C. After complete addition of the mandelic acid solution, the reaction mixture was cooled to aboutacid (Salt 1.13) in 0.016 L of 2-propanol was added. The reaction mixture was maintained for 6 h at about 35 °C before cooling to about 10 °C at a ramp of 10 °C / h. The reaction mixture was maintained at about 10 °C for at least 6 h before filtering using an agitated filter dryer. The solid was washed with 0.9 L of 2-propanol (allowing for percolation before expunging) and vacuum dried at about 50 °C.(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)piperidine • (A)-mandelic acid (Salt 1.13) with 2.33 L of 2-propanol, stirring, cooling to about 10 °C. and wet grinding the suspension at about 10 °C. The suspension was wet grinded using an Ultra Turrax®Magic LAB® at 16000 revolutions per minute (rpm) and 3x6F grinders with the reaction volume recirculated 6 times to give a suspension wherein -50% of the population had a size of -20 pm.

[0360] Compound 1.14. Phenyl isoxazol-3-ylcarbamate

[0361] To a solution of 3-aminoisoxazole (0.190 kg, 2.26 mol) in acetonitrile (1.9 L. 10 vol.) was added pyridine (0.214 kg, 2.71 mol). After cooling the mixture to about 0 °C, a solution of phenyl chloroformate (CICOOPh; 0.353 kg, 2.26 mol) in acetonitrile (1.9 L, 10 vol.) was added over 3 h. The mixture was concentrated under vacuum (6 vol.) and H2O (3.8 L, 20 vol.) was added over 1.5 h at about 20 °C. The solution was filtered, washed with H2O (0.950 L, 5 vol.) four times, and dried to obtain 0.4489 kg (2.198 mol) of phenyl isoxazol-3- ylcarbamate (Compound 1.14) as a white solid.

[0362] Compound 1.15. (R)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide

[0366] Dichloromethane (DCM) (903.8 kg) was charged into a 3,000 L glass-lined reactor (Reactor 1) and stirred for about 10 to 20 min. The mixture was sampled for Karl Fischer titration analysis, wherein the endpoint was determined when a sample possessed < 0.05 wt% of water based on the total weight of the mixture (i.e., the KF < 0.05%). At about 15 °C to 25 °C, / c / 7-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (179.2 kg, 177.2 kg corrected, 823 mol) and tosyl chloride (174.8 kg. 917 mol) were added to Reactor 1 through a solid addition funnel. After the addition, the solid addition funnel was rinsed with DCM (23.4 kg). At about 15 °C to about 25 °C, 4-dimethylamino-pyridine (DMAP) (5.0 kg, 41 mol) was added into Reactor 1 through a solid addition funnel. After the addition, the solid addition funnel was rinsed with DCM (23.4 kg).

[0367] The mixture was adjusted to about 10 °C to about 20 °C, and a solution of TEA (93.6 kg, 925 mol) was added into the mixture at about 10 °C to about 20 °C at a reference rate of 10 to 20 kg / h. The mixture was allowed to react at about 10 °C to about 20 °C. After 2 h, the mixture was sampled until reaction completion. At between about 10 °C to about 20 °C, TEA (85.6kg, 846 mol) was added into the mixture at a reference rate of 30 kg / h to 100 kg / h. At about 10 °C to about 20 °C, purified H2O (716.0 kg) was added into the mixture.

[0368] The mixture was adjusted to about 20 °C to about 30 °C. The mixture was allowed to react at about 20 °C to about 30 °C. After 3 h, the mixture was sampled until the tosylate species were hydrolyzed. The mixture was settled for not longer than 2 h until the mixture layered, followed by separation at about 20 °C to about 30 °C. During the separation, the organic layer was transferred to another glass-lined reactor (Reactor 2). Reactor 1 was rinsed with purified H2O (100.0 kg, 100.0 L), and the rinsing liquor was discharged.

[0369] A 0.7 N HC1 solution was prepared with HC1 (49.2 kg) and purified H2O (671.0 kg). At about 15 °C to about 25 °C. the 0.7 N H Cl solution was added into the organic layer of Reactor 2. The mixture was stirred for around 0.5 to 1 h at about 15 °C to about 25 °C andthen settled for not longer than 1 h until the mixture layered before separation. Reactor 2 was rinsed with purified H2O (99.0 kg. 99.0 L).

[0370] An additional 0.7 N HC1 solution was prepared with HC1 (49.2 kg) and purified H2O (677.0 kg). At about 15 °C to about 25 °C, the 0.7 N HC1 solution was added into the organic layer of Reactor 1. The mixture was stirred for about 0.5 to 1 h at about 15 °C to about 25 °C. The mixture was then allowed to settle for not longer than 1 h until the mixture layered, and the layers were separated. Reactor 1 was rinsed with DCM (100.0 kg. 75.19 L), and the rinsing liquor was discharged.

[0371] At about 15 °C to about 25 °C, purified H2O (718.0 kg, 718.0 L) was added into the organic layer and the mixture was stirred for about 0.5 to 1 h. The mixture was allowed to settle for not longer than 1 h until the mixture layered before separation at about 20 °C to about 30 °C. The aqueous layer was sampled for pH analysis, until a pH of 3 to 4 was observed.

[0372] The mixture was concentrated at T < ~45 °C, under reduced pressure (P < -0.05 MPa) until about 2.5 vol. to 3 vol. remained. The mixture was exchanged with nitrogen to 0 MPa. To the mixture, n-heptane (859.8 kg) was added at T < ~45 °C, and the mixture was concentrated at T < ~45 °C under reduced pressure until about 6.5 vol. to 7.5 vol. remained. The mixture was exchanged with nitrogen.

[0373] The mixture was cooled to about 18 °C to about 26 °C, at a reference rate of about3 °C to 6 °C / hour and then stirred for about 2 to 3 h. The mixture was further cooled to about -2 °C to 6 °C, at a reference rate of about 3 °C to 6 °C / hour. The mixture was stirred at about -2 °C to 6 °C for crystallization. The mixture was filtered with an agitating filter dryer. The filter cake was rinsed with n-heptane (234.6kg), and the product was dried at about 20 °C to about 30 °C to give a white solid (Compound 1.1; 287.2 kg, 286. 1 kg corrected. Yield: 93.4%, Purity: 99.8%, Assay: 99.62%).

[0374] Compound 1.2. tert-butyl 4-((acetylthio)methyl)piperidine-l-carboxylate

[0375] N,N-Dimethylformamide (DMF; 1279.0 kg) was charged into an 8,000 L glass-lined reactor (Reactor 1) and stirred for about 10 min to 20 min. The mixture was sampled for KF analysis until KF < 0. 1 wt.%. The mixture was adjusted to about 15 °C to about 25 °C. To the mixture, te / 7-butyl 4-((tosyloxy)methyl)piperidine-l -carboxylate (Compound 1.1; 275.8kg, 275.0 kg corrected. 744 mol) was added at about 15 °C to about 25 °C. At about 15 °C to about 25 °C, potassium thioacetate (KSAc; 110.2 kg, 945 mol) was added into the mixture. After addition, supplemental DMF (26.0 kg) was charged, and the mixture was heated to about 40 °C to about 50 °C. The mixture is allowed to react at about 40 °C to about 50 °C. After 2 h, the mixture was sampled until the reaction was complete.

[0376] The mixture was cooled to about 15 °C to about 25 °C. At about 15 °C to about 25 °C, purified H2O (1375.0 kg. 1375.0 L) was added into Rector 1 and stirred for 1 h. Methyl tert-butyl ether (MTBE; 1018.6 kg) was added into Reactor 1. The mixture temperature was adjusted to about 15 °C to about 25 °C, and the mixture was stirred for about 0.5 h to 1 h at about 15 °C to about 25 °C. The mixture was then allowed to settle for at least 1 h until the mixture layered before separation. MTBE (1018. 1 kg) was added into the aqueous layer. The resultant mixture was adjusted to about 15 °C to about 25 °C, and the mixture was stirred for about 0.5 h to 1 h at about 15 °C to about 25 °C. The mixture was then allowed to settle for at least 1 h until the mixture layered before separation. The organic layers were combined into Reactor 1. The drum was rinsed with MTBE (41.8 kg).

[0377] Purified H2O (1375.0 kg) was added into the organic layer, and the mixture was adjusted to about 15 °C to about 25 °C. The mixture was stirred for around 0.5 h to 1 h at about 15 °C to about 25 °C and then settled for at least 1 h until the mixture layered before separation. This was repeated two more times.

[0378] At about 15 °C to about 25 °C. the mixture Reactor 1 was circulated through charcoal, and after about 6 h to 8 h, the mixture was colorless or light yellow. The cartridge was rinsed with MTBE (82.6 kg), and the rinsing liquor was transferred into Reactor 1. The mixture was concentrated at T < ~40 °C under reduced pressure until 1.5 vol. to 2.0 vol. (412.5 L to 550 L) remained.

[0379] At T < ~40 °C, n-BuOH (668.4 kg) was added into the mixture. The mixture was concentrated at T < ~55 °C under reduced pressure to give a light-yellow liquid (Compound 1.2; Weight: 583.8 kg, 206.1 kg corrected. Yield: 97.1%, Purity: 98.9%, Assay: 52.86%).

[0380] Compound 1.5b. 3-(difluoromethyl)-4-iodo-l-methyl-lff-pyrazole

[0381] Acetonitrile (MeCN; 391.2 kg) was charged into a 3,000 L glass-lined reactor (Reactor 1) and then stirred for about 10 min to 20 min. The acetonitrile was sampled for KF analysis until KF < 0.1%. The temperature was adjusted to about 15 °C to about 25 °C, and 3-(difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid (Compound 1.4; 107.0 kg, 105.9 kg, 601 mol) was added into the mixture. After addition, acetonitrile (17.0 kg) was transferred into the Reactor 1. To the mixture, sodium bicarbonate (50.4 kg) and sodium periodate (19.6 kg) were added. Iodine (464.0 kg, 1828 mol) was added into the resultant mixture at about 15 °C to about 25 °C with vigorous stirring. Additional acetonitrile (17.4 kg) was charged as a rinse.

[0382] The mixture was heated to about 55 °C to about 65 °C slowly, and nitrogen was bubbled intermittently. The mixture was controlled to react at about 55 °C to about 65 °C. After 2 h, the mixture was slowly heated to about 70 °C to about 80 °C. The mixture was controlled to react at about 70 °C to about 80 °C. After 2 h, the mixture was sampled until reaction completion. Then, the mixture was cooled to about 10 °C to about 20 °C.

[0383] Sodium carbonate-sodium sulfite solution was prepared with sodium carbonate (129.0 kg), sodium sulfite (230.2 kg), and purified H2O (1712.0 kg). At about 10 °C to about 30 °C, Sodium carbonate-sodium sulfite solution was added into the mixture to quench the reaction. After quenching, the mixture was stirred for at least 2 h until the mixture color became light yellow or colorless. The mixture was adjusted to about 30 °C to about 35 °C and stirred for 1 h until there was no solid in the lower aqueous layer.

[0384] At about 30 °C to about 35 °C, the mixture in Reactor 1 was transferred into an 8,000 L glass-lined reactor (Reactor 2). After transferring, Reactor 1 was rinsed with MTBE (555.7 kg), and the mixture was transferred into Reactor 2. The mixture was adjusted to about 30 °C to about 35 °C. The mixture was stirred for about 0.5 h to 1 h at about 30 °C to about 35 °C and then allowed to settle for at least 1 h. The layers were separated, and the organic layer was adjusted to about 15 °C to about 25 °C.

[0385] A sodium sulfite solution was prepared with sodium sulfite (27.0 kg) and purified H2O (539.0 kg), and the sodium sulfite solution was added into organic layer at about 15 °C to about 25 °C. After quenching, the mixture was stirred for at least 1 h until the mixture color became light yellow or colorless. The mixture was allowed to settle for at least 1 h and was separated. Purified H2O (534.0 kg) was added into the organic layer, the temperature was adjusted to about 15 °C to about 25 °C, and the layers were separated.

[0386] The mixture was concentrated at T < ~40 °C under reduced pressure until about 1.0 vol. to 2.0 vol. (107 L to 214 L) remained. MTBE was added and the mixture concentrated until the mixture KF < 1.0 wt.%. The mixture was then concentrated further under reduced pressure to dryness. The mixture was sampled for residual acetonitrile and residual MTBE to confirm that the residual acetonitrile was < 4.0 wt.% and the residual MTBE was < 4.0 wt.%.The mixture was transferred into un-lined steel drums, and the glass-lined reactor was rinsed with 1 -butanol (n-BuOH; 17.2 kg). The rinsing liquid was combined with the intermediate.The appearance was a light-yellow liquid (Compound 1.5b; Weight: 161.2 kg, 147.2 kg corrected, Purity7: 98.5%, Potency (wt.%): 91.31%, Yield: 94.8%).

[0387] Compound 1.6. tert-butyl 4-(((3-(difhioromethyl)-l-methyl-lH-pyrazol-4- yl)thio)methyl)piperidine-l-carboxylate

[0388] 1 -Butanol (n-BuOH; 471.2 kg) was charged into a 3,000 L glass-lined reactor (Reactor 1) and then stirred for about 10 min to 20 min. The mixture was sampled for KF analysis until KF < 0.2%. The mixture was adjusted to about 10 °C to about 30 °C. A solution of tert-butyl 4-((acetylthio)methyl)piperidine-l -carboxylate (Compound 1.2; 510.0 kg, 197.7 kg corrected, 723 mol) in n-BuOH was added into the mixture at about 10 °C to about 30 °C. The drum and charge line were rinsed with n-BuOH (12.2 kg), and the rinses were transferred into Reactor 1 . To the mixture, anhydrous sodium carbonate (125.0 kg) was added into the mixture at about 10 °C to about 30 °C and a rinse of n-BuOH (12.2 kg) was performed. The mixture was bubbled with nitrogen from the bottom valve for about 1 h to 1.5 h until the system was free of oxygen.

[0389] The mixture was heated to about 110 °C to about 125 °C (target: 115 °C), and nitrogen was bubbled intermittently. The mixture was allowed to react at about 110 °C to about 125 °C. After 16 h, the mixture was sampled until reaction completion. The mixture was cooled to about 10 °C to about 30 °C. To the mixture, 3-(difluoromethyl)-4-iodo-l- methyl-177-pyrazole (167.0 kg, 151.65 kg corrected, 588 mol) was added at about 10 °C to about 30 °C, and a rinse of n-BuOH (12.2 kg) w as performed.

[0390] Cuprous iodide (Cui; 22.8 kg) was added into the mixture, and then a rinse of n-BuOH (12.0 kg) was performed. The mixture was degassed with N2 from the bottom valvefor about 1 h to 1.5 h until the system was free of oxygen. The mixture was heated to about 110 °C to about 125 °C (target: 115 °C) and allowed to react. After 16 h. the mixture was sampled until the reaction was complete. The mixture was cooled to about 15 °C to about 25 °C.

[0391] To the mixture, n-heptane (506.4 kg) and purified H2O (757.0 kg) were added at about 15 °C to about 25 °C. The mixture was stirred for not longer than 0.5 h. The mixture was filtered over celite and rinsed with n-BuOH (153.4 kg) and collected in an 8.000 L glass- lined reactor (Reactor 2).

[0392] The mixture in Reactor 2 was stirred at about 15 °C to about 25 °C and then settled and separated. The upper organic layer was left in Reactor 2. Purified H2O (456.0 kg) was added into Reactor 2. Ammonium hydroxide (135.8 kg) was added slowly to Reactor 2. and the actual adding rate was controlled according to the temperature. The mixture was stirred for not longer than 0.5 h.

[0393] A potassium peroxymonosulfate solution was prepared with potassium peroxymonosulfate (605.0 kg) and purified H2O (143.8 kg), and 1 / 4 of the potassium peroxymonosulfate solution (187.4 kg) was added into the mixture in Reactor 2. The mixture was stirred for not longer than 1 h, and the mixture was sampled via inductively coupled plasma mass spectrometry (ICP-MS) until residual Cu was < 30 ppm. The mixture was settled for at least 1 h until the mixture layered before separation at about 15 °C to about 25 °C, and the upper organic layer was left in Reactor 2.

[0394] A sodium fluoride solution was prepared with sodium fluoride (22.8 kg) and purified H2O (757.0 kg). The sodium fluoride solution was added into Reactor 2 and stirred for about 0.5 h to 1 h. The mixture was allowed to settle for at least 1 h until the mixture layered before separation. The organic layer was sampled for oxidability analysis until the oxidability < 0.5 mg / L.

[0395] Reactor 1 was rinsed with purified H2O (152.0 kg), and the mixture in Reactor 2 was transferred into Reactor 1 through a filter. The mixture in Reactor 1 was concentrated at T < ~50 °C under reduced pressure until about 1.5 vol. to 2.5 vol. (227.5 L to 379.1 L) remained. To the mixture, n-heptane (about 528.2 kg to 529.2 kg) was added into the mixture and the mixture was sampled for residual n-BuOH until the residual n-BuOH was < 5 wt.%.

[0396] The mixture was adjusted to about 40 °C to about 50 °C, and the mixture was stirred at this temperature for 1 h. The mixture was cooled to about 20 °C to about 30 °C. The mixture was stirred at about 20 °C to about 30 °C (target: 25 °C) for crystallization.

[0397] The mixture was filtered with a filter. Reactor 1 was rinsed with n-heptane (210.0kg) and the filter cake was rinsed with n-heptane. The product was dried at about 40 °C to give an off-white solid (Compound 1.6; Weight: 183.2 kg, 182.9 kg corrected. Purity: 99%, Potency (wt.%): 99.81%, Yield: 86.1%).

[0399] Acetonitrile (638.7 kg) was charged into a 3,000 L hastelloy reactor (Reactor 1) and stirred for about 10 min to 20 min. The mixture was sampled for KF analysis until KF < 0.1%. The mixture was adjusted to about 10 °C to about 30 °C. To the mixture, / c / 7-butyl 4- (((3 -(difluoromethyl)- 1 -methyl- 17 / -pyrazol-4-yl)thio)methyl)piperidine-l -carboxylate (173.2 kg, 172.9 kg corrected, 478 mol) was added at about 10 °C to about 30 °C and rinsed with acetonitrile (13.8 kg). Diethylaminosulphur trifluoride (DAST; 30.8 kg, 191 mol) was added into the mixture slowly at about 10 °C to about 30 °C, and then a rinse (of funnel) with acetonitrile (7.0 kg) was performed. The mixture was cooled to about -5 °C to about 5 °C. Select-Fluor (l-(Chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate) (219.8 kg, 620 mol) was added portion-wise into the mixture at about -5 °C to about 5 °C and rinsed with acetonitrile (13.8 kg). After addition, nitrogen was bubbled into the mixture intermittently from the lower port. The mixture in Reactor 1 was adjusted to about -10 °C to about -5 °C.

[0400] TEA (72.8kg, 719 mol) was added into the mixture slowly at a reference rate of about 12 to 15 kg / h at about -10 °C to about -5 °C then rinsed with acetonitrile (7.0 kg). The mixture was allowed to react at about -5 °C to about 5 °C. After 8 h, the mixture was sampled until the reaction was complete.

[0401] DCM (692.4 kg) and purified H2O (866.0 kg) were added into the mixture in Reactor 1 at about -5 °C to about 10 °C. The mixture was adjusted to about 15 °C to about 25 °C. The mixture in Reactor 1 was stirred for about 1 h to 2 h and settled for at least 1 h. Then, the layers were separated. The lower organic layer was transferred into a 12,500 L glass- lined reactor (Reactor 2) for temporary storage. The upper aqueous layer was left in Reactor 1 for temporary’ storage.

[0402] DCM (1609.1 kg) was added into the mixture in Reactor 1 at about 15 °C to about 25 °C, stirred for about 1 h to 2 h and settled for at least 1 h. The layers were separated. The lower organic layer was washed three times with purified H2O (865.0 kg) using Reactor 1 and another glass-lined reactor (Reactor 3).

[0403] Reactor 3 was rinsed with DCM (114.2 kg) and all organic streams were combined in Reactor 2. Purified H2O (865.0 kg) was added into the mixture in Reactor 2 at about 15 °C to about 25 °C, stirred for about 0.5 h to 1 h, and settled for at least 1 h until the mixture layered before separation, with the separated organic layer being collected in Reactor 3. The organic layer in Reactor 3 was transferred into Reactor 2 and rinsed with DCM (214.2 kg).

[0404] The mixture in Reactor 2 was adjusted to about 10 °C to about 20 °C. To the mixture, ruthenium(III)chloride trihydrate (0.67 kg) was added at about 10 °C to about 20 °C and rinsed with purified H2O (17.0 kg). A sodium periodate solution was prepared with sodium periodate (203.0 kg) and purified H2O (2474.0 kg). The sodium periodate solution was added into the mixture at a reference rate of about 300 to 700 kg / h and rinsed with purified H2O (86.6 kg).

[0405] The mixture was allowed to react at about 10 °C to about 20 °C. After 8 h, the mixture was sampled until reaction completion. An additional sodium periodate solution (18.0 kg + 3.4 kg) was added into the mixture, followed by a rinse with purified H2O (17.4 kg x 2), and further aging to achieve reaction completion.

[0406] After reaction completion, the mixture was filtered over celite and then rinsed with DCM (459.0 kg) and collected in Reactor 3. The mixture was stirred for about 20 min to 30 min at about 15 °C to about 25 °C and then settled for not longer than 1 h before separation. The lower organic layer was transferred into Reactor 2. The mixture in Reactor 2 was adjusted to about 15 °C to about 25 °C, and then a sodium sulfite solution was added. The sodium sulfite solution was prepared with purified H2O (779.0 kg) and sodium sulfite (87.0 kg).

[0407] Celite filtration was performed on the mixture, followed by a rinse of DCM (467.2 kg). The mixture in Reactor 3 was stirred for about 20 min to 30 min at about 15 °C to about 25 °C. The mixture was allowed to settle, and the layers were separated. The lower organic layer was tested for oxidability analysis until oxidability < 0.5 mg / L.

[0408] The mixture was transferred into Reactor 1. The mixture was concentrated at T < ~40 °C under reduced pressure until about 2.0 vol. to 3.0 vol. (about 346.4 L to 519.6 L) remained. Anhydrous EtOH (686.3 kg) was added into the mixture at T < ~40 °C until residual DCM was < 2.0% and residual acetonitrile was < 2.0%.

[0409] The mixture was adjusted to about 15 to about 25 °C. Purified H2O (346.8 kg) was added into the mixture slowly at a reference rate of about 100 kg / h to 170 kg / h. The mixture was stirred at about 15 °C to about 25 °C for crystallization. After 12 h, the mixture was filtered. Anhydrous EtOH (207.2 kg) and purified H2O (260.0 kg) were added into Reactor 1, and the temperature was adjusted to about 15 °C to about 25 °C. The mixture stirred for about 0.5 h to 1 h, filtered, and then the filter cake was rinsed with EtOH. The solid was dried at T < ~40 °C to yield an off-white solid (Compound 1.8b: Weight: 154.2 kg, 151.9 kg corrected, Purity: 99.3%, Potency (wt.%): 98.49%, Yield: 77.2%).

[0411] THF (536.4 kg) was added into a 3,000 L stainless steel reactor (Reactor 1). The mixture for KF analysis was sampled until KF < 0.05%. Toluene (835.4 kg) was then added into Reactor 1. To Reactor 1, tert-butyl 4-(((3-(difluoromethyl)-l-methyl-17f-pyrazol-4- yl)sulfonyl)fluoromethyl)piperidine-l -carboxylate (161.2 kg, 160.5 kg corrected, 390 mol) was added, followed by a rinse with THF (14.4 kg). The mixture was stirred until the solid dissolved completely. The solution was cooled to about -80 °C to about -70 °C and 1 M lithium bis(trimethylsilyl)amide (LiHMDS) in THF solution (313.0 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg). To the mixture, methyl iodide (CH3I; 44.4 kg) was added slowly. After addition, the charging pipe was rinsed withTHF (6.4 kg), and the rinsing liquid was transferred into Reactor 1. The mixture in Reactor 1 was maintained at about -80 °C to about -70 °C with stirring for 2 h.

[0412] To a THF solution, 1 M LiHMDS (34.8 kg) was slowly added. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1. To the mixture, methyl iodide (5.4 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1. The mixture in Reactor 1 was maintained at about -80 °C to about -70 °C and stirred for 2 h.

[0413] To the mixture, 1 M LiHMDS in THF solution (28.6 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1. To the mixture, methyl iodide (4.4 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1.

[0414] To the mixture, 1 M LiHMDS in THF solution (2.6 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1. To the mixture, methyl iodide (0.4 kg) was added slowly. After addition, the charging pipe was rinsed with THF (6.4 kg), and the rinsing liquid was transferred into Reactor 1 and maintained at about -80 °C to about -70 °C. After 2 h, the mixture was sampled until the reaction was > 96% complete.

[0415] THF (128.4 kg) was added into a 500 L glass-lined reactor (Reactor 2). Acetic acid (46.4 kg) was added into the mixture, followed by rinsing with THF (14.4 kg). The resulting acetic acid-THF solution was added into the mixture in Reactor 1 at about -80 °C to about - 60 °C. The mixture was stirred for about 1 h to 2 h, and the mixture in Reactor 1 was subsequently adjusted to about -20 °C to about 25 °C.

[0416] The mixture in Reactor 1 was transferred into a 5,000 L glass-lined reactor (Reactor 3), followed by a rinse with THF (70.6 kg) and toluene (69.0 kg). The mixture in Reactor 3 was adjusted to about 15 °C to about 25 °C. A sodium sulfite solution was prepared with sodium sulfite (40.0 kg + 40.0 kg) and purified H2O (361.0 kg + 361.0 kg), and the sodium sulfite solution was added into the mixture in Reactor 3 at about 15 °C to about 25 °C. The mixture was stirred for about 20 min to 30 min at about 20 °C to about 30 °C. The mixture was allowed to settle for at least 1 h, and the layers were separated.

[0417] A sodium chloride (NaCl) solution was prepared with sodium chloride (80.4 kg + 80.4 kg) and purified H2O (321.0 kg + 321.0 kg), and the NaCl solution was added into theorganic layer at about 20 °C to about 30 °C. The mixture was stirred for about 20 min to 30 min at about 20 °C to about 30 °C. The mixture was then allowed to settle for at least 1 h, and the layers were separated.

[0418] The organic layer was circulated through charcoal at about 20 °C to about 30 °C until the mixture was light yellow. The charcoal was rinsed with THF (70.6 kg). The mixture was concentrated at T < ~40 °C under reduced pressure until about 1.5 vol. to 2.5 vol. (204.8 L to 401.3 L) remained, followed by nnsing with anhydrous EtOH (62.6 kg). Anhydrous EtOH (253.4 kg) was added into the mixture at T < ~40 °C. The mixture was concentrated at T < ~40 °C under reduced pressure until about 1.5 vol. to 2.5 vol. (204.8 L to 401.3 L) remained. Anhydrous EtOH (253.4 kg) was added into mixture until the volume was about 6.5 vol. to 7.0 vol. Distillation with ethanol was repeated until the residual THF was < 0.5% and the residual toluene was < 1.0%. Anhydrous EtOH (162.2 kg) was added into mixture until the volume was about 5.0 vol. to 5.5 vol. (802.5 L to 882.8 L).

[0419] The mixture was adjusted to about 55 °C to about 65 °C. The mixture was stirred for not longer than 1 h until the mixture dissolved. The mixture was transferred into a 3,000 L glassdined reactor through a liquid material filter. The reactor was rinsed with anhydrous ethanol (150.2 kg).

[0420] The mixture was adjusted to about 37 °C to about 43 °C. Purified H2O (802.6 kg) was added into the mixture. The mixture was cooled to about 10 °C to about 16 °C slowly and held for 2 h. The mixture was filtered, and the cake was rinsed with a solution prepared with anhydrous EtOH (127.0 kg) and purified H2O (161.0 kg). The solid was dried and then recrystallized from EtOH and H2O to give a white solid (Compound 1.11: Weight: 119.0 kg, 119.0 kg corrected, Assay, (wt.%): 101.22%, Yield: 71.7%).

[0422] Boc-deprotection: In a glass-lined reactor (Reactor 1), tert-butyl 4-(l-((3- (difluoromethy 1)- 1 -methyl- I H-pyra / ol-4-yl )sul fony I )- 1 -fluoroethyl)piperidine-l -carboxylate (reference material, 80 kg, 188 mol), 2-propanol (2.00 vol.), and H2O (1.00 vol.) were charged. To Reactor 1, 3N HC1 (2.50 eq.) was also charged. The suspension was heated to about 50 °C and stirred at this temperature for 4 h. Gaseous products (CO2, isobutylene) evolved during stirring, and the reaction mixture turned into a clear solution. Once the reaction was complete, the mixture was cooled to about 20 °C. To the mixture, isopropyl acetate (3.00 vol.) was added, and the internal temperature was adjusted to Ti = ~20 °C. To Reactor 1, 3N sodium hydroxide (NaOH) solution (3.30 eq.) was charged, keeping the internal temperature Ti = ~20 °C. The biphasic mixture was stirred for 30 min, and then agitation was stopped. The layers settled, and the lower aqueous layer was discarded. H2O (3.00 vol.) was charged over the organic layer, and the biphasic mixture was stirred for 30 min. After, agitation was stopped, and the layers were allowed to settle. The lower aqueous layer was discarded.

[0423] Solvent swap: The organic layer was concentrated in vacuo down to 1.70 vol., keeping the temperature Ti = ~20 °C to ~35 °C. To Reactor 1, 2-propanol (5.00 vol.) was charged, and the organic layer was concentrated in vacuo (~80 mbar) down to -1.70 vol., keeping the temperature Ti = -20 °C to -35 °C. The charging of 2-propanol and concentration in vacuo was repeated until isopropyl acetate was not more than 1% volume.suspension stirred at this temperature for 3 h. Finally, the suspension was cooled to Ti = ~5 °C in 3 h, and the suspension was stirred at this temperature for 3 h. The suspension was filtered, and the filter cake was washed with 2-propanol (5.00 vol.) that was cooled to Ti = ~5 °C. The wet filter cake was dried in vacuo (Dry product mass was 39.5 kg; yield was 40%).

[0426] Salt 1.13 (also referred to herein as a chiral acid salt of Formula (IX)) was analyzed by x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), liquid chromatography-mass spectrometry (LCMS), and 1H nuclear magnetic resonance (NMR) spectroscopy. XRPD data for Salt 1.13 is shown in FIG. 4. DSC and TGA thermograms are shown in FIG. 5. LCMS for Salt 1.13 is shown in FIG. 6. 1H NMR for Salt 1.13 is shown in FIG. 7.

[0427] Compound 1.14. Phenyl isoxazol-3-ylcarbamate

[0428] Into a reactor (Reactor 1), 3-aminoisoxazole (1.00 eq., 10.5 kg, 125 mol) and dry acetonitrile (4.00 vol.) were charged. At Ti = ~10 °C to ~25 °C, Reactor 1 was loaded with pyridine (1.20 eq.) and acetonitrile (1.00 vol.). The mixture was cooled to Ti = — 5 °C to~5 °C, and a previously prepared solution of phenyl chloroformate (1.00 eq., 125 mol) in acetonitrile (3.50 vol.) was slowly transferred. The line was rinsed with acetonitrile (1.50 vol.). The mixture was stirred for 1 h at T = —5 °C to ~5 °C), and a sample was taken to confirm reaction completion. Into Reactor 1, purified H2O (10.00 V) was added over not longer than 1 h, and the temperature was allowed to increase to T; = ~2 °C to ~8 °C. The mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed with purified H2O (3 x 5.00 vol.). The wet solid was dried under vacuum at Tj = ~50 °C to give a white solid (Compound 1.14: 87 % yield).(1.00 eq., 43 kg, 90 mol) was suspended in acetonitrile (3.00 vol.) at Ti = ~20 °C and phenyl isoxazol-3-ylcarbamate (94.5 mol. 1.05 eq.) was loaded. The line was rinsed with acetonitrile (0.50 vol.). Diisopropylethylamine (DIPEA) (1.40 eq.) was added, and the line was rinsed with acetonitrile (0.50 vol.). The mixture was heated to T = ~40 °C and stirred at that temperature for not longer than 1 h. Once the reaction was complete, purified H2O (0.90 V) was loaded over not longer than 15 min, keeping Ti = ~40 °C. The mixture was cooled to Ti = ~30 °C over not longer than 15 min. The solution was polish filtered, and the filter was rinsed with a mixture of acetonitrile (0.50 vol.) and purified H2O (0. 10 vol.). Purified H2O (3.00 vol.) was charged over not longer than 30 min at Ti = ~30 °C, and then the mixture was cooled to Ti = ~20 °C over not longer than 15 min. The mixture was seeded at that temperature with (KJ-4-(l-((3-(difluoromethyl)-l-methyl-U7-pyrazol-4-yl)sulfonyl)-l- fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (5 wt.%) and agitated for not longer than 2 h. Purified H2O (6.50 vol.) was charged over 6.5 h. The mixture was stirred for not longer than 8 h. The batch was wet milled at Ti = ~20 °C, and particle size distribution was sampled. The mixture was held for not longer than 1 h, and then the solid was isolated. The solid cake was washed with purified H2O (2 x 2.00 vol.) followed by with MTBE (2 x 2.00vol ). The wet solid cake was dried under vacuum to obtain the desired (R)-4-(l-((3- (difluoromethyl)- 1 -methyl- l#-pyrazol-4-yl)sulfbny 1)- 1 -fluoroethyl)-jV-(isoxazol-3- yl)piperidine-l -carboxamide (Compound 1.15, also referred to herein as a compound of Formula (I); 33.2 kg, assay = 99.8%, 85 % yield). A sample of the product was analyzed by XRPD and confirmed to be Form B.

[0431] Example 3. Recrystallization and Milling

[0432] Example 3.1. Compound 1.15 Purification 1. Recrystallization in MTBE and ACN

[0433] (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N- (isoxazol-3-yl)piperidine-l-carboxamide, prepared according to Example 1, was mixed with acetonitrile (4.38 vol.) and stirred at 120 W / m3. The mixture was heated to ~55 °C and MTBE (4.07 vol.) was added. The mixture was cooled to ~40 °C and a suspension of 5% (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N- (isoxazol-3-yl)piperidine-l-carboxamide seed crystal in MTBE (5% of total mass in 0.33 vol. of MTBE (158 g / L)) was added. The solution was maintained at ~40 °C for 30 min, then MTBE (13 vol., to give a working concentration 48 g / L) was added and the mixture cooled to -10 °C at a cooling rate of -10 °C / h. The mixture was fdtered at -10 °C using an agitated filter dryer equipped with 0.056 m GUEDU Blades. The expurgated product was stirred at 22 revolutions per minute (rpm; 0.032 m diameter stirring) for 5 h while equipped with a H2O cooling jacket to yield purified Form B of (A)-4-(l-((3-(difluoromethyl)-l-methyl-lH- pyrazol-4-yl)sulfonyl)-l -fluoroethyl)-N-(isoxazol-3-yl)piperidine-l -carboxamide with a particle size of 30 pm for 50% of the population.

[0434] To prepare the seed crystal, (A)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide was mixed with MTBE (2.47 vol.). The solution was run through an IKA Magic Lab Ultra-turrax grinding system set to 10 °C and 13,000-17,000 rpm (one pass) to give a particle size of about 15 pm for 50% of the population. The mixture was filtered and the solid dried while stirring at -45 °C.

[0435] Example 3.2. Compound 1.15 Purification 2. Recrystallization in H2O and ACN

[0436] (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N- (isoxazol-3-yl)piperidine-l -carboxamide was mixed with acetonitrile (4 vol.) and stirred at 120 W / m3. H2O (5 vol.) was added, and the mixture was heated to -70 °C. The mixture was cooled to -58 °C and a suspension of 5% (A)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide ground seed crystal in H2O (5% of total mass in 0.5 vol. of H2O (100 g / L)) was added followed by H2O (0.05 vol.). The solution was maintained at ~58 °C for 1 h, then cooled to ~10 °C at a cooling rate of -10 °C / h, filtered at ~10 °C using an agitated filter dryer, washed with H2O (2 x 2 vol.), washed with MTBE ( 2 x 2 vol.), and dried under reduced pressure with stirring to yield purified Form B of (A)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)- l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (78% yield, 99% purity) with a particle size of about 65 pm for 50% of the population.

[0437] To prepare the seed crystal, (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide was mixed with MTBE (2.47 vol.). The solution was run through an IKA Magic Lab Ultra-turrax grinding system set to 10 °C and 13,000-17,000 rpm (one pass) to give a particle size of about 15 pm for 50% of the population. The mixture was filtered and the solid dried while stirring at 45 °C.

[0438] Example 3.3. Compound 1.15 Purification 3. Recrystallization in H2O and ACN

[0440] To prepare the seed crystal, (R)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide was mixed with MTBE (2.47 vol.). The solution was run through an IKA Magic Lab Ultra-turrax grinding system set to 10 °C and 13,000-17,000 rpm (one pass) to give a particle size of about 15 pm for 50% of the population. The mixture was filtered and the solid dried while stirring at ~45 °C.

[0441] Example 3.4. Compound 1.15 Purification 4. Recrystallization in HzO and ACN

[0442] A solution of (J?)-4-(l-((3-(difluoromethyl)-l-metiiyl-lH-pyrazol-4-yl)sulfonyl)-l- fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (100 g) in acetonitrile (4 L, 4 vol.) was heated to 65 °C. H2O ( 5 L, 5 vol.) was added at ~65 °C. The mixture was cooled to ~55 °C and a 3% seed suspension of Form B of (J?)-4-(l-((3-(difluoromethyl)-l-methyl-lH- pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide was added in H2O (1 vol.). The mixture was stirred for 6 h at ~10 °C. After 6 h, the mixture was wet grinded for 30 min using Magic Lab Model DRX2000 / 05 with a 16,000 rpm grinding rate and 80 L / h flow rate. The suspension was then filtered using an agitated filter dryer at ~10 °C, washed with H2O (2 x 2 vol.) at ~10 °C, washed with MTBE (2 x 2 vol.), and dried under reduced pressure at ~45 °C to obtain pure Form B of (J?)-4-(l -((3 -(difluoromethyl)- 1- methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide wherein 50% of the population had a particle size of 11 pm or less.

[0443] To prepare the seed crystal, (7?)-4-(l-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide was mixed with MTBE (2.47 vol.). The solution was run through an IKA Magic Lab Ultra-turrax grinding system set to 10 °C and 13,000-17,000 rpm (one pass ) to give a particle size of about 15 pm for 50% of the population. The mixture was filtered and the solid dried while stirring at ~45 °C.

[0444] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.EQUIVALENTS AND SCOPE

[0445] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from thecontext. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members, are present in, employed in, or otherwise relevant to a given product or process.

[0446] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments and implementations of the invention or aspects of the invention consist, or consist essentially of. such elements and / or features. For purposes of simplicity, those embodiments and implementations have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary’ skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments and implementations of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0447] This application refers to various issued patents, published patent applications, j oumal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any one of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0448] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments and implementationsdescribed herein. The scope of the present embodiments and implementations described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a chiral acid salt of Formula (IX)with a compound of Formula (III)or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted C1-8alkyl or a substituted or unsubstituted aryl, in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the base of step (a) comprises N,N- diisopropylethylamine (DIPEA), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(0H)2), calcium hydroxide (Ca(0H)2), strontium hydroxide (Sr(OH)2), barium hydroxide (Ba(0H)2), ammonium hydroxide (NH4OH), or any combination thereof.

3. The method of claim 1 or 2, wherein the base of the step (a) is DIPEA.

4. The method of any one of claims 1 -3, wherein step (a) takes place in the presence of a solvent, and wherein the solvent is acetonitrile (MeCN).

5. The method of any one of claims 1-4, wherein R1is unsubstituted aryl.

6. The method of any one of claims 1-5, further comprising:(b) recrystallizing the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein step (b) comprises:(b-1) heating the compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first solvent to a temperature of about 55 °C to about 75 °C to form a first heated mixture.

8. The method of claim 7, wherein the first solvent comprises acetonitrile (MeCN).

9. The method of claim 7 or claim 8, wherein step (b) further comprises:(b-2) adding a second solvent to the first heated mixture to form a second mixture.

10. The method of claim 9, wherein the second solvent comprises water, methyl tert-butyl ether (MTBE), or any combination thereof.

11. The method of claim 9 or claim 10, wherein step (b) further comprises:(b-3) reducing the temperature of the second mixture by about 5 °C to about 15 °C.

12. The method of claim 11, wherein step (b) further comprises:(b-4) seeding the second mixture with seed crystals of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1-12, further comprising(c) contacting a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, with (7?)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

14. The method of claim 13, wherein the solvent of step (c) comprises 2-propanol.

15. The method of claim 13 or claim 14, wherein step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and (7?)-mandelic acid with seed crystals of the chiral acid salt of Formula (IX).

16. The method of any one of claims 13-15, further comprising:(d) recrystallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

17. The method of claim 16, wherein the solvent of step (d) comprises water, 2-propanol, or any combination thereof.

18. The method of claim 17, wherein the solvent of step (d) comprises about 25% 2-propanol and about 75% water.

19. The method of any one of claims 13-18, further comprising(e) contacting a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form the compound of Formula (II-R-A), or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxycarbonyl (BOC); 9- fluorenylmethyloxycarbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p-methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); tri chloroethyl chloroformate (troc); a sulfonamide; and a carbamate.

21. The method of claim 20, wherein R2is a BOC protecting group.

22. The method of any one of claims 19-21, wherein the strong acid of step (e) is hydrochloric acid or trifluoroacetic acid.

23. The method of claim 22, wherein the strong acid of step (e) is hydrochloric acid.

24. The method of any one of claims 19-23, wherein the solvent of step (e) comprises water,2-propanol, or any combination thereof.

25. The method of claim 24, wherein the solvent of step (e) comprises water and 2-propanol.

26. A method of preparing a compound of Formula (XI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising two ordered reactions comprising:(g-1) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) to form a fluorinated compound or a pharmaceutically acceptable salt thereof; and(g-2) contacting the fluorinated compound or pharmaceutically acceptable salt thereof with an oxidizing reagent to form the compound of Formula (XI) or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the method takes place in the absence of N- fluorobenzensulfonimide (NFSI).

28. The method of claim 26 or 27, wherein R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyloxycarbonyl (BOC); 9- fluorenylmethyloxycarbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p-methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-m ethoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate.

29. The method of any one of claims 26-28, wherein R2is a BOC protecting group.

30. The method of any one of claims 26-29, wherein the fluorinating reagent of step (g-1) comprises l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate; l-fluoro-2,4,6-trimethyl pyridinium triflate; 1 -fluoropyridinium triflate; or any combination thereof.

31. The method of any one of claims 26-30, wherein the fluorinating reagent of step (g-1) is l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate.

32. The method of any one of claims 26-31 , wherein the oxidizing reagent of step (g-2) comprises hydrogen peroxi de / sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalic acid dehydrate / hydrogen peroxide, meta-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct, permanganate / manganese dioxide, ruthenium chloride hydrate / sodium periodate, oxone, or any combination thereof.

33. The method of any one of claims 26-32, wherein the oxidizing reagent of step (g-2) is ruthenium chloride hydrate / sodium periodate.

34. The method of any one of claims 26-33, wherein the fluorinated compound or pharmaceutically acceptable salt thereof of step (g-1) is a compound of Formula (XII)or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 26-34, wherein step (g-1) takes place in the presence of a base and a solvent.

36. The method of claim 35, wherein the base of step (g-1) comprises triethylamine (TEA); l,4-diazabicyclo[2.2.2]octane (DABCO); N-methyl morpholine; N,N-diisopropylethylamine (DIPEA); quinuclidine; pyridine; 2-methylpyridine; 2,6-dimethylpyridine; 2,6-di-tert- butylpyridine; or any combination thereof.

37. The method of claim 35 or 36, wherein the base of step (g-1) comprises TEA, DABCO, N-methyl morpholine, DIPEA, di isopropyl ethyl amine, or any combination thereof.

38. The method of any one of claims 35-37, wherein the base of step (g-1) is TEA.

39. The method of any one of claims 35-38, wherein the solvent of step (g-1) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof.

40. The method of any one of claims 35-39, wherein the solvent of step (g-1) is MeCN.

41. The method of any one of claims 26-40, wherein step (g-2) takes place in the presence of a solvent.

42. The method of claim 41, wherein the solvent of step (g-2) comprises acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, or any combination thereof43. The method of claim 41 or 42, wherein the solvent of step (g-2) is MeCN.

44. A method of preparing a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, the method comprising:(f) contacting a compound of Formula (XI)or a pharmaceutically acceptable salt thereof, with a methylating reagent to form a compound of Formula (IV) or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the methylating reagent of step (f) is CH3I.

46. The method of claim 44 or 45, wherein step (f) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS).

47. The method of any one of claims 44-46, wherein step (f) takes place in the presence of toluene.

48. The method of any one of claims 44-47, wherein the compound of Formula (XI) or a pharmaceutically acceptable salt thereof is prepared according to the method of any one of claims 26-44.

49. A method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(e-1) contacting a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a strong acid in the presence of a solvent to form a reaction mixture; and(e-2) contacting the reaction mixture of step (e-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the solvent of step (e-1) comprises 2-propanol, water, or any combination thereof.51 . The method of claim 49 or 50, wherein the strong acid of step (e-1) is hydrochloric acid (HC1).

52. The method of any one of claims 49-51, wherein the solvent of step (e-2) comprises isopropyl acetate.

53. The method of claim 49, further comprising(e-1 a) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e-la) to form a second reaction mixture.

54. The method of claim 53, further comprising:(e-3) adding water to the second reaction mixture of step (e-2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-4) separating the organic layer from the aqueous layer; and (e-5) concentrating the separated organic layer.

55. The method of any one of claims 49-54, wherein the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is prepared according to the method of any one of claims 45-49.

56. A method of preparing a chiral acid salt of Formula (IX)comprising:(c) contacting a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, with (7?)-mandelic acid in the presence of a solvent to form the chiral acid salt of Formula (IX).

57. The method of claim 56, wherein the solvent of step (c) comprises 2-propanol.

58. The method of claim 56 or 57, wherein step (c) further comprises seeding a reaction mixture comprising the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof and (7?)-mandelic acid with seed crystals of the chiral acid salt of Formula (IX).

59. The method of any one of claims 56-58, further comprising:(d) recrystallizing the chiral acid salt of Formula (IX) in the presence of a solvent.

60. The method of claim 59, wherein the solvent of step (d) comprises water, 2-propanol, or any combination thereof.

61. The method of claim 59 or 60, wherein the solvent of step (d) comprises about 25% 2- propanol and about 75% water.

62. The method of any one of claims 56-61, wherein the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof is prepared according to the method of any one of claims 50-56.

63. A method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(g-la) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of di ethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form the compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-1-1) contacting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof with a strong acid in the presence of a solvent to form a reaction mixture; and(e-1 -2) contacting the reaction mixture of step (e-1-1) with sodium hydroxide (NaOH) in the presence of a second solvent, without isolating the HC1 salt of the compound of Formula (IV), to form the compound of Formula (II-R-A).

64. The method of claim 63, further comprising(e-1-1 a) contacting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof with HC1 in the presence of 2-propanol and water to form a reaction mixture; and(e-l-2a) adding isopropyl acetate and NaOH to the reaction mixture of step (e-1- la) to form a second reaction mixture.

65. The method of claim 64, further comprising:(e-1-3) adding water to the second reaction mixture of step (e-l-2a) to form a biphasic mixture comprising an aqueous layer and an organic layer;(e-1-4) separating the organic layer from the aqueous layer; and(e-1-5) concentrating the separated organic layer.

66. The method of any one of claims 63-65, further comprising:(h-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is , with Compound 1.5aor a pharmaceutically acceptable salt thereof, in the presence of a palladium catalyst, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

67. The method of any one of claims 63-65, further comprising:(i-1) contacting a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc i with Compound 1.5bp , or a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, a base, and a solvent, to form the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, wherein the copper catalyst is selected from the group consisting of copper iodide, copper bromide, and copper chloride.

69. The method of claim 68, wherein the copper catalyst is copper iodide.

70. The method of any one of claims 67-69, wherein the base of step (i-1) is selected from the group consisting of sodium carbonate, potassium carbonate, and cesium carbonate.

71. The method of any one of claims 67-70, wherein the base of step (i-1) is sodium carbonate.

72. The method of any one of claims 67-71, wherein the solvent of step (i-1) is a protic solvent.

73. The method of claim 72, wherein the protic solvent is selected from a group consisting of IPA, n-BuOH, and ethanol.

74. The method of claim 72 or 73, wherein the protic solvent is n-BuOH.

75. The method of any one of claims 67-74, further comprising:(j) contacting a compound of Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is, with potassium thioacetate to form the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof.

76. The method of claim 75, further comprising:(k) contacting a compound of Formula (XVI)or a pharmaceutically acceptable salt thereof, with tosyl chloride to form the compound of Formula (XV) or a pharmaceutically acceptable salt thereof.

77. The method of claim 76, wherein step (k) takes place in the presence of dichloromethane (DCM), 4-dimethylaminopyridine (DMAP), and triethylamine (TEA).

78. The method of any one of claims 63-77, wherein the fluorinating reagent of step (g-1) comprises l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate, l-fluoro-2,4,6-trimethyl pyridinium triflate, 1 -fluoropyridinium triflate, or any combination thereof.

79. The method of any one of claims 63-78, wherein the fluorinating reagent of step (g-1) is l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate.

80. The method of any one of claims 63-79, wherein the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof is converted to the compound of Formula (XI) or apharmaceutically acceptable salt thereof without isolating the compound of Formula (XII) or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 63-80, wherein the oxidizing reagent of step (g-2) comprises sodium periodate.

82. The method of any one of claims 63-81, wherein the oxidizing reagent of step (g-1) further comprises ruthenium chloride hydrate.

83. The method of any one of claims 63-82, wherein the methylating reagent of step (f) is CH3I.

84. The method of any one of claims 63-83, wherein step (f) takes place in the presence of lithium bis(trimethylsilyl)amide (LiHMDS).

85. The method of any one of claims 63-84, wherein step (f) takes place in the presence of toluene.

86. The method of any one of claims 63-85, wherein R2is a protecting group selected from the group consisting of p-methoxybenzylcarbonyl (MeOZ); tert-butyl oxy carbonyl (BOC); 9- fluorenylmethyloxycarbonyl (FMOC); acetyl (Ac); benzoyl (Bz); benzyl (Bn); p-methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); trichloroethyl chloroformate (troc); a sulfonamide; and a carbamate.

87. The method of any one of claims 63-86, wherein R2is a BOC protecting group.

88. A method of preparing a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof, comprising:(k) contacting a compound of Formula (XVI)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with tosyl chloride to form a compound of Formula (XV)or a pharmaceutically acceptable salt thereof, wherein OTs is(j) contacting the compound of Formula (XV) or a pharmaceutically acceptable salt thereof with potassium thioacetate to form a compound of Formula (VIII)or a pharmaceutically acceptable salt thereof, wherein SAc is(i) contacting the compound of Formula (VIII) or a pharmaceutically acceptable salt thereof with Compound 1.5bp , or a pharmaceutically acceptable salt thereof, in the presence of a copper catalyst, to form a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof;(g-la) contacting the compound of Formula (XIII) or a pharmaceutically acceptable salt thereof with a fluorinating reagent in the presence of diethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2a) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof; and(e-x) deprotecting a compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof.

89. A method of preparing a compound of Formula (I)or a pharmaceutically acceptable salt thereof, comprising:(g-1) contacting a compound of Formula (XIII)or a pharmaceutically acceptable salt thereof, wherein R2is a protecting group, with a fluorinating reagent in the presence of di ethylaminosulfur trifluoride (DAST) and a base to form a compound of Formula (XII)or a pharmaceutically acceptable salt thereof;(g-2) contacting the compound of Formula (XII) or a pharmaceutically acceptable salt thereof with an oxidizing reagent to form a compound of Formula (XI)or a pharmaceutically acceptable salt thereof;(f) contacting the compound of Formula (XI) or a pharmaceutically acceptable salt thereof with a methylating reagent to form a compound of Formula (IV)or a pharmaceutically acceptable salt thereof;(e-x) deprotecting the compound of Formula (IV) or a pharmaceutically acceptable salt thereof to form a compound of Formula (II-R-A)or a pharmaceutically acceptable salt thereof;(c) contacting the compound of Formula (II-R-A) or a pharmaceutically acceptable salt thereof with (A)-mandelic acid in the presence of a solvent to form the chiral acid salt ofFormula (IX); and(a) contacting a chiral acid salt of Formula (IX) with a compound of Formula (III)wherein R1is substituted or unsubstituted C1-8alkyl or a substituted or unsubstituted aryl, in the presence of a base to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

90. A chiral acid salt of Formula (IX):91 . A crystalline form of a chiral acid salt of Formula (IX):

92. The crystalline form of claim 91, wherein the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, and 15.42 ± 0.2 in an X-ray powder diffraction pattern.

93. The crystalline form of claim 91 or claim 92, wherein the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.62 ± 0.2, 10.21 ± 0.2, 11.01 ± 0.2, 13.10 ± 0.2, 14.81 ± 0.2, 15.42 ± 0.2, 17.12 ± 0.2, 18.33 ± 0.2, 18.87 ± 0.2, 19.40 ± 0.2, 19.69 ± 0.2, 20.54 ± 0.2, 23.05 ± 0.2, 23.76 ± 0.2, 24.70 ± 0.2, 25.47 ± 0.2, 26.65 ± 0.2, 27.09 ± 0.2, 27.76 ± 0.2, 28.56 ± 0.2, 32.34 ± 0.2, and 33.37 ± 0.2 in an X-ray powder diffraction pattern.

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