Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof

Abstract

The present disclosure provides methods of making nicotinoyl riboside compounds or derivatives of formula (I): wherein X-, Z1, Z2, n, R1, R2, R3, R4, R5, R6, R7, and R8 are described herein, reduced analogs thereof, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof, and novel crystalline forms thereof.

Description

(19) *EP004744667A2* (11) EP 4 744 667 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 20.05.2026 Bulletin 2026 / 21 (21) Application number: 26166211.8 (22) Date of filing: 10.11.2017 (51) International Patent Classification (IPC): A61K 31 / 706 (2006.01) (52) Cooperative Patent Classification (CPC): C07H 19 / 048; C07D 307 / 20; C07H 19 / 20; C07H 19 / 04 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 11.11.2016 US 201662420737 P 13.09.2017 US 201762558073 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 17870568.7 / 3 538 099 (71) Applicants: • The Queen’s University Of Belfast Belfast, Antrim BT7 1NN (GB) • Chromadex, Inc. Irvine, CA 92618 (US) (72) Inventors: • MIGAUD, Marie Eugenie Lurgan, BT66 7HG (GB) • REDPATH, Philip Portadown, BT63 5SB (GB) • CROSSEY, Kerri Magherafelt, BT45 8QT (GB) • CUNNINGHAM, Richard Portadown, GT62 4DB (GB) • ERICKSON, Aron Longmont, 80504 (US) • NYGAARD, Richard Longmont, 80503 (US) • STORJOHANN, Amanda Westminster, 80020 (US) (74) Representative: FRKelly Waterways House Grand Canal Quay Dublin D02 PD39 (IE) Remarks: This application was filed on 19‑03‑2026 as a divisional application to the application mentioned under INID code 62. (54) EFFICIENT AND SCALABLE SYNTHESES OF NICOTINOYL RIBOSIDES AND REDUCED NICOTINOYL RIBOSIDES, MODIFIED DERIVATIVES THEREOF, PHOSPHORYLATED ANALOGS THEREOF, ADENYLYL DINUCLEOTIDE CONJUGATES THEREOF, AND NOVEL CRYSTALLINE FORMS THEREOF (57) The present disclosure provides methods of making nicotinoyl riboside compounds or derivatives of formula (I): wherein X-, Z1, Z2, n, R1, R2, R3, R4, R5, R6, R7, and R8 are described herein, reduced analogs thereof, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, sol- vates, or prodrugs thereof, and novel crystalline forms thereof. EP 4 74 4 66 7 A 2 Processed by Luminess, 75001 PARIS (FR) Description TECHNICAL FIELD

[0001] The present disclosure relates to synthetic processes for the preparation of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, the synthetic processes comprising processing of reagents by solvent-based processes, liquid-assisted mixing, milling, grinding, solvent-assisted grinding, and / or extrusion, and crystalline forms of nicotinamide riboside, in particular, nicotinamide riboside chloride, derivatives thereof, crystalline forms of nicotinic acid riboside, derivatives thereof, and crystalline forms of nicotinamide mononucleotide, and derivatives thereof. BACKGROUND

[0002] The dietary vitamin B3, which encompasses nicotinamide ("Nam" or "NM"), nicotinic acid ("NA"), and nicoti- namide riboside ("NR"), is a precursor to the coenzyme nicotinamide adenine dinucleotide ("NAD+"), its phosphorylated parent ("NADP+" or "NAD(P)+"), and their respective reduced forms ("NADH" and "NADPH," respectively). Once converted intracellularly to NAD(P)+ and NAD(P)H, vitamin B3 metabolites are used as co-substrates in multiple intracellular protein modification processes, which control numerous essential signaling events (e.g., adenosine dipho- sphate ribosylation and deacetylation), and as cofactors in over 400 redox enzymatic reactions, thus controlling metabolism. This is demonstrated by a range of metabolic endpoints, which include the deacylation of key regulatory metabolic enzymes, resulting in the restoration ofmitochondrial activity and oxygen consumption. Critically,mitochondrial dysfunction and cellular impairment have been correlated to the depletion of the NAD(P)(H)‑cofactor pool, when the NAD(P)(H)‑cofactor pool is present in sub-optimal intracellular concentrations. Vitamin B3 deficiency yields to evidenced compromised cellular activity through NAD(P)+ depletion, and the beneficial effect of additional NAD(P)+ bioavailability through NA, Nam, NR, and nicotinamide mononucleotide ("NMN") supplementation is primarily observed in cells and tissues where metabolism and mitochondrial function have been compromised.

[0003] Despite extensive optimization of solution-based methodologies over many years for nucleotide preparation, difficulties and issues remain in the syntheses of nicotinoyl ribosides, themonophosphorylation of active hydroxyl groups thereof, and subsequent conjugation thereof, with respect to low yields and product stability and isolation from polar solvents. Thecurrentmethodologiesarealsoplaguedbyatomandenergy inefficiencydue, for example, to theuseof large solvent excesses and the need for temperature-controlled reaction conditions.

[0004] The reported syntheses of nicotinamide riboside (NR) are becoming more scalable, but use corrosive and expensive reagents, and lengthy deprotection steps, and thus still display batch-to-batch quality variation, thereby presenting difficulties in maintaining good standards.

[0005] Partially protected nucleosides and nucleotides have found broad-ranging application in order to achieve improved bioavailability of the nucleoside and nucleotide parents. Such partial protection includes hydroxyl modifications with ester, carboxylate, and acetyl groups, in addition to the introduction of hydrolyzable phosphoramidate or mixed anhydride modification of the phosphate monoesters in the form of Protides and CycloSal derivatives. While the former type of protection has becomemore scalable, themodifications at the phosphorus center remain difficult to accomplish at scale, particularly on nucleosidic entities that are highly sensitive to changes in pH and that are readily degraded by heat.

[0006] Reduced nicotinamide riboside ("NRH") has been consistently shown to be more efficient at increasing intracellular NAD+ levels, and surpasses nicotinamide riboside (NR) in that respect. While physiological and potentially therapeutic roles have not yet been examined due to a lack ofmaterial accessible in sufficient quantities for broad-ranging studies, it is anticipated that the phosphorylated formsofNRHand reducednicotinic acid riboside ("NARH"), or derivatives thereof, could also have similar NAD+-boosting capacities.

[0007] The reported syntheses of reduced nicotinamide riboside (NRH) are becomingmorewidely available but remain conducted on small scales, using corrosive and expensive reagents, and lengthy deprotection steps, and thus still display batch-to-batch quality variation, thereby presenting difficulties in maintaining good standards. In the current description, reduced nicotinamide riboside (NRH) generally refers to "reduced pyridine" nucleus, more specifically, the 1,4-dihydro- pyridine compounds.

[0008] Synthetically, the preparation of 5’-nucleotides remains time-consuming, atom-inefficient, and costly, due to the need for numerous protection and deprotection steps. In these preparation methods, the chlorodialkylphosphate, tetraalkylpyrophosphate, chlorophosphite, or phosphoramidite reagents required are also expensive starting materials by virtue of their chemical functionalization and chemical instability, and therefore, consequently associated synthetic difficulties. Phosphorylation reaction conditions are difficult to control and often use non-approved or toxic organic solvents, thus limiting the market of the manufactured compounds.

[0009] One known alternative approach to the protection / deprotection method is to use phosphorus oxychloride (P(O) Cl3) (i.e., Yoshikawa conditions), however there are still drawbacks to this method, as follows. While not being bound by 2 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 theory, in this method, polar trialkyl phosphate solvents, such as P(O)(OMe)3, are used in a large excess, which are believed to enhance reaction rates while limiting the undesirable reactivity of P(O)Cl3 as a chlorinating agent. Thus, it is believed that use of excess P(O)Cl3 / P(O)(OR)3 is a better combination for the chemoselective 5’-O-phosphorylation of unprotected ribosides. However, the use of trialkyl phosphate solvents, such asP(O)(OMe)3, precludes their implementa- tion for the preparation ofmaterials for eventual humanuse, as this class of solvent is highly toxic (known carcinogen, non- GRAS approved) and is difficult to remove from the final polar products. See M. Yoshikawa et al., Studies of Phosphor- ylation. III. SelectivePhosphorylation ofUnprotectedNucleosides, 42BULL.CHEM.SOC. JAPAN3505 (1969); Jaemoon Lee et al., A chemical synthesis of nicotinamide adenine dinucleotide (NAD+), CHEM. COMMUN. 729 (1999); each of which is incorporated by reference herein in its entirety.

[0010] Nicotinamide adenine dinucleotide (NAD+) remains an expensive cofactor, and its commercial availability is simply limited by its complex chemical nature and the highly reactive pyrophosphate bond, which is challenging to form at scale.

[0011] Nicotinoyl ribosides such as nicotinamide riboside (NR) and nicotinic acid riboside ("NAR"), nicotinamide mononucleotide (NMN), and NAD+ are viewed as useful bioavailable precursors of the NAD(P)(H) pool to combat and treat a broad range of non-communicable diseases, in particular those associatedwithmitochondrial dysfunction and impaired cellular metabolism. Optimizing the large-scale syntheses of these vitamin B3 derivatives is therefore highly valuable to make these compounds more widely available to society both in terms of nutraceutical and pharmaceutical entities.

[0012] Reduced nicotinoyl ribosides, such as reduced nicotinamide riboside (NRH), reduced nicotinic acid riboside (NARH), reduced nicotinamide mononucleotide ("NMNH"), reduced nicotinic acid mononucleotide ("NaMNH"), and reduced nicotinamide adenine dinucleotide ("NADH") are viewed as useful bioavailable precursors of the NAD(P)(H) pool to combat and treat a broad range of non-communicable diseases, in particular those associated with mitochondrial dysfunction and impaired cellular metabolism. Optimizing the large-scale syntheses of these vitamin B3 derivatives is therefore highly valuable to make these compounds more widely available to society, both in terms of nutraceutical and pharmaceutical entities.

[0013] Crystalline forms of useful molecules can have advantageous properties relative to the respective amorphous forms of suchmolecules. For example, crystal forms are often easier to handle and process, for example, when preparing compositions that include the crystal forms. Crystalline forms typically have greater storage stability and are more amenable to purification. The use of a crystalline form of a pharmaceutically useful compound can also improve the performance characteristics of a pharmaceutical product that includes the compound. Obtaining the crystalline form also serves to enlarge the repertoire of materials that formulation scientists have available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0014] WO2016 / 014927A2, incorporated by reference herein in its entirety, describes crystalline forms of nicotinamide riboside, including aForm I of nicotinamide riboside chloride. Also disclosed are pharmaceutical compositions comprising the crystalline Form I of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions.

[0015] WO2016 / 144660A1, incorporated by reference herein in its entirety, describes crystalline forms of nicotinamide riboside, includingaForm II of nicotinamide riboside chloride.Alsodisclosedarepharmaceutical compositionscomprising the crystalline Form II of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions.

[0016] In view of the above, there is a need for processes that are atom-efficient in terms of reagent and solvent equivalency, that bypass the need for polar, non-GRAS ("generally recognized as safe") solvents, that are versatile in terms of limitations associated with solubility and reagent mixing, that are time‑ and energy-efficient, and that provide efficient, practical, and scalablemethods for the preparation of nicotinoyl ribosides, reduced nicotinoyl ribosides,modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof.

[0017] In view of the above, there is a need for novel crystalline forms of nicotinoyl ribosides, reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof. SUMMARY OF THE INVENTION

[0018] In an embodiment, the present disclosure relates to a synthetic sequence that enables the efficient production of nicotinoyl ribosides, derivatives thereof, phosphorylatedanalogs thereof, andadenylyl dinucleotide conjugates thereof, or salts, solvates, orprodrugs thereof, viaprocesses thatareenabledby theprocessingof reagentsby liquid-assistedmixing, grinding, milling, and / or extrusion.

[0019] In another embodiment, the present disclosure relates to a synthetic sequence that enables the efficient productionof reducednicotinoyl ribosides, derivatives thereof, phosphorylatedanalogs thereof, andadenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof, via processes that areenabledby theprocessingof reagents by liquid-assisted mixing, grinding, milling, and / or extrusion.

[0020] In yet another embodiment, the present disclosure relates to scalable methods of preparation of nicotinamide 3 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 riboside (NR) and nicotinic acid riboside (NAR), and derivatives thereof, or salts, solvates, or prodrugs thereof, by liquid assisted mixing and / or extrusion.

[0021] In yet another embodiment, the present disclosure relates to scalable methods of preparation of reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH), and derivatives thereof, or salts, solvates, or prodrugs thereof, by liquid-assisted mixing, grinding, and / or extrusion.

[0022] In yet another embodiment, the present disclosure relates to scalable methods of preparation of nicotinamide riboside triacetate ("NRTA") and nicotinic acid riboside triacetate ("NARTA"), and derivatives thereof, or salts, solvates, or prodrugs thereof, by liquid-assisted mixing, grinding, and / or extrusion.

[0023] In yet another embodiment, the present disclosure relates to scalable methods of preparation of reduced nicotinamide riboside triacetate ("NRH-TA") and reduced nicotinic acid riboside triacetate ("NARH-TA"), and derivatives thereof, or salts, solvates, or prodrugs thereof, by biphasic liquid-assisted mixing, grinding, and / or extrusion.

[0024] In yet another embodiment, the present disclosure relates to batch and semi-continuous processes that enable the production of nicotinamide riboside (NR) and nicotinic acid riboside (NAR), and triacetate derivatives thereof, or salts, solvates, or prodrugs thereof, whereby the use of solvents is kept to a minimum, and whereby conversion and reaction times are optimized by the use of sealed conditions, continuous liquid-liquid extraction, and / ormechanochemistry, and an optimized purification sequence.

[0025] In yet another embodiment, the present disclosure relates to batch and semi-continuous processes that enable the production of reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH), and triacetate derivatives thereof, or salts, solvates, or prodrugs thereof, wherein the use of solvents is kept to aminimum, andwhereby conversion and reaction times are optimized by the use of sealed conditions, continuous liquid-liquid extraction, and / or mechanochemistry, and an optimized purification sequence.

[0026] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including, but not limited to, a Form I of nicotinamide riboside chloride ("NR-Cl"), and methods of preparation thereof.

[0027] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including, but not limited to, a "NR methanolate Form II" of nicotinamide riboside chloride (NR-Cl), and methods of preparation thereof.

[0028] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside (NAR), including, but not limited to, a "Form I" of nicotinic acid riboside (NAR), and methods of preparation thereof.

[0029] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinamide, "NR triacetate," or "NRTA"), including, but not limited to, a "Form I" of nicotinamide riboside triacetate (NRTA) chloride, and methods of preparation thereof.

[0030] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinic acid, "NAR triacetate," or "NARTA"), including, but not limited to, a "Form I" of nicotinic acid riboside triacetate (NARTA), and methods of preparation thereof.

[0031] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide ("NMN"), including, but not limited to, a "Form III" of nicotinamide mononucleotide (NMN), and methods of preparation thereof. In yet another embodiment, the present disclosure relates to an amorphous solid form of nicotinamide mono- nucleotide (NMN), and methods of preparation thereof.

[0032] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide (NMN), including, but not limited to, a "Form IV" of nicotinamide mononucleotide (NMN), and methods of preparation thereof.

[0033] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (IV), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0034] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (IV-H), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0035] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (V), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0036] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (VI), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0037] In accordance with one embodiment, the present disclosure provides a novel method for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, such as nicotinoyl ribosides and their derivatives, and including but not limited to the triacetylated forms of NR-Cl (nicotinamide riboside chloride salt form) and NAR (nicotinic acid riboside) (compounds or derivatives having formula (I), wherein R6, R7, and R8 are each acetyl groups), and the fully deprotected forms thereof (compounds or derivatives having formula (I), wherein R6, R7, andR8 are each hydrogen), in commercial quantities. In accordance with such an embodiment, the present disclosure provides a novel method whereby mechanic forces and / or sealed conditions are used to minimize solvent and reagent quantities, decrease reaction times, increase overall conversion, and facilitate product purification in amultistep synthetic sequence, whereby by-product formation isminimized, andwhereby primarily by-products that can be removed readily by filtration or 4 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 evaporation are generated. Prototype product nicotinoyl riboside compounds include compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof: optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent, optionally the counterion is an internal salt; Z1 and Z2 are independently NH or oxygen; n is 0 or 1; R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, - NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; wherein when R1 is hydrogen, Z2 is oxygen, and n is 0, the compound or derivative having formula (I) may optionally take the form of the carboxylate anion conjugate species of the compound or derivative having formula (I), further optionally associatedwith a positively charged counterion selected from the group consisting of calcium,magnesium, potassium, sodium, zinc, and ammonium cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, -NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑SO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6) alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O) (C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O) O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, 5 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, -NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0038] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1), or salts thereof: wherein Z1 and Z2 are independently nitrogen or oxygen; m is 1 or 2; n is 0 or 1; each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero- aryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, - (C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, - ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, - NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, - S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; whereinwheneachR1 is hydrogen, Z2 is oxygen,m is 1, andn is 0, the compoundor derivative having formula (1)may optionally take the formof the carboxylateanion conjugatebasespeciesof the compoundor derivativehaving formula (1), further optionally associated with a positively charged counterion selected from the group consisting of calcium, 6 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 magnesium, potassium, sodium, zinc, and ammonium cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6) alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O) (C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑ NRCC(O) O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0039] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (2), or salts thereof: wherein X’ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, 7 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0040] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (2), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (2a), or salts thereof: wherein R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, sub- stituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O) NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2 (C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substi- tuted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O) 8 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, -OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6) alkylene-ORC; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, - (CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, - (CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), - CH2‑(4-hydroxyphenyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, sub- stituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1‑C4) alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R14 is methyl or phenyl; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0041] Generally, appropriate synthetic processes comprising batch processing or continuous processing of reagents by liquid-assisted mixing, milling, grinding, and / or extrusion are employed as described.

[0042] In accordance with an alternative embodiment, appropriate starting materials for the methods of the present disclosure for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1a), or salts thereof: wherein Z1 and Z2 are independently NH or oxygen; n is 0 or 1; R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; whereinwhenR1 is hydrogen, Z2 is oxygen, and n is 0, the compound or derivative having formula (1a)may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations; 9 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 RA is selected from the group consisting of ‑H, ‑(C1‑C8)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, - (CH2)2COOH, ‑CH2‑(2-imidazoly), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, - (CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), - CH2‑(4-hydroxy- phenyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; each of R2, R3, R4, and R5 is hydrogen; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0043] In accordance with yet another alternative embodiment, appropriate starting materials for the methods of the present disclosure for thepreparationof compoundsor derivatives having formula I, or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1b), or salts thereof: wherein Z1 and Z2 are independently nitrogen or oxygen; m is 1 or 2; n is 0 or 1; each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero- aryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, - (C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, - ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, - NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, - S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; wherein when each R1 is hydrogen, Z2 is oxygen, m is 1, and n is 0, the compound or derivative having formula (1b) may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (1b), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, - (CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, - (CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), - CH2‑(4-hydroxyphenyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, -NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; 10 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 each of R2, R3, R4, and R5 is hydrogen; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0044] In anembodiment, amethodofmakinga compoundor derivative having formula (2), or a salt thereof, can include the steps of: (a) providing a compound or derivative having formula (2a), or a salt thereof, wherein when R14 of the compound or derivative having formula (2a), or salt thereof, is methyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not acetoxy, andwherein when R14 of the compound or derivative having formula (2a) or salt thereof, is phenyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not acetoxy; (b) treating the compound or derivative having formula (2a), or salt thereof, with at least a stoichiometric amount of a Brønsted acid or a nucleophilic substitution reagent in the presence of at least a molar equivalent amount of a polar organic solvent co-reagent; (c) processing the compound or derivative having formula (2a), or salt thereof, the Brønsted acid or nucleophilic substitution reagent, and the polar organic solvent co-reagent so as to produce the compound or derivative having formula (2), or salt thereof; and (d) isolating the compound or derivative having formula (2), or salt thereof.

[0045] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing under sealed conditions, grinding, and extruding. The process described herein effects a preparation of a compound or derivative having formula (2), or salt thereof, under almost solventless conditions.

[0046] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (2), or salt thereof, individually, can be a polar organic solvent from among, for example, preferably, theClass 2Residual Solvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACO- PEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0047] In another embodiment, the nucleophilic substitution reagent of step (b) of the above method of making a compoundor derivative having formula (2), or a salt thereof, is generated in situby reacting anacyl chloridewith analcohol in stoichiometrically equivalent amounts.

[0048] In an embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof,withamolar equivalent amount of a compoundor derivativehaving formula (1), or a salt thereof, optionallywherein eachR1 is a trimethylsilyl ("TMS") group; (c) processing the compound or derivative having formula (2), or salt thereof, and the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); (d) removing by-products resulting from the processing step under reduced pressure and temperature-controlled conditions; (e) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (e1) adding acetone; optionally, (e2) separately isolating unreacted compound or derivative having formula (1), or salt thereof; and (f) isolating the compound or derivative having formula (I), or salt, solvate, or prodrug thereof.

[0049] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, and extruding. The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0050] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0051] In an alternative embodiment of the above method of making a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, the compound or derivative having formula (2), or salt thereof, is further treated with a molar equivalent of a Lewis acid in step (b).

[0052] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, is producedas amixture of alpha- and beta-anomers in ananomeric ratio by%weight of fromabout 1.5:1 to about 1:4 alpha- anomer to beta-anomer.

[0053] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, is produced as the beta-anomer. 11 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0054] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, the alpha‑ and beta-anomers of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, can be separately isolated by a method that can further include the steps of: (c1) adding acetone to, optionally, the compoundor derivative having formula (2), or salt thereof, optionally, the compound or derivativehaving formula (1), or salt thereof, optionallywherein eachR1 is aTMSgroup, and thecompoundor derivative having formula (I), or salt, solvate, or prodrug thereof so as to precipitate the beta-anomer of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof; (c2) filtering, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the compoundor derivative having formula (1), or salt thereof, optionallywhereineachR1 is a TMSgroup, and the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof so as to isolate the beta- anomerof thecompoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof; (c3)washing thebeta-anomer of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, with acetone; (c4) combining the acetone from theaddingandwashing steps; and (c5) removing theacetoneunder reducedpressure;wherein the stps (c1) to (c5) are performed sequentially, following step (c).

[0055] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) addingavolumeofmethanol andwater ina95:5weight:weight ratio to thecompoundor derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at room temperature, so as to dissolveapproximately15%of thecompoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water; (b) stirring the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at 50°Cuntil all of thecompoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally inaparticular anomeric ratio (alpha / beta), apparently dissolves in the volume of methanol and water; (c) cooling the solution of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha / beta), in the volume ofmethanol andwater, to ‑10°Cwith stirring so as to precipitate the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) isolating the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) drying the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0056] In yet another alternative embodiment of the above method of making a crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen, is crystalline Form I of nicotinamide riboside chloride, having formula (XII):

[0057] In yet another alternative embodiment, amethodofmakinga compoundor derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (1), or a salt thereof; optionally, (a1) treating the compound or derivative having formula (1), or salt thereof, with excess trimethylsilylating reagent(s), and, optionally, heating the compound or derivative having formula (1), or salt thereof, and the trimethylsilylating reagent(s), to reflux for about 12 hours so as to produce a compound or derivative having formula (1), or salt thereof, wherein each R1 is a trimethylsilyl ("TMS") group; optionally, (a2) cooling the mixture to room temperature; optionally, (a3) isolating the compound or derivative having formula (1), or salt thereof, wherein each R1 is a TMS group; (b) treating the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, with a molar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent; (c) processing the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, the compound or derivative having formula (2), or salt thereof, and the organic solvent co-reagent so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally produced in a particular anomeric ratio (alpha / beta); (d) adding water to, optionally, the compound or derivative having 12 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 formula (1), or salt thereof, optionally wherein each R1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, the organic solvent co-reagent, and the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta); optionally, (d1) adding saturatedNaHCO3 solution to, optionally, the compound or derivative having formula (1), or salt thereof, optionallywherein eachR1 is aTMSgroup, optionally, the compoundor derivative having formula (2), or salt thereof, the organic solvent co-reagent, the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta), and water; (e) adjusting the pH of the aqueous phase; (f) separating the organic phase from the aqueous phase; (g) freeze-drying the aqueous phase to provide the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); optionally, (g1) treating the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, with a (3<x<100)molar equivalent amount of an alcohol and a reagent selected from the group consisting of at least a sub-molar equivalent amount of a Brønsted inorganic base, a (x≤20) molar equivalent amount of a Brønsted inorganic acid, and a (3≤x<20) molar equivalent amount of an acyl choride; optionally, (g2) processing the compoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof, thealcohol, and the reagent soas toproduce acompoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8areeachhydrogen; and, optionally, (g3) isolating thecompoundorderivativehaving formula (I), or salt, solvate, or prodrug thereof,whereinR6, R7, and R8 are each hydrogen.

[0058] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, and extruding. The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0059] The organic solvent co-reagent employed in the above method of making a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACO- PEIA30<467> (U.S.PHARMACOPEIALCONVENTION2006) (USP30at <467>), incorporatedby referenceherein in its entirety.

[0060] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof,wherein the reagent of step (g1) isBrønsted inorganic base, can further include the step of: (g2a) neutralizing theBrønsted inorganic baseusinga concentratedacid solutionunder controlled conditions;wherein the step (g2a) is performed following step (g2).

[0061] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, wherein the reagent of step (g1) is Brønsted inorganic acid, can further include the step of: (g2a)neutralizing theBrønsted inorganicacidusingaconcentratedbasic solutionundercontrolledconditions,wherein the step (g2a) is performed following step (g2).

[0062] In anembodiment, amethodofmakingacompoundor derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a), or a salt thereof; (c) processing the compound or derivative having formula (2), or salt thereof, and the compound or derivative having formula (1a), or salt thereof, so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); (d) removing by-products resulting from the processing step under reduced pressure and temperature-controlled conditions; (e) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (e1) adding acetone; optionally, (e2) separately isolating unreacted compound or derivative having formula (1a), or salt thereof; and (f) isolating the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof.

[0063] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, and extruding. The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0064] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Sovlents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety. 13 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0065] In another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1b), or a salt thereof; (c) processing the compound or derivative having formula (2), or salt thereof, and the compound or derivative having formula (1b), or salt thereof, so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); (d) removing by-products resulting from the processing step under reduced pressure and temperature-controlled conditions; (e) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (e1) adding acetone; optionally, (e2) separately isolating unreacted compound or derivative having formula (1b), or salt thereof; and (f) isolating the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof.

[0066] In yet another alternative embodiment of the above method of making a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, can further include the steps of: (a1) providing a compound or derivative having formula (2a), or a salt thereof, wherein when R14 of the compound or derivative having formula (2a), or salt thereof, is methyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not acetoxy, andwherein whenR14 of the compound or derivative having formula (2a), or salt thereof, is phenyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not benzoxy; (a2) treating the compound or derivative having formula (2a), or salt thereof, with at least a stoichiometric equivalent amount of a Brønsted acid or a nucleophilic substitution reagent in the presence of at least a molar equivalent amount of a polar organic solvent co- reagent; (a3) processing the compound or derivative having formula (2a), or salt thereof, theBrønsted acid or nucleophilic substitution reagent, and thepolar organic solvent co-reagent so as to produce the compoundor derivative having formula (2), or salt thereof; and (a4) isolating the compound or derivative having formula (2), or salt thereof; wherein the steps (a1) to (a4) are performed sequentially, before step (a).

[0067] In yet another alternative embodiment, the nucleophilic substitution reagent of step (a2) of the above method of making a compound or derivative having formula (2), or a salt thereof, is generated in situ, by reacting an acyl chloridewith an alcohol in stoichiometrically equivalent amounts.

[0068] In an embodiment, the present disclosure provides a novel crystalline Form I of nicotinamide riboside triacetate (NRTA) chloride, according to formula (IX):

[0069] In another embodiment, the above crystalline Form I can be characterized by a powder X-ray diffraction pattern having peaks at 19.6, 22.1, and 26.6 degrees two theta ± 0.2 degrees two theta. In yet another embodiment, the above crystallineForm I canbecharacterizedbyapowderX-raydiffraction patternhavingpeaksat 9.8, 19.2, 19.6, 22.1, and26.6 degrees two theta± 0.2 degrees two theta. In yet another embodiment, the above crystalline Form I can be characterized by a powder X-ray diffraction pattern having peaks at 9.8, 14.5, 18.6, 19.2, 19.6, 22.1, 22.5, and 26.6 degrees two theta± 0.2 degrees two theta. IN yet another embodiment, the above crystalline Form I can be characterized by a powder X-ray diffraction pattern substantially as shown in Figure 18. In yet another embodiment, the above crystalline Form I can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 2± 0.2 degrees two theta.

[0070] In yet another embodiment, the above crystalline Form I can be characterized by an IR spectrumhaving peaks at 626.8, 644.1, and 916.0 cm‑1± 0.2 cm‑1. In yet another embodiment, the above crystalline Form I can be characterized by an IR spectrum having peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, and 1114.7 cm‑1 ± 0.2 cm‑1. In yet another embodiment, the above crystalline Form I can be characterized by an IR spectrum having peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, 1114.7, 1205.3, 1240.0, 1683.6, and 1737.6 cm‑1 ± 0.2 cm‑1. In yet another embodiment, the above crystalline Form I can be characterized byan IR spectrumsubstantially as shown inFigure 24. In yet another embodiment, the above crystalline Form I can be characterized by an IR spectrum having peaks substantially as provided in Table 3± 14 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 0.3 cm‑1.

[0071] In yet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram substantially as shown in Figure 31. In yet another embodiment, the above crystalline Form I can be characterized by aDSC thermogramobtained using a heating rate of 10K / min comprising an endothermic eventwith an onset temperature of 149° C ± 2° C. In yet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram obtainedusingaheating rateof 10K / mincomprisinganendothermiceventwithapeak temperatureof156°C±2°C. Inyet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 149° C± 2° C and a peak temperature of 156° C ± 2° C. In yet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 208°C± 2°C. In yet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with a peak temperature of 215° C ± 2° C. In yet another embodiment, the above crystalline Form I can be characterized by aDSC thermogramobtained using a heating rate of 10 K / min comprisinganendothermic eventwithanonset temperatureof 208°C±2°Candapeak temperatureof 215°C±2° C. In yet another embodiment, the above crystalline Form I can be characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 149° C ± 2° C and a peak temperature of 156° C ± 2° C and an endothermic event with an onset temperature of 208° C ± 2° C and a peak temperature of 215° C ± 2° C.

[0072] In an embodiment, the crystalline NRTA Form I can be prepared by a method that can include the steps of: (a) adding a volume of acetonitrile to the compound or derivative having formula (IX), or salt or solvate thereof, at room temperature, so as to dissolve the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile; (b) adding a volumeof acetone,which is at least equal in volume to the volumeof acetonitrile, to the solution of the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile so as to precipitate the crystalline Form I; and (c) isolating the crystalline Form I.

[0073] In an alternative embodiment of the abovemethod of preparing crystalline NRTA Form I, themethod can further include the steps of: (a1) providing a compound or derivative having formula (2), or a salt thereof: wherein X’ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; each of R6, R7, and R8 is ‑C(O)R’; R’ is methyl; (a2) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a), or a salt thereof, and a molar equivalent amount of TMSOTf; wherein Z2 is NH; n is 0; R1 is hydrogen; each of R2, R3, R4, and R5 is hydrogen; (a3) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1a), or salt thereof, and the TMSOTf so as to produce the compound or derivative having formula (IX), or salt or solvate thereof; and (a4) isolating the compoundor derivative having formula (IX), or salt or solvate thereof;wherein 15 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 the steps (a1) to (a4) are performed sequentially, before step (a). chromatography. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] FIG. 1 depicts a 1H NMR spectrum of the reaction product mixture for the procedure described in Example 1, Part A, performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (2) or a salt thereof. FIG. 2 depicts a 1H NMR spectrum of the reaction product mixture for the procedure described in Example 1, Part B, performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (I) or a salt, solvate, or prodrug thereof. FIG. 3 depicts a 1H NMR spectrum of the reaction product mixture for the procedure described in Example 1, Part B, performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (I) or a salt, solvate, or prodrug thereof, after removal of polar organic solvent co- reagent. FIG. 4 depicts a 1HNMR spectrum of the reaction product precipitated and isolated from the reaction product mixture for the procedure described in Example 1, Part B, performed in accordance with one embodiment of the described method for thepreparationof a compoundor derivativehavinggeneral formula (I) or a salt, solvate, or prodrug thereof. FIG. 5 depicts a 1H NMR spectrum of riboside tetraacetate, recycled from the reaction product mixture for the procedure described in Example 1, Part A (bottom), as compared to standard for riboside tetraacetate (top), performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (2) or a salt thereof. FIG. 6 depicts a 1HNMRspectrumof the reaction product isolated from the reaction productmixture for the procedure described in Example 1, Part B, performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (I) or a salt, solvate, or prodrug thereof. FIG. 7 depicts a 1H NMR spectrum of a compound or derivative having general formula (I), purified subsequent to isolation from the reaction productmixture for theprocedure described inExample1, Part B, performed inaccordance with one embodiment of the describedmethod for the preparation of a compoundor derivative havinggeneral formula (I) or a salt, solvate, or prodrug thereof. FIG. 8 depicts a comparison of 1H NMR spectra of a compound or derivative having general formula (I) as starting material (bottom), the reaction product mixture after treatment at low temperature with a base addition salt according to the procedure described in Example 1, Part D (middle), performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (I-H) or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen, and purified desired product (top). FIG. 9 depicts a comparison of 1H NMR spectra of a compound or derivative having general formula (I) as starting material (bottom), the reactionproductmixtureafter treatment at room temperaturewithabaseaddition salt according to the procedure described in Example 1, Part D (middle), performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (I-H) or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen, and purified desired product (top). FIG. 10 depicts a comparison of 1H NMR spectra of a compound or derivative having general formula (I) as starting material (bottom), the reaction product mixture after treatment at room temperature with acid addition at two different concentrationsaccording to theproceduredescribed inExample1,PartD (middle), performed inaccordancewithone embodiment of the describedmethod for the preparation of a compound or derivative having general formula (Ia-H) or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen, and purified desired product (top). FIG. 11(a) depicts a 1HNMRspectrum of a product filtrate of a compound or derivative having general formula (Ia-H), performed in accordance with one embodiment of the described method for the preparation of a compound or derivative having general formula (Ia-H) or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 11(b) depicts a 1H NMR spectrum of the impurity-containing supernatant remaining after filtration of the product filtrate represented by the 1HNMRspectrumdepicted inFIG. 11(a), performed inaccordancewith oneembodiment of the describedmethod for the preparation of a compound or derivative having general formula (Ia-H) or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 12 depicts a 1H NMR spectrum of the reaction mixture, performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each hydrogen, according to the procedure described in Example 1, Part C, wherein reaction was conducted for 10 minutes at 50 RPM. 16 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 FIG. 13 depicts a 1H NMR spectrum of the reaction mixture, performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each hydrogen, according to the procedure described in Example 1, Part C, wherein reaction was conducted for 10 minutes at 100 RPM. FIG. 14 depicts a 1H NMR spectrum of the reaction mixture, performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each hydrogen, according to the procedure described in Example 1, Part C, wherein reaction was conducted for 15 minutes at 250 RPM. FIG. 15 provides an X-ray powder diffraction pattern for the previously described Form I of crystalline nicotinamide riboside chloride (NR-Cl), the compound having formula (VII), prepared according to an embodiment of the presently disclosedmethods for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 16 provides an X-ray powder diffraction pattern for the presently disclosedNRmethanolate Form II of crystalline nicotinamide riboside chloride (NR-Cl), the compound having formula (VII), prepared according to amembodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 17 provides an X-ray powder diffraction pattern for the presently disclosed Form I of crystalline nicotinic acid riboside (NAR), the compound having formula (VIII), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 18 provides an X-ray powder diffraction pattern for the presently disclosed Form I of crystalline nicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinamide, "NR triacetate," or "NRTA"), the com- pound having formula (IX), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (Ia), or a salt, solvate, or prodrug thereof. FIG. 19 provides an X-ray powder diffraction pattern for the presently disclosed Form I of crystalline nicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinic acid, "NAR triacetate," or "NARTA"), the com- pound having formula (X), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (Ia), or a salt, solvate, or prodrug thereof. FIG. 20 provides an X-ray powder diffraction pattern for the presently disclosed Form III of crystalline nicotinamide mononucleotide (NMN), the compound having formula (XI), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IIa), or a salt, solvate, or prodrug thereof. FIG. 21 provides anX-ray powder diffraction pattern for the presently disclosed amorphous solid formof nicotinamide mononucleotide (NMN), the compound having formula (XI), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IIa), or a salt, solvate, or prodrug thereof. FIG. 22 provides a solid state IR spectrum for the presently disclosed NR methanolate Form II of crystalline nicotinamide riboside chloride (NR-Cl), the compound having formula (VII). FIG.23providesasolid state IRspectrum for thepresentlydisclosedFormIof crystallinenicotinicacid riboside (NAR), the compound having formula (VIII). FIG. 24 provides a solid state IR spectrum for the presently disclosed Form I of crystalline nicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinamide, "NR triacetate," or "NRTA"), the compound having formula (IX). FIG. 25 provides a solid state IR spectrum for the presently disclosed Form I of crystalline nicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinic acid, "NAR triacetate," or "NARTA"), the compound having formula (X). FIG. 26 provides a solid state IR spectrum for the presently disclosed Form III of crystalline nicotinamide mono- nucleotide (NMN), the compound having formula (XI). FIG. 27 provides a solid state IR spectrum for the presently disclosed amorphous solid form of nicotinamide mononucleotide (NMN), the compound having formula (XI). FIG. 28 provides an X-ray powder diffraction pattern for the presently disclosed Form IV of crystalline nicotinamide mononucleotide (NMN), the compound having formula (XI), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IIa), or a salt, solvate, or prodrug thereof. FIG. 29 provides a solid state IR spectrum for the presently disclosed Form IV of crystalline nicotinamide mono- nucleotide (NMN), the compound having formula (XI). FIG. 30 provides a DSC thermogram for a sample of the presently disclosed crystalline NR methanolate Form II of nicotinamide riboside chloride that was heated at a rate of 10 K / min. 17 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 FIG. 31providesaDSC thermogram for a sample of the presently disclosedForm Iof crystallinenicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinamide, "NR triacetate," or "NRTA"), the compound having formula (IX), which was heated at a rate of 10 K / min. FIG. 32providesaDSC thermogram for a sampleof the presently disclosedForm I of crystallinenicotinic acid riboside (NAR), the compound having formula (VIII), which was heated at a rate of 10 K / min. FIG. 33providesaDSC thermogram for a sampleof the presently disclosedForm I of crystallinenicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinic acid, "NAR triacetate," or "NARTA"), the compound having formula (X), which was heated at a rate of 10 K / min. FIG. 34 provides a DSC thermogram for a sample of the presently disclosed amorphous solid form of nicotinamide mononucleotide (NMN), the compound having formula (XI), which was heated at a rate of 10 K / min. FIG. 35 provides a DSC thermogram for a sample of the presently disclosed Form III of crystalline nicotinamide mononucleotide (NMN), the compound having formula (XI), which was heated at a rate of 10 K / min. FIG. 36 provides a DSC thermogram for a sample of the presently disclosed Form IV of crystalline nicotinamide mononucleotide (NMN), the compound having formula (XI), which was heated at a rate of 10 K / min. FIG. 37 provides an X-ray powder diffraction pattern for the presently disclosed amorphous solid form of reduced nicotinamide riboside (NRH, Compound 9, infra), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IVa-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 38 provides an X-ray powder diffraction pattern for the presently disclosed amorphous solid form of reduced nicotinic acid riboside (NARH, Compound 9, infra), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IVa-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen. FIG. 39 provides an X-ray powder diffraction pattern for the presently disclosed amorphous solid form of crystalline reduced nicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑1,4-dihydronicotinamide, "NRH triacetate," or "NRH-TA," Compound 7, infra), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IVa), or a salt, solvate, or prodrug thereof. FIG. 40 provides an X-ray powder diffraction pattern for the presently disclosed amorphous solid form of crystalline reduced nicotinic acid triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑1,4-dihydronicotinic acid, "NARH triace- tate," or "NARH-TA," Compound 8, infra), prepared according to an embodiment of the presently disclosed methods for the preparation of a compound or derivative having general formula (IVa), or a salt, solvate, or prodrug thereof. FIG.41depicts acomparisonof 1HNMRspectraof reducednicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta- D-ribofuranosyl)‑1,4-dihydronicotinamide, "NRH triacetate," or "NRH-TA," Compound 7, infra), prepared using ordinary solvent-based laboratory techniques (top), with reduced nicotinamide riboside triacetate (NRH-TA), per- formed in accordancewith one embodiment of the describedmethods for the preparation of a compound or derivative having general formula (IVa), or a salt, solvate, or prodrug thereof (bottom). FIG.42depictsa comparisonof 1HNMRspectraof reducednicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta- D-ribofuranosyl)‑1,4-dihydronicotinic acid, "NARH triacetate," or "NARH-TA," Compound 7, infra), prepared using ordinary solvent-based laboratory techniques (top), with reduced nicotinic acid riboside triacetate (NARH-TA), performed in accordance with one embodiment of the described methods for the preparation of a compound or derivative having general formula (IVa), or a salt, solvate, or prodrug thereof (bottom). FIG. 43 depicts a comparison of 1H NMR spectra of reduced nicotinamide riboside (1‑(beta-D-ribofuranosyl)‑1,4- dihydronicotinamide, "NRH," Compound 9, infra) prepared using ordinary solvent-based laboratory techniques (top), with reduced nicotinamide riboside (NRH), performed in accordancewith one embodiment of the describedmethods for the preparation of a compound or derivative having general formula (IVa-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen (bottom). FIG. 44 depicts a comparison of 1H NMR spectra of reduced nicotinic acid riboside (1-beta-D-ribofuranosyl)‑1,4- dihydronicotinic acid, "NARH," Compound 10, infra) prepared using ordinary solvent-based laboratory techniques (top), with reduced nicotinic acid riboside (NARH), performed in accordance with one embodiment of the described methods for the preparation of a compound or derivative having general formula (IVa-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen (bottom). FIG. 45 depicts a 19F NMR spectrum of product nicotinic acid riboside (NAR), the compound having formula (VIII), prepared according to an embodiment of the described methods for the preparation of a compound or derivative having general formula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen, showing the absence of any fluorine shifts corresponding to the absence of any fluorine-containing species in the product, and wherein the method includes the use of a Lewis acid including a trifluoromethanesulfonate ("triflate") species. FIG. 46 depicts a 19F NMR spectrum of product nicotinic acid riboside triacetate (NARTA), the compound having 18 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 formula (X), prepared according to an embodiment of the described methods for the preparation of a compound or derivative having general formula (Ia), or a salt, solvate, or prodrug thereof, showing the absence of any fluorine shifts corresponding to the absence of any fluorine-containing species in the product, andwherein themethod includes the use of a Lewis acid including a trifluoromethanesulfonate ("triflate") species. DETAILED DESCRIPTION

[0075] In an embodiment, the present disclosure relates to a synthetic sequence that enables the efficient production of nicotinoyl ribosides, the triacetates thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof, via processes that are enabled by the processing of reagents by liquid-assisted mixing, grinding, milling, and / or extrusion.

[0076] In another embodiment, the present disclosure relates to a synthetic sequence that enables the efficient production of reduced nicotinoyl ribosides, the triacetates thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof, via processes that are enabled by the processing of reagents by liquid-assisted mixing, grinding, milling, and / or extrusion.

[0077] In yet another embodiment, thepresent disclosure relates to the scalablemethodsof preparation of nicotinamide riboside (NR) and nicotinic acid riboside (NAR), and derivatives thereof, or salts, solvates, or prodrugs thereof, by liquid- assisted mixing, grinding, and / or extrusion.

[0078] In yet another embodiment, the present disclosure relates to the scalable methods of preparation of reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH), and derivatives thereof, or salts, solvates, or prodrugs thereof, by liquid-assisted mixing, grinding, and / or extrusion.

[0079] In yet another embodiment, the present disclosure relates to the scalable methods of preparation of reduced nicotinamide riboside triacetate (NRH-TA) and reduced nicotinic acid riboside triacetate (NARH-TA), and derivatives thereof, or salts, solvates, or prodrugs thereof, by biphasic liquid-assisted mixing, grinding, and / or extrusion.

[0080] In yet another embodiment, the present disclosure relates to the batch processes that enable the production of nicotinamide riboside (NR) and nicotinic acid riboside (NAR), or salts, solvates, or prodrugs thereof, whereby the use of solvents in kept to a minimum, and whereby conversion and reaction times are optimized by the use of sealed conditions and / or mechanochemistry, and an optimized purification sequence.

[0081] In yet another embodiment, the present disclosure relates to the batch and sami-continuous processes that enable the production of reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH), and triacetate derivatives thereof, or salts, solvates, or prodrugs thereof, wherein the use of solvents is kept to aminimum, andwhereby conversion and reaction times are optimized by the use of sealed conditions, continuous liquid-liquid extraction, and / or mechanochemistry, and an optimized purification sequence.

[0082] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including, but not limited to, a Form I of nicotinamide riboside chloride ("NR-Cl"), and methods of preparation thereof.

[0083] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including, but not limited to, a "NR methanolate Form II" of nicotinamide riboside chloride (NR-Cl), and methods of preparation thereof.

[0084] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside (NAR), including, but not limited to, a "Form I" of nicotinic acid riboside (NAR), and methods of preparation thereof.

[0085] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotinamide, "NR triacetate," or "NRTA"), including, but not limited to, a "Form I" of nicotinamide riboside triacetate (NRTA) chloride, and methods of preparation thereof.

[0086] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside triacetate (1‑(2’,3’,5’-triacetyl-beta-D-ribofuranosyl)‑nicotininic acid, "NAR triacetate," or "NARTA"), including, but not limited to, a "Form I" of nicotinic acid riboside triacetate (NARTA), and methods of preparation thereof.

[0087] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide ("NMN"), including, but not limited to, a "Form III" of nicotinamide mononucleotide (NMN), and methods of preparation thereof. In yet another embodiment, the present disclosure relates to an amorphous solid form of nicotinamide mono- nucleotide (NMN), and methods of preparation thereof. In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide (NMN), including, but not limited to, a "Form IV" of nicotinamide mononucleotide (NMN), and methods of preparation thereof.

[0088] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (III), or salts, solvates, or prodrugs thereof, and methods of prepation thereof.

[0089] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (IV), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0090] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (IV-H), or salts, solvates, or prodrugs thereof, and methods of preparation thereof. 19 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0091] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (V), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0092] In yet another embodiment, the present disclosure relates to crystalline forms of compounds or derivatives having formula (VI), or salts, solvates, or prodrugs thereof, and methods of preparation thereof.

[0093] In accordance with an embodiment, the present disclosure provides a novel method whereby sealed conditions and / ormechanic forcesareused tominimizesolventquantities, decrease reaction times, increaseoverall conversion, and facilitate product purification in amultistep synthetic sequence, whereby by-product formation isminimized, andwhereby primarily by-products that can be removed readily by filtration or evaporation are generated.

[0094] Additionally, the methods of the present disclosure address limitations of existing technologies to produce compounds or derivatives such as nicotinoyl ribosides, reduced nicotinoyl ribosides, the triacetates thereof, derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof.

[0095] In accordance with one embodiment, the present disclosure provides a novel method for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, such as nicotinoyl ribosides and their derivatives, and including but not limited to the triacetylated forms of NR-Cl (nicotinamide riboside chloride salt form) and NAR (nicotinic acid riboside) (compounds or derivatives having formula (I), wherein R6, R7, and R8 are each acetyl groups), and the fully deprotected forms thereof (compounds or derivatives having formula (I), wherein R6, R7, andR8 are each hydrogens), in commercial quantities. In accordance with such an embodiment, the present disclosure provides a novel method whereby mechanic forces and / or sealed conditions are used to minimize solvent and reagent quantities, decrease reaction times, increase overall conversion, and facilitate product purification in amultistep synthetic sequence, whereby by-product formation isminimized, andwhereby primarily by-products that can be removed readily by filtration or evaporation are generated. Prototype product nicotinoyl riboside compounds include compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof: optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent optionally the counterion is an internal salt; optionally X- is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and, optionally X- is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propanoic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (being lactic acid, the anion of lactic acid being lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, and trifluoroacetate; and, optionallyX- is ananionof anunsubstitutedmonocarboxylic acid selected from formicacid, acetic acid, propionic acid, or butyric acid, being formate, acetate, propionate, and butyrate, respectively; and, optionally X- is an anion of a substituted or unsubstituted amino acid, i.e., amino-monocarboxylic acid or an amino- dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respec- tively; and, optionally X- is an anion of ascorbic acid, being ascorbate; and, optionally X- is a halide selected from fluoride, chloride, bromide, or iodide; and, optionally X- is an anion of a substituted or unsubstituted sulfonate, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; and, optionally X- is an anion of a substituted or unsubstituted carbonate, further optionally hydrogen carbonate; and, optionally X- is an anion of a substituted or unsubstituted glutathione or glutathione disulfide; 20 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 wherein the substituted carboxylic acid, substituted monocarboxylic acid, substituted propanoic acid, substituted acetic acid, substituted amino acid, substituted sulfonate, substituted carbonate, substituted glutathione, and substituted glutathione disulfide are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; Z1 and Z2 are independently NH or oxygen; n is 0 or 1; R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, - NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; wherein when R1 is hydrogen, Z2 is oxygen, and n is 0, the compound or derivative having formula (I) may optionally take the formof thecarboxylateanionconjugatebasespeciesof thecompoundor derivativehaving formula (I), further optionally associated with a positively charged counterion selected from the group consisting of alkali metal, alkaline earth metal, transition metal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; each RC is independently selected from the group consisting of hydrogen, ‑(C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, - (C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, - (C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, - NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑SO2(C1‑C6)alkyl, ‑SO2NRB 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6) alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O) (C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O) O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- 21 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0096] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1), or salts thereof: wherein Z1 and Z2 are independently nitrogen or oxygen; m is 1 or 2; n is 0 or 1; each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero- aryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, - (C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, - ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, - NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, - S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; wherein when R1 is hydrogen, Z2 is oxygen, m is 1, and n is 0, the compound or derivative having formula (1) may optionally take the formof the carboxylateanion conjugatebasespeciesof the compoundor derivativehaving formula (1), further optionally associated with a positively charged counterion selected from the group consisting of alkali metal, alkaline earth metal, transition metal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and 22 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 ‑(C1‑C6)alkylene-ORB; R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6) alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O) (C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O) O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0097] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (2), or salts thereof: wherein X’ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate, phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloro- methanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent optionally the counterion is an internal salt; optionally X- is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and, optionally X- is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propanoic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (being lactic acid; the anion of lactic acid being lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, and trifluoroacetate; and, optionally X- is an anion of a substitutedmonocarboxylic acid selected from formic acid, acetic acid, propionic acid, or butyric acid, being formate, acetate, propionate, and butyrate, respectively; and, optionally X- is an anion of a substituted or unsubstituted amino acid, i.e., amino-monocarboxylic acid or an amino- dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respec- tively; and, optionally X- is an anion of ascorbic acid, being ascorbate; and, optionally X- is a halide selected from fluoride, chloride, bromide, or iodide; and, optionally X- is an anion of a substituted or unsubstituted sulfonate, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; and, optionally X- is an anion of a substituted or unsubstituted carbonate, further optionally hydrogen carbonate; and, optionally X- is an anion of a substituted or unsubstituted glutathione or glutathione disulfide; wherein the substituted carboxylic acid, substituted monocarboxylic acid, substituted propanoic acid, substituted acetic acid, substituted amino acid, substituted sulfonate, substituted carbonate, substituted glutathione, and substituted glutathione disulfide are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) 23 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substitutents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑ C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0098] In accordance with an alternative embodiment, prototype product nicotinoyl riboside compounds include compounds or derivatives having formula (Ia), or salts, solvates, or prodrugs thereof: optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, 24 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent optionally the counterion is an internal salt; optionally X- is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and, optionally X- is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propanoic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (being lactic acid, the anion of lactic acid being lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, and trifluoroacetate; and, optionallyX- is ananionof anunsubstitutedmonocarboxylic acid selected from formicacid, acetic acid, propionic acid, or butyric acid, being formate, acetate, propionate, and butyrate, respectively; and, optionally X- is an anion of a substituted or unsubstituted amino acid, i.e., amino-monocarboxylic acid or an amino- dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respec- tively; and, optionally X- is an anion of ascorbic acid, being ascorbate; and, optionally X- is a halide selected from fluoride, chloride, bromide, or iodide; and, optionally X- is an anion of a substituted or unsubstituted sulfonate, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; and, optionally X- is an anion of a substituted or unsubstituted carbonate, further optionally hydrogen carbonate; and, optionally X- is an anion of a substituted or unsubstituted glutathione or glutathione disulfide; wherein the substituted carboxylic acid, substituted monocarboxylic acid, substituted propanoic acid, substituted acetic acid, substituted amino acid, substituted sulfonate, substituted carbonate, substituted glutathione, and substituted glutathione disulfide are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; Z1 and Z2 are independently NH or oxygen; n is 0 or 1; R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑ NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; wherein whenR1 is hydrogen, Z2 is oxygen, and n is 0, the compound or derivative having formula (Ia)may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (Ia), further optionally associated with a positively charged counterion selected from the group consisting of alkali metal, alkaline earth metal, transition metal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; 25 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 each of R2, R3, R4, and R5 is hydrogen; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0099] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (Ia), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1a), or salts thereof: wherein Z1 and Z2 are independently NH or oxygen; n is 0 or 1; R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, - N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; 26 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 whereinwhenR1 is hydrogen, Z2 is oxygen, and n is 0, the compound or derivative having formula (1a)may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of alkali metla, alkaline earth metal, transition metal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; each RC is independently selected from the group consisting of hydrogen, ‑(C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitaminB7 ester biotinyl; wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substitutedwith one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6) alkyl, ‑OC(O)NRB 2, - (C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O)NRB 2, - NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alky- lene-ORB; each of R2, R3, R4, and R5 is hydrogen; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0100] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (Ia), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (1b), or salts thereof: wherein Z1 and Z2 are independently nitrogen or oxygen; m is 1 or 2; n is 0 or 1; each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero- aryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, - (C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, - NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, - S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; wherein when R1 is hydrogen, Z2 is oxygen, m is 1, and n is 0, the compound or derivative having formula (1) may optionally take the formof the carboxylateanion conjugatebasespeciesof the compoundor derivativehaving formula (1), further optionally associated with a positively charged counterion selected from the group consisting of alkali metal, alkaline earth metal, transition metal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) 27 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; each of R2, R3, R4, and R5 is hydrogen; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0101] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (Ia), or salts, solvates, or prodrugs thereof, include compounds or derivatives having formula (2), or salts thereof: wherein X’ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate, phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloro- methanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent optionally the counterion is an internal salt; optionally X- is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and, optionally X- is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propanoic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (being lactic acid; the anion of lactic acid being lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, and trifluoroacetate; and, optionally X- is an anion of a substitutedmonocarboxylic acid selected from formic acid, acetic acid, propionic acid, or butyric acid, being formate, acetate, propionate, and butyrate, respectively; and, optionally X- is an anion of a substituted or unsubstituted amino acid, i.e., amino-monocarboxylic acid or an amino- dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respec- tively; and, optionally X- is an anion of ascorbic acid, being ascorbate; and, optionally X- is a halide selected from fluoride, chloride, bromide, or iodide; and, optionally X- is an anion of a substituted or unsubstituted sulfonate, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; and, optionally X- is an anion of a substituted or unsubstituted carbonate, further optionally hydrogen carbonate; and, optionally X- is an anion of a substituted or unsubstituted glutathione or glutathione disulfide; wherein the substituted carboxylic acid, substituted monocarboxylic acid, substituted propanoic acid, substituted acetic acid, substituted amino acid, substituted sulfonate, substituted carbonate, substituted glutathione, and substituted glutathione disulfide are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the 28 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRc, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑ C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0102] In accordancewith suchanembodiment, appropriate startingmaterials for themethodsof thepresent disclosure for the preparation of compounds or derivatives having formula (2), or salts thereof, include compounds or derivatives having formula (2a), or salts thereof: R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, 29 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑ NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R14 is methyl or phenyl; provided that the absolute configuration of C** is R or S, or a mixture of R and S. Definitions

[0103] As used in the specification and the appended claims, the singular forms of "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0104] Asusedherein, the term "Lewisacid" refers toanychemical species that canaccept apair of nonbondingvalence electrons, i.e., an electron-pair acceptor. Without limitation, non-limiting examples of Lewis acids include BF3, TMSOTf, and SnCl4.

[0105] As used herein, the term "solvent" refers to a compound or mixture of compounds including, but not limited to, water, water in which an ionic compound has been dissolved, acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2- butanol, t-butyl alcohol ("TBA"), 2-butanone, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichlor- oethane ("DCE"), diethylene glycol, diethyl ether ("Et2O"), diglyme (diethylene glycol dimethyl ether), 1,2-dimethox- yethane ("DME"), N,N-dimethylformamide ("DMF"), dimethylsulfoxide ("DMSO"), 1,4-dioxane, ethanol, ethyl acetate ("EtOAc"), ethylene glycol, glycerin, heptanes, hexamethylphosphoramide ("HMPA"), hexamethylphosphorus triamide ("HMPT"), hexane, methanol ("MeOH"), methyl t-butyl ether ("MTBE"), methylene chloride ("DCM," "CH2Cl2"), N- 30 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 methyl‑2-pyrrolidinone ("NMP"), nitromethane, pentane, petroleum ether, 1-propanol ("n-propanol," "n-PrOH"), 2-pro- panol ("isopropanol," "iPrOH"), pyridine, tetrahydrofuran ("THF"), toluene, triethylamine ("TEA," "Et3N"), o-xylene, m- xylene, and / or p-xylene, and the like. Solvent classes may include hydrocarbon, aromatic, aprotic, polar, alcoholic, and mixtures thereof.

[0106] Asusedherein, the terms "mechano-chemicalmixing," "mechanochemistry," and "mechanical processing" refer to standard techniques known to those of ordinary skill in the art, in which chemical startingmaterials and / or reagents with disparate solubility properties are reacted, for example, by direct milling, liquid assisted-milling, triturating, mixing, or grinding, generally in theabsenceof solvents. Interchangeable termsmay include "mechanic-chemical," or the like.SeeF. Ravalico et al., Rapid synthesis of nucleotide pyrophosphate linkages in a ball mill, 9 ORG. BIOL. CHEM. 6496 (2011); DritanHasa et al., Cocrystal Formation throughMechanochemistry: FromNeat and Liquid-AssistedGrinding to Polymer- AssistedGrinding, 127 ANGEWANDTECHEMIE 7371 (2015); and references cited therein, all of which are incorporated by reference herein in their entireties.

[0107] Asused herein, the term "liquid-assistedmixing" refers to a standard technique known to those of ordinary skill in theart, inwhich thekineticsof solid-stategrinding isacceleratedbyadditionofa small amountof liquidduringmixing. Itwas discovered in 2001 that not only did small amounts of liquid speed up the solid-state reaction, but in numerous cases, addition of small amounts of liquid allowed the formation of newsolid forms that could not otherwise bemade.SeeN.Shan et al.,Mechanochemistry and co-crystalformation: effect of solvent on reaction kinetics,CHEM.COMMC’NS2732 (2002), incorporated by reference herein in its entirety. Between 2002 and 2005 it was discovered that the exact outcome of the solid-state grinding could be controlled by careful choice of the added liquid.SeeA.V. Trask et al., Achieving Polymorphic and Stoichiometric Diversity in Cocrystal Formation: Importance of Solid-State Grinding, Powder X-ray Structure Differentiation, and Seeding, 5 CRYSTAL GROWTH & DESIGN 2233 (2005), incorporated by reference herein in its entirety. Between 2005 and 2007, it was further demonstrated that this liquid-assisted mixing approach is significantly more effective in searching for alternate solid forms of drug candidates than other previously used methods, e.g., conventional solution crystallization or melt growth. See S. Karki et al., Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding, 4 MOLECULAR PHARMACEUTICS 347 (2007); A.V. Trask et al., Screening for crystalline salts viamechanochemistry, CHEM.COMMC’NS51 (2006); each of which is incorporated by reference herein in its entirety. Liquid-assistedmixing isamethod that is rapidandenvironmentally friendlybecause it eliminates theneed to use large amounts of solvents, cutting down on waste and lost revenue.

[0108] As used therein, the term "extrusion" refers to a standard technique known to those of ordinary skill in the art, in which a rawmaterial is chemically converted into a product of unique shape and density by forcing it through a die under defined conditions. See J. Thiry et al., A review of pharmaceutical extrusion: Critical process parameters and scaling-up, 479 INT’L J. PHARMACEUTICS 227 (2015), incorporated by reference herein in its entirety. An extruder is composed of twodifferent parts: a conveying systemanda die system. The conveying system transports thematerial through the barrel via the action of Archimedes’ infinite screws, which can also impart a degree of distributive mixing if needed. The die system then forms the material into the desired shape. See id. Pharmaceutical extrudates are generally produced by heating and then softening a mixture of a drug and a thermoplastic polymer, followed by extrusion of the molten mass through a die, resulting in the production of cylinders of films depending on the shape of the die. In addition, other excipients, such as surfactants, salts, superdisintegrants, plasticizers, and antioxidants may be added during the extrusion process if required. See K. Hughey et al., The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus®-based solid dispersions, 48 EUR. J. PHARM. SCI. 758 (2013); M.A. Repka et al., Pharmaceutical applications of hot-melt extrusion: part II, 33 DRUGDEV. INDUS. PHARM. 1043 (2007), each of which is incorporated by reference herein in its entirety. Themost common additives are plasticizers, which facilitate the extrusion process by reducing the glass transition temperature of the polymers. See M.M. Crowley et al., Pharmaceutical applications of hot-melt extrusion: part I, 33 DRUG DEV. INDUS. PHARM. 909 (2007), incorporated by reference herein in its entirety. The release of the active pharmaceutical ingredient ("API") and the quality of the final product can be fine- tuned by modifying the excipients. For example, some polymers have a different dissolution pH, which can allow the targeting of a specific part of the gastro-intestinal tract.SeeD.A.Miller et al., Targeted intestinal delivery of supersaturated itraconazole for improved oral absorption, 25 PHARM. RES. 1450 (2008), incorporated by reference herein in its entirety. Some polymers can also control the release of the API in order to observe an immediate, delayed, or sustained release. See S. Janssens et al., The use of a new hydrophilic polymer, Kollicoat IR®, in the formulation of solid dispersions of itraconazole, 30EUR. J. PHARM.ScI. 288 (2007); L.D. Bruce et al., Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid, 59 EUR. J. PHARM. BIOPHARM. 85 (2005); E. Verhoeven et al., Xanthan gum to tailor drug release of sustained-release ethylcellulosemini-matrices prepared via hot-melt extrusion: in vitro and in vivo evaluation, 63 EUR. J. PHARM. BIOPHARM. 320 (2006); each of which is incorporated by reference herein in its entirety. Another very important aspect to bear in mind is the affinity between the API and the polymer matrix, especially when aiming for enhancement of the bioavailability of poorly soluble drugs. See Shah et al., Melt extrusion with poorly soluble drugs, 453 INT’L J. PHARM. 233 (2013), incorporated by reference herein in its entirety. It is for this reason that a screening process of different polymers is generally needed in order to obtain the best solid dispersion.SeeSarode et al., 31 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation, 48 EUR. J. PHARM. SCI. 371 (2002), incorporated by reference here in its entirety. The formulation step is therefore very important, because it will have a critical impact on the final quality of the product.

[0109] Because extrusion is a complex process, which is very versatile and flexible, the process parameters need to be taken into account in order to obtain the best final product. See Romanski et al., The importance of monitoring process parameters as amethod for quality control for hot melt extrusion, AAPSANNUALMEETING, SANANTONIO, TX (2013), incorporated by reference herein in its entirety. A typical extrusion setup consists of: amotor, which acts as a drive unit; an extrusion barrel; a rotating screw; and an extrusion die.SeeR.Chokshi &H. Zia, Hot-melt extrusion technique: a review, 3 IRAN J. PHARM. RES. 3 (2004), incorporated by reference herein in its entirety. The extruder must be able to rotate the screw at a predetermined speed. At the same time, the torque and shear generated by the extruded material, and the screws must be compensated. The extruder is connected to a central control unit in order to control the process parameters, such as screw speed and temperature, and therefore pressure. This electronic control unit will also act as a monitoring system. See M. Maniruzzaman et al., A review of hot-melt extrusion: process technology to pharma- ceutical products, ISRNPHARM. (2012), incorporated by reference herein in its entirety. A very important characteristic to consider, regardless of whether the extrusion equipment is a single screw ("ssEr") or twin screw extruder ("tsEr"), is the length to diameter ratio (L / D) of the screws. The L / D typically ranges from about 20 to about 40:1 (mm). Another important characteristic is the diameter of the screws, because this will determine the size of the equipment and its throughput. The screwdiameters of pilot extruders range fromabout 12 to about 30mm,while the productionmachines for pharmaceutical scaling-up are much larger, with diameters typically exceeding about 50 to about 60 mm. SeeG. Andrews et al., A Basic Guide: Hot-Melt Extrusion, 13 UKICRS (2008), incorporated by reference herein in its entirety. Process analytical technology such as near infrared ("NIR") and Raman, can also be applied to the extruder setup via probes in order to control in-line the quality of the final product. See F. Krier et al., PAT tools for the control of co-extrusion implants manufacturing process, 458 INT’L J. PHARM. 15 (2013), incorporated by reference herein in its entirety. Throughout the whole process, the temperature of the different sections is controlled by electrical heating bands around the barrel or by heating cartridges inside the barrel, and is monitored by thermocouples.

[0110] Temperature is the first factor to take into account in the extrusion process, because the polymer has to be processed above its glass transition temperature (Tg), but below its degradation temperature (Tdeg). The API can be processed below or above its melting temperature (Tm) depending on whether a miscibility regime or a solubilization regime, respectively, is being used.SeeM.A.Repka et al., Melt extrusion, AAPS (2013), incorporated by reference herein in its entirety. It is well known that the temperature influences the viscosity of the melt. See J. Breitenbach, Melt extrusion fromprocess to drug delivery technology, 54 EUR. J. PHARM. BIOPHARM. 107 (2002), incorporated by reference herein in its entirety.Therefore, anequilibriumhas tobe foundbetween,on theonehand, a low temperaturewhere themelt shows high viscosity, and thus a high torque, and on the other hand, an elevated temperature where the torque is reduced due to the low viscosity of the melt but where both the polymer and the API could be degraded. The product temperature can consequently be a major determinant factor in the quality of the final product. It is important to note that the product temperature will be different from the barrel temperature. Indeed, mechanical energy is often transferred from the screws into the molten material.

[0111] It is well known that modification of the screw configuration allows for modification of the production method, as the different screw elements can be optimized to suit particular applications. See Breitenbach (2002); Chokshi & Zia (2004). Moreover, the residence time of themix in the barrel will also be influenced by the type of element used during the process. For example, adding kneading elements will increase the residence time. See H. Liu et al., Effects of screw configurationon indomethacindissolutionbehavior ineudragit EPO,31ADV.POLYM.TECH.331 (2012);P.R.Wahl et al., InlinemonitoringandaPATstrategy for pharmaceutical hotmelt extrusion, 455 INT’LJ.PHARM.159 (2013); eachofwhich is incorporatedby referenceherein in its entirety.Screwconfiguration isa very important parameter in theamorphizationof the API using twin screw hot melt extrusion ("tsHME"). In their study, Nakamichi et al. concluded that at least one mixing zone was needed in order to obtain smooth and homogeneous extrudates while processing nifedipine and hydroxypro- pylmethylcellulosephthalatewith thekneedingpaddlepositionedat the level of thesecond thirdof thebarrel.K.Nakamichi et al., The role of the kneadingpaddle and theeffects of screw revolution speedandwater content on thepreparation of SD using twin-screw extruder, 241 INT’L J. PHARM. 203 (2002), incorporated by reference herein in its entirety. The samples were recovered from the screw directly and analyzed by DSC and x-ray diffraction ("XRD"). Moreover, when studying the release of the drug in vitro, supersaturation was only observed when the kneading paddle was present. Verhoeven et al. observed the same result while extruding ethylcellulose with metoprolol tartrate ("MPT"). Further, these authors changed the number of mixing zones and their position within the barrel, but mixing efficacy and drug release were found not to be effected by those changes. See E. Verhoeven et al., Influence of formulation and process parameters on the release characteristics of ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion, 69 EUR. J. PHARM. BIOPHARM. 312 (2008), incorporated by reference herein in its entirety.

[0112] Thescrewspeedalsoneeds tobeadapted foreachpurpose,because it hasan impactonseveral factors involved in the extrusion process. On the one hand, if amorphization is targeted, the screw speed would need to be high in order to 32 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 obtain a high shear mixing with reduced residence time. On the other hand, in order to obtain high purity cocrystals, the screw speed would need to be reduced so as to increase the residence time, and consequently, the mixing time.

[0113] Regarding feedingmaterial into the extruder, first of all, varying the feed rate, while maintaining the screw speed as constant, will change the fill level of the extrusion barrel, because increasing the feed rate will increase the filling rate. See E. Reitz et al., Residence time modeling of hot melt extrusion processes, 85 EUR. J. PHARM. BIOPHARM. 1200 (2013), incorporated by reference herein in its entirety. Almeida et al. concluded that a balance needs to be found between feed rate and screw speed in order to maintain a constant melt flow. See A. Almeida et al., Upscaling and inline process monitoring via spectroscopic techniques of ethylene vinyl acetate hot-melt extruded formulations, 439 INT’L J. PHARM. 223 (2012), incorporated by reference herein in its entirety. Generally, the filling percentage of the extruder barrel is comprised between about 20% and about 50%, and this can be calculated by using the following equation: where "FR" is the feed rate (g / min), "RTD" is the mean residence time (min), "ρ" is the bulk viscosity of the polymer / mix (g / mL), and "Vfree" is the extruder free volume (mL). See A. Swanborough, A practical approach to scale-up from bench- top. Twin Screw Extruders, THERMO FISHER SCIENTIFIC INC. (2006), incorporated by reference herein in its entirety.

[0114] Before scaling up the extrusion process, it is recommended tomeasure the specificmechanical energy ("SME") on a laboratory scale extruder to allow the prediction of the performance of a production extruder, operating under similar conditionsof screwspeedand residence time.SeeSwanborough, 2006. Therefore, all of theparameters describedabove need tobeadapted in order to obtain the same results.Whenscalingup theextrusionprocess, larger screws, higher screw speeds, and higher feeding rates will be used. However, two factors-the SME and the residence time-must bemaintained at a similar level, even if the scale of the process is increased. Therefore, the critical parameters of the process must be adapted in order to fit these two factors.

[0115] In accordance with one embodiment, methods for preparation of the present disclosure comprise processing by extruding, wherein the extruder is a 11-millimeter, stainless steel, twin screw jacketed extruder, and wherein the processing by extruding includes interchangeable mixing elements, independent heating and cooling zones, program- mable feeding, and liquid injection ports.

[0116] Without limitation, non-limiting examples of Brønsted acids include HI, HCl, HBr, H2SO4, H3O+, HNO3, H3PO4, and CH3CO2H. Without limitation, non-limiting examples of Brønsted bases include CH3 -, CH2=CH-, H-, NH2 -, HC≡C-, CH3O-, HO-, HS-, CO3 ‑2, NH3, HCO2 -, MeO-, and EtO-.

[0117] Without limitation, andwithout being bound by theory, as used herein, the terms "oxidizing agent," "oxidant," and "electron acceptor" refer to species that gain electrons and are reduced in a chemical reaction. An oxidizing agent is normally in oneof its higher possible oxidation statesbecause itwill gain electronsandbe reduced.Without limitation, non- limiting examples of oxidizing agents include, but are not limited to, O2, O3, H2SO4, and the halogen elements.

[0118] Without limitation, and without being bound by theory, as used herein, the terms "reducing agent," "reductant," and "electron donor" refer to species that lose electrons and are oxidized in a chemical reaction. A reducing agent is typically in one of its lower possible oxidation states because it will lose electrons and be oxidized.Without limitation, non- limiting examples of reducing agents include, but are not limited to, H2, CO, Fe, Zn, and the alkali metal elements.

[0119] Without limitation, and without being bound by theory, as used herein, the term "catalysis" or "catalytic" refers an increase in the rate of a chemical reaction of a substrate species due to the participation of an additional chemical species called a "catalyst," which is not consumed in the catalyzed reaction and can continue to act repeatedly in subsequent repetitions of the same chemical reaction. In particular embodiments, by "catalytic amount" is meant that a chemical species is present in no greater an amount than 10%molar equivalent amount relative to the amount of substrate. In other embodiments, by "catalytic amount" is meant that a chemical species is present in no greater an amount than 5% molar equivalent amount relative to the amount of substrate. In yet other embodiments, by "catalytic amount" is meant that a chemical species is present in no greater an amount than 3%molar equivalent amount relative to the amount of substrate. In yet other embodiments, by "catalytic amount" is meant that a chemical species is present in no greater an amount than 1% molar equivalent amount relative to the amount of substrate.

[0120] According to particular embodiments, the compounds or derivatives prepared according to embodiments of the methods of the present disclosure can comprise compounds or derivatives, or salts, solvates, or prodrugs thereof, or crystalline forms thereof, substantially freeof solventsor otherby-products, generally, or aparticular solvent or by-product. In certain embodiments, by "substantially free" ismeant greater than about 80% free of solvents or by-products, or greater than about 80% free of a particular solvent or by-product, more preferably greater than about 90% free of solvents or by- products, or greater than about 90% free of a particular solvent or by-product, even more preferably greater than about 95% free of solvents or by-products, or greater than about 95% free of a particular solvent or by-product, even more preferably greater than about 98% free of solvents or by-products, or greater than about 98% free of a particular solvent or 33 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 by-product, evenmorepreferablygreater thanabout99%freeof solventsorby-products, or greater thanabout99%freeof a particular solvent or by-product, even more preferably greater than about 99.99% free of solvents or by-products, or greater than about 99.99% free of a particular solvent or by-product, andmost preferably quantitatively free of solvents or by-products, or quantitatively free of a particular solvent or by-products.

[0121] According to particular embodiments, the compounds or derivatives prepared according to embodiments of the methods of the present disclosure can comprise compounds or derivatives, or salts, solvates, or prodrugs thereof, or crystalline forms thereof, substantially freeof solventsor otherby-products, generally, or aparticular solvent or by-product. In certain embodiments, by "substantially free" is meant leass than about 10,000 ppm of solvents or by-products, or less thanabout 10,000ppmofaparticular solvent or by-product, evenmorepreferably less thanabout 1,000ppmof solventsor by-products, or less than about 1,000 ppm of a particular solvent or by-product, evenmore preferably less than about 100 ppmof solvents or by-products, or less thanabout 100ppmof a particular solvent or by-product, evenmorepreferably less than about 10 ppm of solvents or by-products, or less than about 10 ppm of a particular solvent or by-product, even more preferably less than 5 ppm of solvents or by-products, or less than 5 ppm of a particular solvent or by-product, and most preferably, an undetectable amount of solvents or by-products, or an undetectable amount of a particular solvent or by- product.

[0122] The term "alkyl," by itself or as part of another substituent means, unless otherwise stated, a straight, branched, or cyclic chain hydrocarbon ("cycloalkyl") having the number of carbon atoms designated (i.e., C1‑C6 means one to six carbons). Examples includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl, and cyclopropyl. Most preferred are ‑(C1‑C3)alkyl, particularly ethyl, methyl, and isopropyl.

[0123] The term "alkenyl," employed alone or in combination with other terms, means unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain, the unsaturation meaning a carbon-carbon double bond (-CH=CH‑), branchedchain, or cyclic hydrocarbongrouphaving thestatednumberof carbonatoms.Examples includevinyl, propenyl, allyl, crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, cyclopentenyl, cyclopentadienyl, and the higher homologs and isomers. Functional groups representing an alkene are exemplified by -CH=CH-CH2‑ and CH2=CH-CH2‑.

[0124] "Substituted alkyl" or "substituted alkenyl" mean alkyl or alkenyl, respectively, as defined above, substituted by one, two, or three substituents. The substituentsmay, for example, be selected from the group consisting of halogen, ‑OH, ‑NH2, ‑N(CH3)2, -C(=O)OH, ‑C(=O)O(C1‑C4)alkyl,methoxy, ethoxy, trifluoromethyl, ‑C(=O)NH2, -SO2NH2, ‑C(=NH)NH2, ‑C≡N, and ‑NO2, preferably selected from halogen and ‑OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoromethyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0125] The term "alkynyl," employed alone or in combinationwith other terms,means, unless otherwise stated, a stable carbon-carbon triple bond-containing radical (-C=C‑), branched chain, or cyclic hydrocarbon group having the stated number of carbon atoms. Examples include ethynyl and propargyl.

[0126] The term "alkoxy," employed alone or in combination with other terms, means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy ("isopropoxy"), and the higher homologs and isomers. Preferred are ‑(C1‑C3)alkoxy, particularly ethoxy and methoxy.

[0127] The terms "carbamyl" or "carbamoyl"mean thegroup ‑C(=O)NRR’,whereinRandR’ are independently selected fromhydrogenor ahydrocarbyl functional group, orwhereinRandR’ combined formaheterocycle. Examplesof carbamyl groups include: ‑C(=O)NH2 and ‑C(=O)N(CH3)2.

[0128] The term "cyano" refers to a ‑C≡N group.

[0129] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatommay be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: ‑O-CH2‑CH2‑CH3, ‑CH2‑CH2‑CH2‑OH, ‑CH2‑CH2‑NH-CH3, ‑CH2‑S-CH2‑CH3, and ‑CH2‑CH2‑S(=O)‑CH3. Up to two heteroatoms may be consecutive, such as, for example, ‑CH2‑NH-OCH3, or ‑CH2‑CH2‑S-S-CH3.

[0130] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a monovalent fluorine, chlorine, bromine, or iodine atom.

[0131] The term "nitro" refers to a ‑NO2 group.

[0132] The term "(Cx‑Cy)perfluoroalkyl," wherein x<y, means an alkyl group with a minimum of x carbons and a maximum of y carbons, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is ‑(C1‑C6)perfluoroalkyl, more preferred is ‑(C1‑C3)perfluoroalkyl, most preferred is ‑CF3.

[0133] The term "aromatic" generally refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

[0134] The term "aryl," employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings) wherein such rings may 34 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 be attached together in a pendant manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl; anthracyl; and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.

[0135] The term "2‑(methylenyl)phenyl," employed alone or in combination with other terms, means, unless otherwise stated, a substituted phenyl diradical having the following structural formula:

[0136] The terms "heterocycle" or "heterocyclyl" or "heterocyclic," by themselves or as part of another substituent, mean, unless otherwise stated, an unsubstituted or substituted, stable,mono‑ ormulti-cyclic heterocyclic ring system that consistsof carbonatomsandat least oneheteroatom independently selected from thegroupconsistingofN,O,andS,and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.

[0137] The terms "heteroaryl" or "heteroaromatic" refer to a heterocyclic having aromatic character. Similarly, the term "heteroaryl(C1‑C3)alkyl"meansa functional groupwherein a one to three carbonalkylene chain is attached to a heteroaryl group, e.g., ‑CH2‑CH2-pyridyl. The term "substituted heteroaryl(C1‑C3)alkyl" means a heteroaryl(C1‑C3)alkyl functional group in which the heteroaryl group is substituted. A polycyclic heteroaryl may include fused rings. Examples include indole, 1H-indazole, 1H-pyrrolo[2,3-b]pyridine, and the like. A polycyclic heteroarylmay include one ormore rings that are partially saturated. Examples include indoline, tetrahydroquinoline, and 2,3-dihydrobenzofuryl.

[0138] The term "heterocycle(C1‑C3)alkyl," by itself or as part of another substituent, means, unless otherwise stated, a functional groupwherein a (C1‑C3)alkylene chain is attached to aheterocyclic group, e.g.,morpholino-CH2‑CH2‑. As used herein, the term "substituted heterocycle(C1‑C3)alkyl" means a heterocycle(C1‑C3)alkyl functional group in which the heterocycle group is substituted.

[0139] Examples of non-aromatic heterocycles include monocyclic groups such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,4-dihydropyridine, 1,2,3,6-tetrahydropyridine, piperazine, N- methylpiperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro‑1,3-dioxepin, and hexamethyleneoxide.

[0140] Examples of heteroaryl groups include: pyridyl; pyrazinyl; pyrimidinyl, particularly 2‑ and 4-pyrimidinyl; pyrida- zinyl; thienyl; furyl; pyrrolyl, particularly 2-pyrrolyl; imidazolyl; thiazolyl; oxazolyl; pyrazolyl, particularly 3‑ and 5-pyrazolyl; isothiazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,3,4-triazolyl; tetrazolyl; 1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,3,4-thiadia- zolyl; and 1,3,4-oxadiazolyl.

[0141] Polycyclic heterocycles include both aromatic and non-aromatic polycyclic heterocycles. Examples of polycyclic heterocycles include: indolyl, particularly 3‑, 4‑, 5‑, 6‑, and 7-indolyl; indolinyl; indazolyl, particularly 1H-indazol‑5-yl; quinolyl; tetrahydroquinolyl; isoquinolyl, particularly 1‑ and 5-isoquinolyl; 1,2,3,4-tetrahydroisoquinolyl; cinnolyl; quinox- alinyl, particularly 2‑and5-quinoxalinyl; quinazolinyl; phthalazinyl; naphthyridinyl, particularly 1,5‑and1,8-naphthyridinyl; 1,4-benzodioxanyl; coumaryl; dihydrocoumaryl; benzofuryl, particularly 3‑, 4‑, 5‑, 6‑, and 7-benzofuryl; 2,3-dihydroben- zofuryl; 1,2-benzisoxazolyl; benzothienyl, particularly 3‑, 4‑, 5‑, 6‑, and 7-benzoethienyl; benzoxazolyl; benzothiazolyl, particularly 2‑ and 5-benzothiazolyl; purinyl; benzimidazolyl, particularly 2-benzimidazolyl; benztriazolyl; thioxanthinyl; carbazolyl; carbolinyl; acridinyl; pyrrolizidinyl; pyrrolo[2,3-b]pyridinyl, particularly 1H-pyrrolo[2,3-b]pyridine‑5-yl; and quinolizidinyl. Particularly preferred are 4-indolyl, 5-indolyl, 6-indolyl, 1H-indazol‑5-yl, and 1H-pyrrolo[2,3-b]pyridine‑5-yl.

[0142] The aforementioned listing of heterocyclic and heteroaryl moieties is intended to be representative and not limiting.

[0143] The term "substituted"means that an atomor group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the term "substituted" refers to any levels of substitution, namelymono‑, di‑, tri‑, tetra‑, or penta‑ substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position.

[0144] D-Ribosestereochemistryhasbeen indicated in compoundsor derivativeshaving formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and (VI), or salts, solvates, or prodrugs thereof. It is understood that the configuration at the anomeric carbon can be reversed (i.e., L‑), or can be a mixture of D‑ and L‑.

[0145] SyntheticPreparation ofCompoundsorDerivativesHavingFormulae (I), (I-H), (II), (III), (IV), (IV-H), (V), and (VI), or Salts, Solvates, or Prodrugs Thereof

[0146] In anembodiment, amethodofmakinga compoundor derivative having formula (2), or a salt thereof, can include the steps of: 35 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 (a) providing a compound or derivative having formula (2a), or a salt thereof, wherein when R14 of the compound or derivative ehaving formula (2a), or salt thereof, is methyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not acetoxy, andwhereinwhenR14 of the compound or derivative having formula (2a), or salt thereof, is phenyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not benzoxy; (b) treating the compound or derivative having formula (2a), or salt thereof, with at least a stoichiometric amount of a Brønsted acid or a nucleophilic substitution reagent, optionally generated in situ from an alcohol and an acyl chloride, in the presence of at least a molar equivalent amount of a polar organic solvent co-reagent; (c) processing the compound or derivative having formula (2a), or salt thereof, the Brønsted acid or nucleophilic substitution reagent, optionallygenerated in situ fromanalcoholandanacyl chloride, and thepolar organic solvent co- reagent so as to produce the compound or derivative having formula (2), or salt thereof; optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted compound or derivative having formula (2a), or salt thereof; and (d) isolating the compound or derivative having formula (2), or salt thereof.

[0147] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing under sealed conditions, milling, grinding, and extruding. Liquid-assisted mixing under sealed conditions may be performed between about 5 Hz and about 50 Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40Hz for about 15min to about 180min, andmost preferably betweenabout 20Hzandabout 30Hz for about 60 min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75 RPM and about 150 RPM, and most preferably between about 100 RPM and about 130 RPM.

[0148] The process described herein effects a preparation of a compound or derivative having formula (2), or salt thereof, under almost solventless conditions.

[0149] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (2), or salt thereof, can be a polar organic solvent from among, for example, preferably, the Class2ResidualSolvents listed inTable2, or optionally, for non-humanuse, theClass3ResidualSolvents listed inTable3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVEN- TION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety).

[0150] In another embodiment, a method of making a compound or derivative having formula (2), or a salt thereof, can include the steps of: (a) providing a compound or derivative having formula (2a), or a salt thereof, wherein when R14 of the compound or derivative having formula (2a), or salt thereof, ismethyl, thenX’ of the comoundor derivative having formula (2), or salt thereof, is not acetoxy, and wherein when R14 of the compound or derivative having formula (2a), or salt thereof, is phenyl, then X’ of the compound or derivative having formula (2), or salt thereof, is not benzoxy; (b) treating the compound or derivative having formula (2a), or salt thereof, with a (1<x<10) equivalent amount of a nucleophilic substitution reagent, optionally generated in situ by reacting an acyl chloride with an alcohol, in stoichiometrically equivalent molar amounts and in the presence of a molar (0<x<10) equivalent amount of a polar organic organic solvent co-reagent; (c) processing the compound or derivative having formula (2a), or salt thereof, the nucleophilic substitution reagent, and the polar organic solvent co-reagent, so as to produce the compound or derivative having formula (2), or salt thereof; optionally, (c1) evaporating any volatile by-products resulting from the processing step under reduced pressure and temperature-controlled conditions; and (d) isolating the compound or derivative having formula (2), or salt thereof.

[0151] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0152] The process described herein effects a preparation of a compound or derivative having formula (2), or salt thereof, under almost solventless conditions. 36 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0153] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (2), or salt thereof, can be a polar organic solvent from among, for example, preferably, the Class2ResidualSolvents listed inTable2, or optionally, for non-humanuse, theClass3ResidualSolvents listed inTable3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVEN- TION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0154] In an embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1), or a salt thereof; optionally, (b1) treating the compoundor derivative having formula (2), or salt thereof, and the compoundor derivative having formula (1), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1), or salt thereof; and (d) isolating the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio.

[0155] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0156] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0157] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha / beta) can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0158] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) adding a volume ofmethanol andwater in a 95:5weight:weight ratio to the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally inaparticular anomeric ratio (alpha / beta), at room temperature, soas to dissolve approximately 15% of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water; (b) stirring the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at 50° C until all of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), apparently dissolves in the volume ofmethanol and water; (c) cooling the solution of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water, to ‑10° C with stirring so as to precipitate the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) filtering the volumeofmethanol andwater and the crystalline formof thecompoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), so as to isolate the crystalline 37 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) drying the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0159] The process described herein effects a preparation of a crystalline form of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0160] In another embodiment, a method of making a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing riboside tetraacetate; (b) treating the riboside tetraacetatewith amolar equivalent amount of a compoundor derivative having formula (1), or a salt thereof; optionally, (b1) treating the riboside tetraacetate and the compound or derivative having formula (1), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the riboside tetraacetate, the compoundor derivativehaving formula (1), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted riboside tetraacetate; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1), or salt thereof; and (d) isolating the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio.

[0161] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0162] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0163] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0164] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) adding a volume ofmethanol andwater in a 95:5weight:weight ratio to the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally inaparticular anomeric ratio (alpha / beta), at room temperature, soas to dissolve approximately 15% of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water; (b) stirring the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at 50° C until all of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), apparently dissolves in the volume ofmethanol and water; (c) cooling the solution of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water, to ‑10° C with stirring so as to precipitate the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); 38 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 (d) filtering the volumeofmethanol andwater and the crystalline formof thecompoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), so as to isolate the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) drying the crystalline form of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0165] The process described herein effects a preparation of a crystalline form of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0166] In yet another embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (1), or a salt thereof; optionally, (a1) treating the compound or derivative having formula (1), or salt thereof, with excess trimethylsi- lylating reagent(s), and, optionally, heating the compound or derivative having formula (1), or salt thereof, and the trimethylsilylating reagent(s), to reflux for about 12 hours so as to produce a compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group; optionally, (a2) cooling the mixture to room temperature; optionally, (a3) removing the trimethylsilylating reagent(s); (b) treating the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMSgroup, with amolar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent; optionally, (b1) treating the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMSgroup, and the compoundor derivativehaving formula (2), or a salt thereof, in anorganic solvent co-reagent,with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, and the organic solvent co-reagent so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally produced in a particular anomeric ratio (alpha / beta); (d) adding water to, optionally, the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta); optionally, (d1) adding saturated NaHCO3 solution to, optionally, the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta), and water; optionally, (d2) adjusting the pH of the aqueous phase; optionally, (d3) separating the organic phase from the aqueous phase; (e) freeze-drying the aqueous phase to provide the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); optionally, (e1) dissolving the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol in a gas pressure tube; optionally, (e2) cooling the solution of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol to ‑78° C; optionally, (e3) bubbling ammonia gas into the solution of the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol; optionally, (e4) sealing the pressure tube; optionally, (e5) raising the temperature to ‑20°C; optionally, (e6) cooling the pressure tube at ‑20° C for about 12 hours to about 4 days, so as to produce a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen; 39 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 optionally, (e7) unsealing the gas pressure tube; and optionally, (e8) isolating the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen.

[0167] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0168] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0169] The organic solvent co-reagent employed in the above method of making a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACO- PEIA30<467> (U.S.PHARMACOPEIALCONVENTION2006) (USP30at <467>), incorporatedby referenceherein in its entirety.

[0170] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) dissolving the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in a volume of methanol; (b) adding a volume of acetone, of an equal volume to the volume of methanol, to the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol; (c) precipitating the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) isolating the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e)washing the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), with cold methanol.

[0171] The process described herein effects a preparation of a crystalline form of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0172] In yet another embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1) or a salt thereof; optionally, (b1) treating the compoundor derivative having formula (2), or salt thereof, and the compoundor derivative having formula (1), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (I), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8areeach ‑C(O)R’, andR’ ismethyl or ‑C1alkyl, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1), or salt thereof; and (d) isolating the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio. 40 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0173] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0174] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0175] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, andwherein R’ ismethyl or ‑C1alkyl, optionally inaparticular anomeric ratio (alpha / beta), canbeapolar organic solvent fromamong, for example, preferably, theClass2ResidualSolvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0176] In yet another embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing riboside tetraacetate; (b) treating the riboside tetraacetate with a stoichiometrically equivalent amount of a compound or derivative having formula (1), or a salt thereof; optionally, (b1) treating the riboside tetraacetate and the compound or derivative having formula (1), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the riboside tetraacetate, compoundor derivative having formula (1), or salt thereof, and, optionally, the TMSOTf soas toproduce thecompoundorderivativehaving formula (I), or salt, solvate, or prodrug threof,whereinR6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted riboside tetraacetate; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1), or salt thereof; and (d) isolating the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio.

[0177] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0178] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0179] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, andwherein R’ ismethyl or ‑C1alkyl, optionally inaparticular anomeric ratio (alpha / beta), canbeapolar organic solvent fromamong, for example, preferably, theClass2ResidualSolvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0180] In yet another embodiment, amethod ofmaking a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: 41 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 (a) providing a compound or derivative having formula (1), or a salt thereof; optionally, (a1) treating the compound or derivative having formula (1), or salt thereof, with excess trimethylsi- lylating reagent(s), and, optionally, heating the compound or derivative having formula (1), or salt thereof, and the trimethylsilylating reagent(s), to reflux for about 12 hours so as to produce a compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group; optionally, (a2) cooling the mixture to room temperature; optionally, (a3) removing the trimethylsilylating reagent(s); (b) treating the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMSgroup, with amolar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent; optionally, (b1) treating the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMSgroup, and the compoundor derivativehaving formula (2), or salt thereof, in anorganic solvent co-reagent,with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, and the organic solvent co-reagent soas toproduce thecompoundor derivativehaving formula (I), or salt, solvate, or prodrug thereof,wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally wherein each R1 is a TMS group, optionally produced in a particular anomeric ratio (alpha / beta); (d) adding water to, optionally, the compound or derivative having formula (1), or salt thereof, optionally wherein each R1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta); optionally, (d1) adding saturated NaHCO3 solution to, optionally, the compound or derivative having formula (1), or salt thereof, optionally wherein eachR1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, whereinR6, R7, andR8 are each ‑C(O)R’, andwhereinR’ is methyl or ‑C1alkyl, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta), and water; optionally, (d2) adjusting the pH of the aqueous phase; optionally, (d3) separating the organic phase from the aqueous phase; and (e) freeze-drying the aqueous phase to provide the compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0181] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0182] The process described herein effects a preparation of a compound or derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0183] The organic solvent co-reagent employed in the above method of making a compound of derivative having formula (I), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, theClass 2Residual Solvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACO- PEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0184] In anembodiment, amethodofmakingacompoundor derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: 42 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a), or a salt thereof; optionally, (b1) treating the compoundor derivative having formula (2), or salt thereof, and the compoundor derivative ehaving formula (1a), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1a), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1a), or salt thereof; and (d) isolating the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio.

[0185] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0186] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0187] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0188] In a particular embodiment, a method of making a crystalline form of a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) adding a volume ofmethanol andwater in a 95:5weight:weight ratio to the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at room temperature, so as to dissolve approximately 15% of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water; (b) stirring the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at 50° C until all of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), apparently dissolves in the volume ofmethanol and water; (c) cooling thesolutionof thecompoundor derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water, to ‑10° C with stirring so as to precipitate the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) filtering the volume of methanol and water and the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), so as to isolate the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) drying the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0189] The process described herein effects a preparation of a crystalline form of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0190] In another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or 43 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing riboside tetraacetate; (b) treating the riboside tetraacetate with amolar equivalent amount of a compound or derivative having formula (1a), or a salt thereof; optionally, (b1) treating the riboside tetraacetate and the compound or derivative having formula (1a), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the riboside tetraacetate, the compound or derivative having formula (1a), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted riboside tetraacetate; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1a), or salt thereof; and (d) isolating the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio.

[0191] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, and extruding. Liquid-assitedmixingmay be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0192] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0193] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0194] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) adding a volume ofmethanol andwater in a 95:5weight:weight ratio to the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at room temperature, so as to dissolve approximately 15% of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water; (b) stirring the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), at 50° C until all of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), apparently dissolves in the volume ofmethanol and water; (c) cooling thesolutionof thecompoundor derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol and water, to ‑10° C with stirring so as to precipitate the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) filtering the volume of methanol and water and the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), so as to isolate the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) drying the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0195] The process described herein effects a preparation of a crystalline form of a compound or derivative having 44 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0196] In yet another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (1a), or a salt thereof; optionally, (a1) treating the compound or derivative having formula (1a), or salt thereof, with excess trimethylsi- lylating reagent(s), and, optionally, heating the compound or derivative having formula (1a), or salt thereof, and the trimethylsilylating reagent(s), to reflux for about 12 hours so as to produce a compound or derivative having formula (1a), or salt thereof, optionally wherein each R1 is a TMS group; optionally, (a2) cooling the mixture to room temperature; optionally, (a3) removing the trimethylsilylating reagent(s); (b) treating thecompoundor derivativehaving formula (1a), or salt thereof, optionallywherein eachR1 isaTMSgroup, with amolar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent; optionally, (b1) treating the compoundor derivative having formula (1a), or salt thereof, optionallywherein eachR1 is a TMSgroup, and the compoundor derivativehaving formula (2), or salt thereof, in anorganic solvent co-reagent,with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (1a), or salt thereof, optionally wherein each R1 is a TMS group, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, and the organic solvent co-reagent so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally produced in a particular anomeric ratio (alpha / beta); (d) addingwater to, optionally, thecompoundor derivativehaving formula (1a), or salt thereof, optionallywherein each R1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta); optionally, (d1) adding saturatedNaHCO3 solution to, optionally, the compound or derivative having formula (1a), or salt thereof, optionally wherein eachR1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally wherein eachR1 is a TMSgroup, optionally in a particular anomeric ratio (alpha / beta), and water; optionally, (d2) adjusting the pH of the aqueous phase; optionally, (d3) separating the organic phase from the aqueous phase; (e) freeze-drying the aqueous phase to provide the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); optionally, (e1) dissolving the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol in a gas pressure tube; optionally, (e2) cooling the solution of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol to ‑78° C; optionally, (e3) bubbling ammonia gas into the solution of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in methanol; optionally, (e4) sealing the pressure tube; optionally, (e5) raising the temperature to ‑20°C; optionally, (e6) cooling the pressure tube at ‑20° C for about 12 hours to about 4 days, so as to produce a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen; optionally, (e7) unsealing the gas pressure tube; and optionally, (e8) isolating the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each hydrogen.

[0197] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most 45 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0198] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0199] The organic solvent co-reagent employed in the above method of making a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally inaparticular anomeric ratio (alpha / beta), canbeapolar organic solvent from among, for example, preferably, the Class 2 Residual Solvents listed in Table 2, or optionally, for non-human use, the Class 3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACO- PEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467), incorporated by reference herein in its entirety.

[0200] In a particular embodiment, a method of making a crystalline form of the compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) dissolving the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in a volume of methanol; (b) adding a volume of acetone, of an equal volume to the volume of methanol, to the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), in the volume of methanol; (c) precipitating the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); (d) isolating the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta); and (e) washing the crystalline form of the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), with cold methanol.

[0201] The process described herein effects a preparation of a crystalline form of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta).

[0202] In yet another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, andwhereinR’ ismethyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (2), or a salt thereof; (b) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a) or a salt thereof; optionally, (b1) treating the compoundor derivative having formula (2), or salt thereof, and the compoundor derivative having formula (1a), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1a), or salt thereof, and, optionally, TMSOTf soas to produce the compoundor derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted compound or derivative having formula (2), or salt thereof; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1a), or salt thereof; and (d) isolating the compoundorderivativehaving formula (Ia), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio.

[0203] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM. 46 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0204] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0205] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8areeach ‑C(O)R’, andwherein R’ ismethyl or ‑C1alkyl, optionally inaparticular anomeric ratio (alpha / beta), canbeapolar organic solvent fromamong, for example, preferably, theClass2ResidualSolvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0206] In yet another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, andwhereinR’ ismethyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing riboside tetraacetate; (b) treating the riboside tetraacetate with a stoichiometrically equivalent amount of a compound or derivative having formula (1a), or a salt thereof; optionally, (b1) treating the riboside tetraacetate and the compound or derivative having formula (1a), or salt thereof, with a molar equivalent amount of TMSOTf; (c) processing the riboside tetraacetate, the compound or derivative having formula (1a), or salt thereof, and, optionally, the TMSOTf so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each - C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally produced in a particular anomeric ratio (alpha / beta); optionally, (c1) removing by-products resulting from the processing step under reduced pressure and tempera- ture-controlled conditions; optionally, (c2) separately isolating unreacted riboside tetraacetate; optionally, (c3) adding acetone; optionally, (c4) separately isolating unreacted compound or derivative having formula (1a), or salt thereof; and (d) isolating the compoundorderivativehaving formula (Ia), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio.

[0207] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0208] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0209] Thepolar organic solvent co-reagent and isolation solvent employed in theabovemethodofmakinga compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8areeach ‑C(O)R’, andwherein R’ ismethyl or ‑C1alkyl, optionally inaparticular anomeric ratio (alpha / beta), canbeapolar organic solvent fromamong, for example, preferably, theClass2ResidualSolvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0210] In yet another embodiment, a method of making a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof, wherein R6, R7, andR8 are each ‑C(O)R’, andwhereinR’ ismethyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can include the steps of: (a) providing a compound or derivative having formula (1a), or a salt thereof; optionally, (a1) treating the compound or derivative having formula (1a), or salt thereof, with excess trimethylsi- lylating reagent(s), and, optionally, heating the compound or derivative having formula (1a), or salt thereof, and the trimethylsilylating reagent(s), to reflux for about 12 hours so as to produce a compound or derivative having formula (1a), or salt thereof, optionally wherein each R1 is a TMS group; 47 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 optionally, (a2) cooling the mixture to room temperature; optionally, (a3) removing the trimethylsilylating reagent(s); (b) treating thecompoundor derivativehaving formula (1a), or salt thereof, optionallywherein eachR1 isaTMSgroup, with amolar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent; optionally, (b1) treating the compoundor derivative having formula (1a), or salt thereof, optionallywherein eachR1 is a TMSgroup, and the compoundor derivativehaving formula (2), or salt thereof, in anorganic solvent co-reagent,with a molar equivalent amount of TMSOTf; (c) processing the compound or derivative having formula (1a), or salt thereof, optionally wherein each R1 is a TMS group, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, and the organic solvent co-reagent so as to produce the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally wherein each R1 is a TMS group, optionally produced in a particular anomeric ratio (alpha / beta); (d) addingwater to, optionally, thecompoundor derivativehaving formula (1a), or salt thereof, optionallywherein each R1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, whereinR6,R7, andR8are each ‑C(O)R’, andwhereinR’ ismethyl or ‑C1alkyl, optionallywherein eachR1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta); optionally, (d1) adding saturatedNaHCO3 solution to, optionally, the compound or derivative having formula (1a), or salt thereof, optionally wherein eachR1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, optionally, the TMSOTf, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof,whereinR6,R7, andR8areeach ‑C(O)R’, andwhereinR’ is methyl or ‑C1alkyl, optionally wherein each R1 is a TMS group, optionally in a particular anomeric ratio (alpha / beta), and water; optionally, (d2) adjusting the pH of the aqueous phase; optionally, (d3) separating the organic phase from the aqueous phase; and (e) freeze-drying the aqueous phase to provide the compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0211] Processing can be carried out under batch processing conditions or by continuously processing. Continuously processing may include one or more methods of agitation selected from the group consisting of liquid-assisted mixing, milling, grinding, andextruding. Liquid-assistedmixingmaybeperformedbetweenabout 5Hzandabout 50Hz for about 1 min to about 500 min, preferably between about 10 Hz and about 40 Hz for about 15 min to about 180 min, and most preferably between about 20 Hz and about 30 Hz for about 60min to about 120min. Grindingmay be performed between about 50RPMand about 200RPM, preferably between about 75RPMand about 150RPM, andmost preferably between about 100 RPM and about 130 RPM.

[0212] The process described herein effects a preparation of a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof, wherein R6, R7, and R8 are each ‑C(O)R’, and wherein R’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta).

[0213] The organic solvent co-reagent and isolation solvent employed in the above method of making a compound or derivative having formula (Ia), or salt, solvate, or prodrug thereof,whereinR6,R7, andR8areeach ‑C(O)R’, andwhereinR’ is methyl or ‑C1alkyl, optionally in a particular anomeric ratio (alpha / beta), can be a polar organic solvent from among, for example, preferably, theClass2ResidualSolvents listed in Table 2, or optionally, for non-humanuse, theClass 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated by reference herein in its entirety.

[0214] It is understood that the pHcanbeadjusted to the isoelectric point of the product compound(s) or derivative(s), or near neutral pH. Precipitation of the product compound(s) or derivative(s) can be carried out using an appropriate water miscible, or other generally nontoxic, solvent. 48 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0215] An embodiment of the chemoselective, and optionally stereoselective, synthesis of a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally in a particular anomeric ratio (alpha / beta), is shown above in Scheme A.

[0216] An embodiment of the chemoselective synthesis of a compound or derivative having formula (I-H), or a salt, solvate, or prodrug thereof, is shown above in Scheme B.

[0217] An alternative embodiment of the chemoselective synthesis of a compound or derivative having formula (I-H), or a salt, solvate, or prodrug thereof, is shown above in Scheme C. 49 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0218] An embodiment of the chemoselective synthesis of a compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, is shown above in Scheme D.

[0219] An alternative embodiment of the chemoselective synthesis of a compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, is shown above in Scheme E. 50 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0220] An embodiment of the chemoselective synthesis of a compound or derivative having formula (III), or a salt, solvate, or prodrug thereof, is shown above in Scheme F.

[0221] An embodiment of the chemoselective, and optionally stereoselective, synthesis of a compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, is shown above in Scheme G. 51 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0222] An embodiment of the chemoselective synthesis of a compound or derivative having formula (IV-H), or a salt, solvate, or prodrug thereof, is shown above in Scheme H.

[0223] An alternative embodiment of the chemoselective synthesis of a compound or derivative having formula (IV-H), or a salt, solvate, or prodrug thereof, is shown above in Scheme I.

[0224] An embodiment of the chemoselective synthesis of a compound or derivative having formula (V), or a salt, solvate, or prodrug thereof, is shown above in Scheme J.

[0225] An alternative embodiment of the chemoselective synthesis of a compound or derivative having formula (V), or a salt, solvate, or prodrug thereof, is shown above in Scheme K. 52 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0226] An embodiment of the chemoselective synthesis of a compound or derivative having formula (VI), or a salt, solvate, or prodrug thereof, is shown above in Scheme L.

[0227] In the embodiments shown above in Schemes A - L: optionallywhereinX- as counterion isabsent, orwhenX- is present, X- is selected from thegroupconsistingof fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluor- oacetate; optionally wherein when X- is absent, optionally the counterion is an internal salt; optionally X- is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and, optionally X- is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propanoic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (being lactic acid, the anion of lactic acid being lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, and trifluoroacetate; and, optionallyX- is ananionof anunsubstitutedmonocarboxylic acid selected from formicacid, acetic acid, propionic acid, or butyric acid, being formate, acetate, propionate, and butyrate, respectively; and, optionally X- is an anion of a substituted or unsubstituted amino acid, i.e., amino-monocarboxylic acid or an amino- dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respec- tively; and, optionally X- is an anion of ascorbic acid, being ascorbate; and, optionally X- is a halide selected from fluoride, chloride, bromide, or iodide; and, optionally X- is an anion of a substituted or unsubstituted sulfonate, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; and, optionally X- is an anion of a substituted or unsubstituted carbonate, further optionally hydrogen carbonate; and, optionally X- is an anion of a substituted or unsubstituted glutathione or glutathione disulfide; wherein the substituted carboxylic acid, substituted monocarboxylic acid, substituted propanoic acid, substituted acetic acid, substituted amino acid, substituted sulfonate, substituted carbonate, substituted glutathione, and substituted glutathione disulfide are substituted with one to five substituents independently selected from the group 53 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; wherein X’ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate, phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloro- methanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; each Y1 and Y2 is independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8) cycloalkyl, substitutedaryl, substitutedheteroaryl, substitutedheterocycle, andsubstitutedaminoaresubstitutedwith one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, - ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O) NRC 2, ‑NRCSO2NRC 2, - SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; or, alternatively, Y1 and Y2 taken together are selected from the group consisting of sodium, potassium, lithium, magnesium, calcium, strontium, barium, and substituted or unsubstituted 2‑(methylenyl)phenyl; wherein the sub- stituted 2‑(methylenyl)phenyl is substituted with one to four substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; each W1 and W2 is independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8) cycloalkyl, substitutedaryl, substitutedheteroaryl, substitutedheterocycle, andsubstitutedaminoaresubstitutedwith one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O) NRC 2, ‑NRCSO2NRC 2, - SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1 ‑C6)alkylene-ORC; or, alternatively, W1 and W2 taken together are selected from the group consisting of sodium, potassium, lithium, magnesium, calcium, strontium, barium, and substituted or unsubstituted 2‑(methylenyl)phenyl; wherein the sub- stituted 2‑(methylenyl)phenyl is substituted with one to four substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; or, alternatively, Y1 and W1 taken together are selected from the group consisting of sodium, potassium, lithium, magnesium, calcium, strontium, barium, and substituted or unsubstituted 2‑(methylenyl)phenyl; wherein the sub- stituted 2‑(methylenyl)phenyl is substituted with one to four substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, - C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; optionally wherein Y3 is oxygen, sulfur, or absent; optionally wherein W3 is oxygen, sulfur, or absent; each of Z1 and Z2 is independently NH or oxygen; each of Z3, Z4, Z5, and Z6 is independent nitrogen or oxygen; m is 1 or 2; n is 0 or 1; q is 1 or 2; 54 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 t is 1 or 2; u is 1 or 2; each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero- aryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, TMS, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2, and - C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, - (C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, - C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, - (C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, - NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; whereinwhenR1 is hydrogen, Z2 is oxygen,m is 1, and n is 0, the compoundor derivativemayoptionally take the form of the carboxylate anion conjugate base species of the compound or derivative, further optionally associated with a positively charged counterion selected from the group consisting of alkali metal, alkaline earthmetal, transitionmetal, and base addition cations; RA is selected from the group consisting of ‑H, ‑(C1‑C6)alkyl, - (CH2)3‑NH-C(NH2)(=NH), ‑CH2C(=O)NH2, ‑CH2COOH, ‑CH2SH, ‑(CH2)2C(=O)‑NH2, ‑(CH2)2COOH, ‑CH2‑(2-imidazolyl), ‑CH(CH3)‑CH2‑CH3, ‑CH2CH(CH3)2, ‑(CH2)4‑NH2, ‑(CH2)2‑S-CH3, phenyl, ‑CH2-phenyl, ‑CH2‑OH, ‑CH(OH)‑CH3, ‑CH2‑(3-indolyl), ‑CH2‑(4-hydroxyphe- nyl), ‑CH(CH3)2, ‑NH2, and ‑CH2‑CH3; each RB is independently hydrogen or ‑(C1‑C8)alkyl; eachRC is independently selected from the group consisting of hydrogen, - (C1‑C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compound or derivative having formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6) alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RB, ‑C(O)ORB, ‑C(O)NRB 2, - C(=NRB)NRB 2, ‑ORB, ‑OC(O)(C1‑C6)alkyl, ‑OC(O) O(C1‑C6)alkyl, ‑OC(O)NRB 2, ‑(C1‑C6)alkylene-NRB 2, ‑NRB 2, ‑NRBC(O)RB, ‑NRBC(O)O(C1‑C6)alkyl, ‑NRBC(O) NRB 2, ‑NRBSO2NRB 2, ‑SRB, ‑S(O)RB, ‑SO2RB, ‑OSO2(C1‑C6)alkyl, ‑SO2NRB 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORB; R2 and R3 are each independently selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, - NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R4 is selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, -ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O) NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; wherein C* has an absolute configuration of R or S, or a mixture of R and S; R5 is selected from the group consisting of hydrogen, ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O) NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and - (C1‑C6)alkylene-ORC; R6 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, glutathione ester, glutathione disulfide ester, aryl(C1‑C4) alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, ‑C**H‑(RA)‑NH2,and ‑C**H‑(RA)‑CO2RB;wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, - C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R’ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substitutedorunsubstitutedaryl, substitutedorunsubstitutedheteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A 55 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 ester, resveratrol ester, aryl(C1‑C4)alkyl, heterocycle(C1‑C4)alkyl, ‑N(RA)‑CO2RC, ‑N(RA)‑CO2RB, - C**H‑(RA)‑NH2, and ‑C**H‑(RA)‑CO2RB; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, sub- stituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O) ORC, -C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6)alky- lene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R7 and R8 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R9 and R10 are independently selected from the group consisting of hydrogen, - C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of - (C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, - C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, - OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, - NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, - OSO2(C1‑C6)alkyl, ‑SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R11 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, substi- tuted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1‑C4)alkyl, and substituted hetero- cycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, - (C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, - C(=NRC) NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, - (C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O) RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, - NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, ‑SO2NRC 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; R12 is selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, - C(O)NHR’, substituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsub- stituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1‑C4)alkyl, and sub- stituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, - (C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, - C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, ‑OC(O)NRC 2, - (C1‑C6)alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, ‑NRCC(O)NRC 2, - NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6) alkyl, ‑SO2NRC 2, - (C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; each R13 is independently selected from the group consisting of hydrogen, ‑C(O)R’, ‑C(O)OR’, ‑C(O)NHR’, sub- stituted or unsubstituted (C1‑C8)alkyl, substituted or unsubstituted (C1‑C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1‑C4)alkyl, and substituted or unsubstituted heterocycle(C1‑C4)alkyl; wherein the substituted (C1‑C8)alkyl, substituted (C1‑C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted ar- yl(C1‑C4)alkyl, and substituted heterocycle(C1‑C4)alkyl are substituted with one to five substituents independently selected from the group consisting of ‑(C1‑C6)alkyl, ‑(C2‑C6)alkenyl, ‑(C2‑C6)alkynyl, halogen, ‑CN, ‑NO2, ‑C(O)RC, ‑C(O)ORC, ‑C(O)NRC 2, ‑C(=NRC)NRC 2, ‑ORC, ‑OC(O)(C1‑C6)alkyl, ‑OC(O)O(C1‑C6)alkyl, - OC(O)NRC 2, ‑(C1‑C6) alkylene-NRC 2, ‑NRC 2, ‑NRCC(O)RC, ‑NRCC(O)O(C1‑C6)alkyl, -NRCC(O)NRC 2, ‑NRCSO2NRC 2, ‑SRC, ‑S(O)RC, ‑SO2RC, ‑OSO2(C1‑C6)alkyl, - SO2NRC 2, ‑(C1‑C6)perfluoroalkyl, and ‑(C1‑C6)alkylene-ORC; provided that the absolute configuration of C** is R or S, or a mixture of R and S. 56 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0228] As discussed above, the existing prior art approaches, for themost part, utilize solvent-mediated approaches to prepare the nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof. Such processes are cumbersome, inefficient, and not scalable.

[0229] Asused herein, the terms "trimethylsilylating agent(s)" or "trimethylsilylating reagent(s)," alone or in combination with other terms, refer to compounds that include one or more tetravalent silicon atoms each covalently bonded to three methyl groups (i.e., trimethylsilyl ("TMS") group) and, upon reaction with organic compounds containing an oxygen- hydrogen or nitrogen-hydrogen covalent bond, yield an organic compoundwherein the hydrogen of the oxygen-hydrogen or nitrogen-hydrogen covalent bond has been replaced with the trimethylsilyl (TMS) group such that the silicon atom is instead covalently bonded to the oxygen or nitrogen. The trimethylsilylating is preferably carried out by dissolving the organic compound in excess molar equivalents of hexamethyldisilazane ("HMDS") as a trimethylsilylating reagent, optionally with at least a catalytic amount of ammonium sulfate ("(NH4)2SO4"). Preferred reaction conditions include a temperature of 0° C to reflux and a time of about 2 hours to about 12 hours. It is noted that trimethylsilylating can also be carriedout bydissolvinganorganic compound inanorganic solvent and reacting itwith excess trimethylsilyl chloride in the presence of an excess of organic amine base, for example, triethylamine ("Et3N" or "TEA"), optionally further in the presence of HMDS. It is noted that trimethylsilylating can alternatively be carried out by using excess bis(trimethylsilyl) acetamide ("BSA") as a trimethylsilylating reagent. The person skilled in the art knows further processes that can be used to introduce trimethylsilyl groups, because trimethylsilylating agent(s) and reagent(s) have been extensively documented in the chemical literature.

[0230] As used herein, the terms "phosphorylating agent" or "phosphorylating reagent," alone or in combination with other terms, refer to compounds that includeaphosphorusatom in the+5oxidation state and, upon reactionwith hydroxyl- containing compounds, yield a phosphate triester.

[0231] One suitable phosphorylating agent or reagent is phosphorus oxychloride (POCl3). Other suitable phosphor- ylating agents or reagents (or phosphorus reagent systems) include compounds having formula P(O)Cl(ORX)(ORY) that include CAS Numbers 2524‑64‑3, 6609‑64‑9, 814‑49‑3, 14254‑41‑2, 2574‑25‑6, 813‑77‑4, 1499‑17‑8, 2510‑89‑6, 819‑43‑2, 5381‑98‑6, 538‑37‑4, 57188‑46‑2, 81639‑99‑8, 17672‑53‑6, 4090‑55‑5, 17776‑78‑2, 6630‑13‑3, 56119‑60‑9, 77075‑54‑8, 89104‑48‑3, 6546‑97‑0, 6630‑15‑5, 16383‑57‑6, 381‑44‑2, 124648‑60‑8, 17788‑08‑8, 58377‑73‑4, 6630‑14‑4, 17158‑87‑1, 17677‑92‑8, 51103‑92‑5, 52258‑06‑7, 56623‑07‑5, 58377‑74‑5, 85363‑77‑5, 112966‑13‑9, 167907‑25‑7, 179695‑78‑4, 877458‑32‑7, 1424937‑89‑2, 1424939‑04‑7, 2035‑83‑8, 127164‑51‑6, 6719‑79‑5, 59819‑52‑2, 69919‑18‑2, 77181‑80‑7, 4040‑23‑7, 6533‑33‑1, 6719‑82‑0, 6719‑84‑2, 22939‑24‑8, 27315‑40‑8, 28888‑24‑6, 61550‑37‑6, 73992‑66‑2, 86531‑53‑5, 96357‑53‑8, 108249‑87‑2, 343863‑91‑2, 875893‑99‑5, 714‑87‑4, 6087‑94‑1, 13674‑83‑4, 56883‑17‑1, 88805‑00‑9, 92401‑83‑7, 93115‑98‑1, 120628‑26‑4, 130312‑59‑3, 315179‑27‑2, 1388636‑60‑9, 1388636‑61‑0; and compounds having formula P(O)Cl2(ORZ) that include CAS Numbers 770‑12‑7, 1498‑51‑7, 15074‑54‑1, 777‑52‑6, 677‑24‑7, 772‑79‑2, 4167‑02‑6, 1455‑05‑6, 31651‑76‑0, 53676‑22‑5, 18868‑46‑7, 53676‑18‑9, 940‑18‑1, 84681‑46‑9, 878‑17‑1, 105053‑57‑4, 149864‑64‑2, 6964‑36‑9, 18350‑98‑6, 53676‑17‑8, 60223‑35‑0, 25359‑51‑7,2035‑84‑9, 2196‑02‑3, 382608‑79‑9, 775‑08‑6, 30333‑08‑5, 1479‑10‑3, 2213‑71‑0, 5305‑82‑8, 5995‑77‑7, 13674‑82‑3, 13825‑97‑3, 17788‑07‑7, 19430‑76‑3, 19430‑77‑4, 20056‑41‑1, 20464‑68‑0, 31735‑82‑7, 36196‑79‑9, 41998‑90‑7, 52198‑45‑5, 53121‑39‑4, 53121‑41‑8, 99884‑77‑2, 105053‑58‑5, 125440‑36‑0, 140468‑02‑6, 140468‑03‑7, 184528‑24‑5, 870673‑87‑3, 916893‑01‑1, 1498‑52‑8, 20464‑67‑9, 38135‑34‑1, 41240‑73‑7, 62485‑00‑1, 78840‑91‑2, 313946‑12‑2, 1242826‑74‑9. RX, RY, and RZ may be the same or different, and include, but are not limited to, simple alkyl.

[0232] Asusedherein, the terms "phosphitylatingagent" or "phosphitylating reagent," aloneor in combinationwithother terms, refer to compounds that include a phosphorus atom in the +3 oxidation state and, upon reaction with hydroxyl- containing compounds, yield a phosphite triester.

[0233] As used herein, the term "thiophosphorylating agent," alone or in combination with other terms, refers to compounds that include a phosphorus atom in the +5 oxidation state and with a bond to a sulfur atom, and which, upon reaction with hydroxyl-containing compounds, yield a thiophosphate triester. One suitable thiosphorylating reagent is phoshoryl thiochloride (P(S)Cl3).

[0234] As used herein, the term "carbodiimide reagent," alone or in combination with other terms, refers to alkylcarbo- diimide reagents, including, but not limited to, dicyclohexylcarbodiimide ("DCC"), diisopropylcarbodiimide ("DCI"), and ethyl‑(N’,N-dimethylamino)propylcarbodiimide hydrochloride ("EDC"). Without being bound by theory, it is believed that carbodiimide reagents can activate one phosphate monoester for displacement with another, with subsequent formation of a pyrophosphate linkage.

[0235] Asusedherein, the term "divalentmetal salt," aloneor in combinationwith other terms, refers to ionic compounds that include a cationic species arising from ametallic element that can attain a formal charge of +2 (i.e., "divalent"). Such metallic elements include, but are not limited to zinc (i.e., "Zn+2"), magnesium (i.e., "Mg+2"), manganes (i.e., "Mn+2"), and cadmium (i.e., "Cd+2"). Without being bound by theory, it is believed that divalent metal salts will facilitate the reaction of activated monophosphates as, for example, morpholidates or phosphoroimidazolates, with another monophosphate, to achieve the desired pyrophosphate linkage and produce the desired adenylyl dinucleotide conjugate. 57 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55

[0236] Without being bound by theory, it is believed that a monophosphate can be activated as a phosphoramidate by reactionwith an appropriate amine. The activatedmonophosphate could then be reactedwith anothermonophosphate to achieve the desired pyrophosphate linkage and produce the desired adenylyl dinucleotide conjugate. Non-limiting examples of amines include, for example,morpholine, and other amines that are presently disclosed herein. Alternatively, without being bound by theory, it is believed that amonophosphate can be activated by reactionwith an acid, in an amount ranging from catalytic amounts up to stoichiometric or molar equivalent amounts. Non-limiting examples of acids are presently disclosed herein.

[0237] The person of ordinary skill in the art knows further processes that can be used to introduce pyrophosphate linkages, because conditions and reagents for the syntheses of pyrophosphate linkages have been extensively docu- mented in the chemical literature.

[0238] The compounds or derivatives having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI), or salts, solvates, or prodrugs thereof, synthesized by the methods of the present disclosure, and intermediates, may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization, or chromatography, including flash column chromatography, preparative TLC, HPTLC,HPLC,or rp-HPLC.Onepreferredmethod for purificationof thecompoundsorderivativeshaving formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI), or salts, solvates, or prodrugs thereof, comprises crystallizing the compound or derivative, or salt, solvate, or prodrug thereof, from a solvent, to form, preferably, a crystalline form of the compound or derivative, or salt, solvate, or prodrug thereof. Following crystallization, the crystallization solvent is removed by a process other than evaporation, for example, filtration or decanting, and the crystals are thenpreferablywashedusing pure solvent (or a mixture of pure solvents). Preferred solvents for crystallization include water; alcohols, particularly alcohols containing up to four carbon atoms, such as methanol, ethanol, isopropanol, butan‑1-ol, butan‑2-ol, and 2-methyl‑2- propanol; ethers, for example diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; carboxylic acids, for example formic acid and acetic acid; hydrocarbon solvents, for example pentane, hexane, and toluene; and mixtures thereof, particularly aqueous mixtures such as aqueous methanol, ethanol, iso- propanol, and acetone. Pure solvents, preferably at least analytical grade, andmore preferably pharmaceutical grade are preferably used. In a preferred embodiment of the processes of the invention, the products are so isolated. In the compoundsor derivativeshaving formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI), or salts, solvates, or prodrugs thereof, synthesized by themethods of the present disclosure, the compounds or derivatives having formula (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI), or salts, solvates, or prodrugs thereof, synthesized by the methods of the present disclosure, are preferably in or prepared from a crystalline form, preferably prepared according to such a process. Alternatively, the compounds or derivatives having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI), or salts, solvates, or prodrugs thereof, synthesized by themethodsof the present disclosure, canbe isolated using lyophilization or freeze-drying techniques, following ion-exchange purification, thus avoiding use of non-aqueous solvents.

[0239] The synthetic methods described above reflect a convergent synthesis strategy. Thus, two components may be synthesized and elaborated separately prior to condensing or coupling the compounds to form the target compounds. These convergent synthetic schemes allow for arrangement of the assembly steps of the backbone of the target compounds and derivatization of derivatizable functionalities to accommodate functional group sensitivity and / or to allow for functional groups or elements to be introduced either before or after the assembly of the backbone of the target compounds via the condensation or coupling reactions described.

[0240] It will be appreciated by one skilled in the art that certain aromatic substituents in compounds synthesized by the methods of the present disclosure, intermediates used in the processes above, or precursors to the compounds synthesized by the methods of the present disclosure, may be introduced by employing aromatic substitution reactions to introduce or replace a substituent, or by using functional group transformations to modify an existing substituent, or a combination thereof. Such reactions may be effected either prior to or immediately following the processes mentioned above, and are included as part of the process aspect of the invention. The reagents and reaction conditions for such procedures are known in the art. Specific examples of procedures that may be employed include, but are not limited to, electrophilic functionalization of an aromatic ring, for example via nitration, halogenation, or acylation; transformation of a nitro group to an amino group, for example via reduction, such as by catalytic hydrogenation; acylation, alkylation, or sulfonylation of an amino or hydroxyl group; replacement of an amino group by another functional group via conversion to an intermediate diazoniumsalt followedby nucleophilic or free radical substitution of the diazoniumsalt; or replacement of a halogen by another group, for example via nucleophilic or organometallically-catalyzed substitution reactions.

[0241] Additionally, in the aforesaid processes, certain functional groups that would be sensitive to the reaction conditions may be protected by protecting groups. A protecting group is a derivative of a chemical functional group that would otherwise be incompatible with the conditions required to perform a particular reaction that, after the reaction has been carried out, can be removed to regenerate the original functional group, which is thereby considered to have been "protected."Anychemical functionality that isastructural componentof anyof the reagentsused tosynthesizecompounds synthesized by themethods of the present disclosuremay be optionally protectedwith a chemical protecting group if such a protecting group is useful in the synthesis of compounds synthesized by the methods of the present disclosure. The 58 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 person skilled in theart knowswhenprotectinggroupsare indicated, how toselect suchgroups, andprocesses that canbe used for selectively introducingandselectively removing them, becausemethodsof selectingandusingprotectinggroups have been extensively documented in the chemical literature. Techniques for selecting, incorporating, and removing chemical functional groups may be found, for example, in THEODORAW. GREENE & PETER G.M. WUTS, PROTEC- TIVEGROUPS INORGANIC SYNTHESIS (JohnWiley & Sons, Inc. 1999), the entire disclosure of which is incorporated herein by reference.

[0242] In addition to use of a protecting group, sensitive functional groupsmay be introduced as synthetic precursors to the functional groups desired in the intermediate or final product. An example of this is an aromatic nitro (-NO2) group. The aromatic nitro group does not undergo any of the nucleophilic reactions of an aromatic amino group. However, the nitro group can serve as the equivalent of a protected amino group because it is readily reduced to the amino group under mild conditions that are selective for the nitro group over most other functional groups.

[0243] It will be appreciated by one skilled in the art that the processes described are not the exclusivemeans by which compounds synthesized by the methods of the present disclosure may be synthesized and that an extremely broad repertoire of synthetic organic reactions is available to bepotentially employed in synthesizing compoundssynthesizedby the methods of the present disclosure. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods may be identified by reference to the literature, including reference sources such as COMPREHENSIVE ORGANIC SYNTHESIS (B.M. Trost & I. Fleming eds., Pergamon Press 1991); COMPRE- HENSIVE ORGANIC FUNCTIONAL GROUP TRANSFORMATIONS (A.R. Katritzky, O. Meth-Cohn, & C.W. Rees eds., PergamonPress 1996); COMPREHENSIVEORGANIC FUNCTIONALGROUPTRANSFORMATIONS II (A.R. Katritzky & R.J.K. Taylor eds., 2d ed., Elsevier 2004); COMPREHENSIVE HETEROCYCLIC CHEMISTRY (A.R. Katritzky & C.W. Rees eds., Pergamon Press 1984); COMPREHENSIVE HETEROCYCLIC CHEMISTRY II (A.R. Katritzky, C.W. Rees, & E.F.V. Scriven eds., PergamonPress 1996); and J.MARCH, ADVANCEDORGANICCHEMISTRY (4th ed., JohnWiley& Sons, Inc. 1992). Salts of Compounds or Derivatives Synthesized According to the Methods of the Present Disclosure

[0244] The compounds or derivatives synthesized by themethods of the present disclosure may take the form of salts. The term "salts" embraces addition salts of free acids or free bases that are compounds or derivatives synthesized by the methodsof thepresent disclosure.The term "pharmaceutically acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications.

[0245] Suitable pharmaceutically acceptable acid solution salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoroacetic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sul- fanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric, and galacturonic acid. In the present examples of compounds or derivatives having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), or (VI), or salts, solvates, or prodrugs thereof, i.e., compounds containing amino groups, pyridine, or reduced pyridine, said compounds can be isolated as salts of inorganic acids or strong organic acids, e.g., hydrochloric acid or trifluoroacetic acid.

[0246] Suitable pharmaceutically acceptable base addition salts of compounds or derivatives synthesized by the methods of the present disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transitionmetal salts suchas, for example, calcium,magnesium,potassium, sodium,andzinc salts. Further, baseaddition salts of compounds synthesized by the methods of the present disclosure include, for example, ammonium salts. Pharmaceutically acceptable base addition salts also include organic saltsmade frombasic amines such as, for example, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylgluca- mine), tromethamine (tris(hydroxymethyl)aminomethane), and procaine.

[0247] All of these salts may be prepared by conventional means from the corresponding compounds or derivatives having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), (VI), or salts, solvates, or prodrugs thereof, by reacting, for example, the appropriate acid or basewith the compoundor derivative having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), or (VI), or salts, solvates, or prodrugs thereof. Preferably, the salts are in crystalline form, or alternatively in dried or freeze-dried form. The person skilled in the art will know how to prepare and select suitable salt forms for example, as described in P.H. STAHL & C.G. WERMUTH, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION, AND USE (Wiley-VCH 2002).

[0248] The term "prodrug" as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and / or metabolic chemical reaction(s), or a combination of each. Standard prodrugs are formed using groups 59 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 attached to functionality, e.g., ‑OH, ‑SH, ‑COOH, ‑NR2, associated with the drug, that cleave in vivo. Standard prodrugs include, but are not limited to, carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonylox- yalkyl, as well as esters of hydroxyl, thiol, and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate.Thegroups illustratedareexemplary, not exhaustive, andoneskilled in theart could prepare other known varieties of prodrugs. Such prodrugs of the compounds or derivatives having formula (I), (I-H), (II), (III), (IV), (IV-H), (V), and / or (VI) fall within the scopeof themethodsof the present invention. Prodrugsmust undergo some form of a chemical transformation to produce the compound or derivative that is biologically active or is a precursor of the biologically active compound. In somecases, theprodrug is biologically active, usually less than thedrug itself, andserves to improvedrugefficacyorsafety through improvedoral bioavailability, pharmacodynamichalf-life, etc.Asusedherein, the term "derivative," alone or in combination with other terms, can include a prodrug.

[0249] The nutraceutical compositions of the present disclosure may be administered in combination with a nutraceu- tically acceptablecarrier. Theactive ingredients insuch formulationsmaycomprise from1%byweight to99%byweight, or alternatively, 0.1% by weight to 99.9% by weight. "Nutraceutically acceptable carrier" means any carrier, diluents, or excipient that is compatiblewith the other ingredients of the formulation andnot deleterious to the user. In accordancewith one embodiment, suitable nutraceutically acceptable carriers can include ethanol, aqueous ethanol mixtures, water, fruit, and / or vegetable juices, and combinations thereof. Delivery System

[0250] Suitable dosage forms include tablets, capsules, solutions, suspensions, powders, gums, and confectionaries. Sublingual delivery systems include, but are not limited to, dissolvable tabs under and on the tongue, liquid drops, and beverages. Edible films, hydrophilic polymers, oral dissolvable films, or oral dissolvable strips can be used. Other useful delivery systems comprise oral or nasal sprays or inhalers, and the like.

[0251] Fororal administration, acompoundorderivativehaving formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), or (VI), or a salt, solvate, or prodrug thereofmaybe further combinedwithoneormore solid inactive ingredients for thepreparation of tablets, capsules, pills, powders, granules, or other suitable dosage forms. For example, the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents, absorbents, or lubricating agents. Other useful excipients include magnesium stearate, calcium stearate, mannitol, xylitol, sweeteners, starch, carboxymethylcellulose, microcrystalline cellulose, silica, gelatin, silicon dioxide, and the like.

[0252] The compounds or derivatives synthesized by the methods of the present disclosure, together with a conven- tional adjuvant, carrier, or diluents, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof. Such forms include solids, and in particular, tablets, filled capsules, powder, and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principals, and such unit dosage formsmay contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

[0253] The compounds or derivatives synthesized by the methods of the present disclosure can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the followingdosage forms may comprise, as the active component, either a chemical compound or derivative synthesized by the methods of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug of a chemical compound or derivative synthesized by the methods of the present disclosure.

[0254] For preparing pharmaceutical compositions from a chemical compound or derivative synthesized by the methods of the present disclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier canbeoneormore substances thatmayalsoact asdiluents, flavoringagents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0255] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active components. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0256] The powders and tablets preferably contain from about five or ten to about seventy percent of the active compound(s) or derivative(s) synthesized by themethods of the present disclosure. Suitable carriers aremicrocrystalline cellulose, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmeltingwax, cocoabutter, and the like, andother excipientsmay includemagnesiumstearate, stearic acid, talc, silicon dioxide, etc. The term "preparation" is intended to include the formulation of active compoundwith encapsulatingmaterial as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Tablets, powders, capsules, pills, sachets, and lozenges are included. Tablets, powders, 60 EP 4 744 667 A2 5 10 15 20 25 30 35 40 45 50 55 capsules, pills, sachets, and lozenges can be used as solid forms suitable for oral administration.

[0257] Liquidpreparations includesolutions, suspensions, andemulsions, for example,water orwater-propyleneglycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Thechemical compoundsor derivatives synthesizedby themethodsof the present disclosuremay thusbe formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) andmay be presented in unit dose for example in ampoules, pre-filled syringes, small volume infusion, or inmulti-dose containerswith anaddedpreservative). Thecompositionsmay takesuch formsassuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulation agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0258] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizingand thickeningagents, asdesired.Aqueoussuspensionssuitable for oral usecanbe made by dispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0259] Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoredbase, usually sucroseandacacia or tragacanth; pastilles comprising theactive ingredient in an inert base suchas gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in suitable liquid carrier.

[0260] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette, or spray. The compositions may be provided in single or multi-dose form. In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound or derivative will generally have a small particle size, for example, of the order of 5microns or less. Such a particle sizemay be obtained bymeans known in the art, for example by micronization.

[0261] Thepharmaceutical preparationsare preferably in unit dosa...

Claims

1. A crystalline Form I of nicotinamide riboside triacetate (NRTA) chloride according to formula (IX):

2. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 19.6, 22.1, and 26.6 degrees two theta ± 0.2 degrees two theta.

3. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 9.8, 19.2, 19.6, 22.1, and 26.6 degrees two theta ± 0.2 degrees two theta.

4. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 9.8, 14.5, 18.6, 19.2, 19.6, 22.1, 22.5, and 26.6 degrees two theta ± 0.2 degrees two theta.

5. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 18.

6. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 2 ± 0.2 degrees two theta.

7. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks at 626.8, 644.1, and 916.0 cm-1 ± 0.2 cm-1.

8. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, and 1114.7 cm-1 ± 0.2 cm-1.

9. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, 1114.7, 1205.3, 1240.0, 1683.6, and 1737.6 cm-1 ± 0.2 cm-1.

10. The crystalline Form I of claim 1 that is characterized by an IR spectrum substantially as shown in Figure 24.

11. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks substantially as provided in Table 3 ± 0.2 cm-1.

12. The crystalline Form I of claim 1 that is characterized by a DSC thermogram substantially as shown in Figure 31.

13. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 149° C ± 2° C.

14. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with a peak temperature of 156° C ± 2° C.

15. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 149° C ± 2° C and a peak temperature of 156° C ± 2° C.

16. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 208° C ± 2° C.

17. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with a peak temperature of 215° C ± 2° C.

18. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 208° C ± 2° C and a peak temperature of 215° C ± 2° C.

19. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K / min comprising an endothermic event with an onset temperature of 149° C ± 2° C and a peak temperature of 156° C ± 2° C and an endothermic event with an onset temperature of 208° C ± 2° C and a peak temperature of 215° C ± 2° C.

20. The crystalline Form I of claim 1 that is prepared by a method comprising the steps of: (a) adding a volume of acetonitrile to the compound or derivative having formula (IX), or salt or solvate thereof, at room temperature, so as to dissolve the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile; (b) adding a volume of acetone, which is at least equal in volume to the volume of acetonitrile, to the solution of the compound or derivative having formula (IX), or salt or solvate thereof, in the volume of acetonitrile so as to precipitate the crystalline Form I; and (c) isolating the crystalline Form I.

21. The crystalline Form I of claim 20 that is prepared by a method further comprising the steps of: (a1) providing a compound or derivative having formula (2), or a salt thereof: wherein X' is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO2, acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO2, citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy; each of R6, R7, and R8 is -C(O)R'; R' is methyl; (a2) treating the compound or derivative having formula (2), or salt thereof, with a molar equivalent amount of a compound or derivative having formula (1a), or a salt thereof, and a molar equivalent amount of TMSOTf; wherein Z2 is NH; n is 0; R1 is hydrogen; each of R2, R3, R4, and R5 is hydrogen; (a3) processing the compound or derivative having formula (2), or salt thereof, the compound or derivative having formula (1a), or salt thereof, and the TMSOTf so as to produce the compound or derivative having formula (IX), or salt or solvate thereof; and (a4) isolating the compound or derivative having formula (IX), or salt or solvate thereof; wherein the steps (a1) to (a4) are performed sequentially, before step (a).

22. The crystalline Form I of claim 21, wherein the processing of step (a3) is selected from the group consisting of batch processing, liquid-assisted mixing, milling, grinding, and extruding.

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