Nicotinate and Nicotinamide Riboside-Based Compounds and Their Derivatives

Abstract

Disclosed herein are compounds related to triphenylphosphonio and triphenylphosphonium derivatives of nicotinate and nicotinamide riboside, and methods of making and using the compounds to treat skin ailments or conditions associated with or caused by inflammation, sun damage, or natural aging. Also disclosed herein is a method for making nicotinic acid mononucleoside (NAMN).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 304,904, filed January 31, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Nicotinamide adenine dinucleotide (NAD) and its derivative compounds are known as essential coenzymes in intracellular redox reactions in all living organisms. Several lines of evidence also indicate that NAD is involved in several important signaling pathways in mammalian cells, including poly-ADP-ribosylation in DNA repair (Non-Patent Document 1), mono-ADP-ribosylation and G-protein-coupled signaling in immune responses (Non-Patent Document 2), and the synthesis of ADP-cyclic ribose and nicotinate adenine dinucleotide phosphate (NAADP) in intracellular calcium signaling (Non-Patent Document 3). Recently, NAD and its derivatives have also been shown to play important roles in transcriptional regulation (Non-Patent Document 4). Specifically, the discovery of Sir2 NAD-dependent deacetylase activity (e.g., Non-Patent Documents 5-7) has attracted attention to this new role of NAD.

[0003] NAD+ is thought to be linked to the aging process. This is demonstrated in the replicative life span of S. cerevisiae, which is typically defined as the number of buds or "daughter cells" produced by an individual "mother cell" (Non-Patent Document 8). Mother cells exhibit increased size, slowed cell cycle, enlarged nucleoli, and a steady-state NAD + They undergo age-dependent changes, including increased levels of ribosomes, increased gluconeogenesis and energy stores, and sterility due to loss of silencing at telomeres and mating type loci (Non-Patent Documents 9-14).

[0004] The major regulator of aging in yeast is the Sir2 silencing protein (Non-Patent Documents 15-19). Sir2 is a component of the heterotrimeric Stir2 / 3 / 4 complex that catalyzes the formation of silent heterochromatin at telomeres and two silent mating-type loci (Non-Patent Document 20). Sir2 is also a component of the RENT complex, which silences rDNA loci and is required for exit from telophase (Non-Patent Documents 21, 22). This complex has also recently been shown to directly stimulate transcription of rRNA by PolI and to be involved in the regulation of nucleolar structure (Non-Patent Document 23).

[0005] Biochemical studies have shown that Sir2 readily deacetylates the amino-terminal tails of histones H3 and H4, resulting in the formation of 1-O-acetyl-ADP-ribose and nicotinamide (Non-Patent Documents 24-27). Strains with additional copies of SIR2 exhibit increased rDNA silencing (Non-Patent Document 28) and a 30% longer lifespan (Non-Patent Document 29). It has recently been shown that additional copies of the C. elegans SIR2 homolog, sir-2.1, significantly extend the lifespan of the organism (Non-Patent Document 30). This means that the SIR2-dependent regulatory pathway for aging arose early in evolution and is well conserved (Non-Patent Document 31).

[0006] In most organisms, there are two pathways for NAD+ biosynthesis. NAD+ can be synthesized de novo from tryptophan or recycled in four steps from nicotinamide via the NAD+ salvage pathway. Bacterial NAD +The first step in the salvage pathway, hydrolysis of nicotinamide to nicotinic acid and ammonia, is catalyzed by the pncA gene product (Non-Patent Document 32). A S. cerevisiae gene with homology to pncA, YGL037, was recently assigned the name PNC1(SGD) (Non-Patent Document 33). Nicotinate phosphoribosyltransferase, encoded by the NPT1 gene in S. cerevisiae, converts nicotinic acid from this reaction to nicotinic acid mononucleotide (NaMN) (Non-Patent Documents 34-37). At this point, NAD + Salvage pathway and de novo NAD + The pathways converge, and NaMN is converted to desamido-NAD by nicotinate mononucleotide adenylyltransferase (NaMNAT). + (NaAD). In S. cerevisiae, there are two putative open reading frames (ORFs) with homology to bacterial NaMNAT genes, YLR328 (Non-Patent Document 38) and an uncharacterized ORF, YGR010 (Non-Patent Documents 39, 40). In Salmonella, the final step in the regeneration of NAD+ is catalyzed by NAD synthase (Non-Patent Document 41).

[0007] Sir2 is a limiting component of yeast longevity. A single additional copy of the SIR2 gene extends yeast lifespan by 40% (Non-Patent Documents 42-44). Recently, an increased dose of the Sir2 homologue Sir2.1 has been shown to extend the lifespan of the nematode C. elegans (Non-Patent Document 45). The closest human homologue, SIRT1, has been shown to inhibit apoptosis by deacetylating p53 (Non-Patent Documents 46, 47). These findings suggest that Sir2 and its homologues have conserved roles in regulating survival at the cellular and organismal levels.

[0008] Recently, much insight has been gained into the biochemistry of Sir2-like deacetylases (reviewed by ). In vitro, Sir2 has specificity for lysine 16 of histone H4 and lysines 9 and 14 of histone H3 (49-51). The Sir2 reaction requires NAD+ as a cofactor, allowing the regulation of Sir2 activity through changes in the availability of this cosubstrate (52-55). Sir2 deacetylation is coupled to the cleavage of the high-energy glycosidic bond that connects the ADP-ribose moiety of NAD+ to nicotinamide. Upon cleavage, Sir2 catalyzes the transfer of the acetyl group to ADP-ribose (). The product of this transfer reaction is a new metabolite, O-acetyl-ADP-ribose, which has recently been shown to cause delays / blocks in the embryonic cell cycle and oocyte maturation (60).

[0009] Another product of deacetylation is nicotinamide, a precursor of nicotinic acid and a form of vitamin B3 (Non-Patent Document 61). High doses of nicotinamide and nicotinic acid are often used interchangeably to self-treat a variety of conditions, including anxiety, osteoarthritis, and psychiatric illness, and nicotinamide is currently in clinical trials as a treatment for cancer and type I diabetes (Non-Patent Document 62). Despite the important biological role of NAD+ and its association with the aging process, there remains a need for methods to form NAD+ precursors in a simple and cost-effective manner. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Menissier de Murcia et al.,EMBO J.,22:2255-2263(2003) [Non-Patent Document 2] Corda and Di Girolamo,EMBO J.,22:1953-8(2003) [Non-Patent Document 3] Lee, Annu. Rev. Pharmacol. Toxicol., 41: 317-345 (2001)

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[0011] In one aspect, the disclosure provides a compound having a structure represented by formula (VI) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, Q does not exist, [ka] or H, R 1 HPO 4 , H 2 PO 4 , -OH, -Oacyl, or -OC(O)R 4 and R 2 and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4 -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; X is O, NH, NR 7 , or S, L is a bond, C 1~20 Alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or -R 11 -SSR 11 - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NRb C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is -C(O)NH 2 , -C(O)OH, -R 5 , -P(R 7 ) 3 , -NH 2 , -NHR 5 , [ka] -SH or -OH, R 5 is -C(O)R 4 , [ka] and R 7 is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 9 and R 10 are independently -H, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 11 is C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Z is H or C 1~20 or Z and R are alkyl 1 are optionally joined together as a bond to form a macrocycle; where X is O, NH, or NR 7 and L is C 1~20 When Y is alkyl, aryl, heteroaryl, or alkoxy, Y is -C(O)NH 2 , -C(O)OH, -R 5 , -NH 2 , -NHR 5 , -SH, or -OH.

[0012] In further examples, the disclosure provides methods of making and using the disclosed compounds.

[0013] In another aspect, the disclosure provides a method of producing nicotinic acid mononucleoside (NAMN). [Brief description of the drawings]

[0014] [Figure 1]1 is a graphical depiction of average total NAD concentrations from NAD assays comparing nicotinic acid mononucleotide (NaMN, Sample 1) with nicotinamide mononucleotide (NMN). [Diagram 2] FIG. 1 is a graphical depiction of average total NAD concentrations from NAD assays comparing 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)-methyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)-pyridin-1-ium (7, sample 2) with nicotinamide mononucleotide (NMN). [Diagram 3] FIG. 1 is a graphical depiction of average total NAD concentrations from NAD assays comparing 6-(nicotinamide)hexyl)triphenylphosphonium (10, sample 5) with nicotinamide mononucleotide (NMN). [Figure 4A] 1 is a schematic depiction of an exemplary flow chemistry set-up for synthesizing the compounds disclosed herein. [Figure 4B] 1 is a schematic depiction of an exemplary flow chemistry set-up for synthesizing the compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Compounds of formula (VI) and related formulae In one aspect, the disclosure relates to a compound having a structure represented by formula (VI) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, Q does not exist, [ka] or H, R 1 HPO 4 , H 2 PO 4 , -OH, -Oacyl, or -OC(O)R 4 and R 2and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4 -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; X is O, NH, NR 7 , or S, L is a bond, C 1~20 Alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or -R 11 -SSR 11 - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -C-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b, -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is -C(O)NH 2 , -C(O)OH, -R 5 , -P(R 7 ) 3 , -NH 2 , -NHR 5 , [ka] -SH or -OH, R 5 is -C(O)R 4 , [ka] and R 7is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 9 and R 10 are independently -H, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 11 is C 1-10 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Z is H or C 1~20 or Z and R are alkyl 1 are optionally joined together as a bond to form a macrocycle; where X is O, NH, or NR 7 and L is C 1~20 When Y is alkyl, aryl, heteroaryl, or alkoxy, it is preferably -C(O)NH 2 , -C(O)OH, -R 5 , -NH 2 , -NHR 5 , -SH, or -OH.

[0016] In certain embodiments, the compound has formula VIa: [ka] wherein: R 20 is H, P(O) 2 OH, P(O)(OH) 2 , or acyl, R 21 and R 22 are each independently H or acyl; R 23 is H, alkyl, cycloalkyl, aralkyl, or aryl; R 24 is H or alkyl, X 20 is O,N(R 24 ), or S, G is an anion.

[0017] In certain embodiments, R 2 is H. In certain embodiments, R 2 is P(O)(OH) 2 In certain embodiments, R 2 is acyl (e.g., alkyl acyl or heteroaryl acyl).

[0018] In certain embodiments, R 21 is H. In certain embodiments, R 21 is acyl (e.g., alkyl acyl or heteroaryl acyl).

[0019] In certain embodiments, R 22 is H. In certain embodiments, R 22 is acyl (e.g., alkyl acyl or heteroaryl acyl).

[0020] In certain embodiments, X 20 is O. In certain embodiments, X 20 is NH. In certain embodiments, X 20 is S.

[0021] In certain embodiments, R 23 is H. In certain embodiments, R 23 is alkyl. In certain embodiments, R 23 is alkylaminoalkyl. In certain embodiments, R 23 is alkylamidoalkyl. In certain embodiments, R 23 is aralkyl (e.g., benzyl). In certain embodiments, R 23 is aryl (e.g., phenyl). In certain embodiments, R 23 is cycloalkyl (e.g., cyclohexyl).

[0022] In certain embodiments, R 23 is a triarylphosphonium (e.g., P + (Ph) 3 In certain embodiments, R 23 is substituted with vinyl (e.g., phenylvinyl such as dihydroxyphenylvinyl or diacetylphenylvinyl). In certain embodiments, R 23 is substituted with an amide. In certain embodiments, R 23 teeth, [ka] In certain embodiments, R 23 is substituted with an ester. In certain embodiments, R23 teeth, [ka] In certain embodiments, R 23 is substituted with halo (e.g., bromo). In certain embodiments, R 23 is substituted with alkyl.

[0023] In certain embodiments, G is a pharma- ceutically acceptable anion.

[0024] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of wherein G is a pharma- ceutically acceptable anion.

[0025] In certain embodiments, the compound has formula VIb: [ka] wherein: R 30 is alkyl, aryl, heteroaryl, or cycloalkyl; X 30 is O,N(R 34 ), or S, R 34is H or alkyl.

[0026] In certain embodiments, X 30 is NH. In certain embodiments, X 30 is O.

[0027] In certain embodiments, R 30 is alkyl. In certain embodiments, R 30 is cycloalkyl. In certain embodiments, R 30 is aryl. In certain embodiments, R 30 is heteroaryl.

[0028] In certain embodiments, R 30 is a triarylphosphonium (e.g., P + (Ph) 3 In certain embodiments, R 30 is substituted with alkyl. In certain embodiments, R 30 is substituted with hydroxyl. In certain embodiments, R 30 is substituted with an amide (e.g., an alkyl amide, an ester alkyl amide, an alkylaryl alkyl amide, an arylamino aralkyl amide, a retionyl amide, or a triarylphosphonium alkyl amide). 30 is substituted with amino (e.g., triarylphosphonium alkylamino). In certain embodiments, R 30 is substituted with alkoxy (e.g., triarylphosphonium alkoxy). In certain embodiments, R 30 is substituted with alkenyl (e.g., arylvinyl). In certain embodiments, R 30 is substituted with an ester (e.g., an alkylaryl ester, an arylaminoaralkyl ester, a retionyl ester, or a triarylphosphonium alkyl ester).

[0029] In certain embodiments, the compound is [ka] [ka] [ka] [ka] is selected from the group consisting of wherein G is a pharma- ceutically acceptable anion.

[0030] A further aspect of the invention relates to a nicotinate / nicotinamide riboside compound or derivative of formula (V), or a salt, hydrate, or solvate thereof: [ka] During the ceremony, Q does not exist, [ka] or H, R 1 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 2 and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4 -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; X is O, NH, NR 7 , or S, L is a bond, C 1~20 Alkyl, aryl, heteroaryl, aryl alkyl aryl, aryl alkyl, alkoxy, -R 11 -SSR 11 - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R band wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is -C(O)NH 2 , -C(O)OH, -R 5 , -P(R 7 ) 3 , -NH 2 , -NHR 5 , [ka] -SH or -OH, R 5 is -C(O)R 4 , [ka] and R 7 In each occurrence, C 1~6 independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8 HPO 4 , H 2 PO4 , -OH, or -OC(O)R 4 and R 9 and R 10 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 11 is C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Z is H or C 1~20 or Z and R are alkyl 1 are optionally joined together as a bond to form a macrocycle; where X is O, NH, or NR 7 and L is C 1~20 When Y is alkyl, aryl, heteroaryl, or alkoxy, Y is -C(O)NH 2 , -C(O)OH, -R 5 , -NH 2 , -NHR 5, -SH, or -OH.

[0031] In some embodiments, the compound or derivative of Formula (V) is a compound of Formula (Va), or a salt, hydrate, or solvate thereof: [ka] wherein Q, X, L, and Y are as defined for the compound of formula (V).

[0032] In some embodiments of the compound of formula (V), Q is, [ka] and R 1 is H 2 PO 4 and R 2 is -OH, R 3 is -OH, X is NH; Y is -P(R 7 ) 3 It is.

[0033] Compounds of this embodiment include, but are not limited to, the following: [ka] [ka] and combinations thereof.

[0034] In some embodiments of the compound of formula (V), Q does not exist R 2 is -OH, R 3 is -OH, X is NH; Y is -P(R 7 )3 It is.

[0035] Compounds of this embodiment include, but are not limited to, the following: [ka] and combinations thereof.

[0036] A further aspect of the invention relates to a nicotinate / nicotinamide riboside compound or derivative of formula (IV), or a salt, hydrate, or solvate thereof: [ka] During the ceremony, R 1 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 2 and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4 -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~20 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2, -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; R 5 , R 6 , R 7 , R 8 are independently lone pairs, H, C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl and C 3~10 Cycloalkyl is optionally selected from -alkyl, -O-alkyl, -N(R 9 ) 2 is replaced by R 9 is -H, or C 1~10 It is an alkyl.

[0037] In some embodiments of the compound of formula (IV), R 1 is H 2 PO 4 and R 2 is -OH, R 3 is -OH, G is a pharma- ceutically acceptable anion.

[0038] Compounds of this embodiment include, but are not limited to, [ka] and combinations thereof, wherein G is a pharma- ceutically acceptable anion.

[0039] In some embodiments, the compound or derivative of formula (IV) is a compound of formula (IVa), or a salt, hydrate, or solvate thereof: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is as defined for compounds of formula (IV).

[0040] In some embodiments of the compound of Formula (IVa), R 1 is H 2 PO 4 and R 2 is -OH, R 3 is -OH, G is a pharma- ceutically acceptable anion.

[0041] Compounds of this embodiment include, but are not limited to: [ka] and combinations thereof, wherein G is a pharma- ceutically acceptable anion.

[0042] A further aspect of the invention relates to a nicotinate / nicotinamide riboside compound or derivative of formula (IV) or a salt, hydrate, or solvate thereof: [ka] During the ceremony, R 1 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 2 and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4-H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~20 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; R 5 , R 6 , R 7 , R 8 are independently lone pairs, H, C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl and C 3~10 Cycloalkyl is optionally selected from -alkyl, -O-alkyl, -N(R 9 ) 2 is replaced by R 9 is -H, or C 1~10 It is an alkyl.

[0043] In some embodiments of the compound of formula (IV), R 1 is H 2 PO 4 and R 2 is -OH, R 3 is -OH.

[0044] Compounds of this embodiment include, but are not limited to, [ka] and combinations thereof.

[0045] In some embodiments, the compound or derivative of formula (IV) is a compound of formula (IVa), or a salt, hydrate, or solvate thereof: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is as defined for compounds of formula (IV).

[0046] In some embodiments of the compound of Formula (IVa), R 1 H 2 PO 4 and R 2 is -OH, R 3 is -OH.

[0047] Compounds of this embodiment include, but are not limited to: [ka] and combinations thereof.

[0048] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0049] In some embodiments, the compound or derivative of formula (V) and / or formula (Va) is formed into a composition with a carrier. These compositions can be useful for pharmaceutical and / or cosmetic applications. In some embodiments, the carrier is a pharma- ceutically acceptable carrier. In some embodiments, the carrier is a cosmetically acceptable carrier.

[0050] The present disclosure also includes all suitable isotopic variations of the compounds of the present disclosure.Isotopic variations of the compounds of the present invention are defined as those in which at least one atom has the same atomic number, but is replaced by an atom with an atomic mass different from the atomic mass that is usually or predominantly found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively: 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 Included in the isotopes are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as I. Thus, the recitation of "hydrogen" or "H" includes, unless otherwise specified, 1 H (protium), 2 H (deuterium), and 3 H (tritium). Certain isotopic variations of the compounds of the present invention, such as 3 H or 14 Those incorporating one or more radioactive isotopes, such as C, are useful in drug and / or substrate tissue distribution studies. Tritiated and carbon-14, i.e. 14In C, isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and therefore may be preferred in some circumstances. Such variations may also have advantageous optical properties, for example, resulting from changes in vibrational modes with heavier isotopes. Isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art using appropriate isotopic variations of suitable reagents, such as by the exemplary methods or by the preparations described in the following examples.

[0051] Methods of Treatment Using Compounds of Formula (VI) In one aspect, the disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutic amount of a compound of the disclosure or a pharma- ceutically acceptable salt thereof. In certain embodiments, the disease or disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, AIDS, fulminant hepatitis, Creutzfeldt-Jakob disease, retinitis pigmentosa, cerebellar degeneration, myelodysplasia, aplastic anemia, ischemic disease, myocardial infarction, stroke, liver disease, alcoholic hepatitis, hepatitis B, hepatitis C, osteoarthritis, atherosclerosis, alopecia, ultraviolet skin damage, lichen planus, skin atrophy, cataracts, graft rejection, and cell death caused by surgery, drug therapy, chemical exposure, or radiation exposure.

[0052] In one aspect, the disclosure provides a method of treating a skin condition in a subject in need thereof, comprising administering to the subject a therapeutic amount of a compound of the disclosure or a pharma- ceutically acceptable salt thereof. In certain embodiments, the skin condition is selected from the group consisting of contact dermatitis, irritant contact dermatitis, allergic contact dermatitis, atopic dermatitis, actinic keratosis, dyskeratosis, eczema, epidermolysis bullosa disease, exfoliative dermatitis, seborrheic dermatitis, erythema multiforme, erythema nodosum, damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer, and the effects of natural aging.

[0053] In one aspect, the disclosure provides a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutic amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0054] The compounds and compositions disclosed herein can be used in a method of increasing NAD+ levels in a cell, the method comprising contacting a cell with a compound described herein under conditions effective to increase the level of NAD+ in the cell.

[0055] In some embodiments, the cell may be a skill cell. The skill cell may be contacted with a pharmaceutical or cosmetic composition comprising a compound disclosed herein.

[0056] Another aspect of the present invention relates to a method of treating a skin affliction or condition, comprising administering a therapeutically effective amount of the composition disclosed herein to a subject in need of such treatment. The skin affliction or condition may be a disorder or disease associated with or resulting from inflammation, sun damage, or natural aging. For example, the composition may be used to treat contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratotic disorders (including eczema), epidermolysis bullosa (including pemphigus), exfoliative dermatitis, seborrheic dermatitis, erythema (including erythema multiforme and erythema nodosum), damage caused by the sun or other light sources. The composition may be utilized to prevent or treat discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer, and the effects of natural aging. In another embodiment, the compositions described herein may be used to treat (e.g., promote healing of) wounds and / or burns, including thermal, chemical, or electrical burns. The formulations may be applied to the skin or mucosal tissue within the context of an effective dosing regimen to produce the desired result. The compositions may be administered as an ointment, lotion, cream, microemulsion, gel, or as a solution.

[0057] Another aspect of the present invention relates to a method for increasing intracellular NAD+ in a subject, comprising administering to the subject an effective amount of a compound disclosed herein to increase intracellular NAD+ in the subject, hi some embodiments, the subject is a human subject.

[0058] The compositions of the present invention may also be used as preventative agents, e.g., chemopreventive compositions. When used for chemoprevention, sensitive skin is treated prior to visible pathology in a particular individual. For example, the compounds described herein may be administered to subjects who have recently received or are likely to receive a radiation dose. A dose of radiation may be received beginning as part of a work-related or medical procedure, e.g., working in a nuclear power plant, flying in an airplane, administering radioactive dye for X-ray, CAT scan, or medical imaging, and the agent may be administered as a preventative measure. Radiation exposure may be unintentionally received, e.g., as a result of an industrial accident, an act of terrorism, or an act of war involving radioactive material. In such cases, the agent may be administered as soon as possible after exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome. The compounds described herein may also be used to protect non-cancerous cells from the effects of chemotherapy, to protect neurons, e.g., when preventing neurological damage, hematologic toxicity, renal toxicity, and gastrointestinal toxicity resulting from chemotherapy.

[0059] Following administration of the compound described herein, the level of the factor, for example, NAD+, NADH or nicotinamide, in the subject can be measured.Cells can be obtained from the subject after administration of the compound described herein to the subject, such as by obtaining a biopsy, and the factor is determined in the biopsy.Alternatively, biomarkers, such as plasma biomarkers, can be tracked.The cell can be any cell of the subject, but when the agent is administered locally, the cell is preferably a cell located near the administration site.

[0060] Other factors that may be monitored include symptoms of aging, weight, body mass, blood glucose levels, blood lipid levels, and any other factors that may be measured to monitor a disease or condition described herein.

[0061] Another aspect of the present invention relates to a method of treating a disease or disorder associated with cell death or protecting cells from cell death, comprising administering a composition described herein to a subject in need thereof. For example, the compounds described herein can be administered to a subject for the treatment of a chronic disease. Exemplary diseases include diseases associated with neuronal cell death, neuronal dysfunction, or muscle cell death or dysfunction, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, AIDS, fulminant hepatitis, Creutzfeldt-Jakob disease, retinitis pigmentosa, cerebellar degeneration, myelodysplasia, aplastic anemia, ischemic disease, myocardial infarction, stroke, liver disease, alcoholic hepatitis, hepatitis B, hepatitis C, osteoarthritis, atherosclerosis, alopecia, UV light skin damage, lichen planus, skin atrophy, cataracts, graft rejection, and cell death due to surgery, drug therapy, chemical exposure, or radiation exposure.

[0062] In another embodiment, the compositions described herein are used to reduce the rate of aging in a subject. The compounds described herein can be delivered, such as by injection, to tissues or organs in a subject to prevent or treat diseases or afflictions associated with aging, the process of aging itself, cell death, infection, and toxic agents, to extend the lifespan of cells or to protect cells from certain stresses. For example, the agents can be taken by the subject as a food supplement. The compounds described herein can be components of a multivitamin complex. In some embodiments, the skin can be protected from aging (e.g., wrinkles, loss of elasticity, etc.) by treating skin or epithelial cells with the compounds described herein.

[0063] The contents of all figures and all references, Genbank sequences, journal publications, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference in their entirety. Furthermore, if a definition or use of a term in a reference incorporated herein by reference conflicts with the definition of that term provided herein, the definition of that term provided herein shall apply and the definition of that term in the reference shall not apply.

[0064] The following examples are merely illustrative and should not be construed as limiting the scope of the disclosure in any way, since many variations and equivalents will become apparent to those of skill in the art upon reading this disclosure.

[0065] Method for preparing the compound of formula (VI) Provided herein are methods for the preparation of nicotinate / nicotinamide riboside-based compounds and derivatives. Ribosylated nicotinamide has a relatively labile glycosidic bond, making its synthesis and its manipulation difficult (Makarov and Migaud, Beilstein J. Org. Chem. 15:401-430 (2019), incorporated herein by reference in its entirety). Many existing coupling reactions can cleave this labile glycosidic bond, resulting in nicotinic acid and ribonucleotides. Furthermore, coupling protocols known in the art can result in intermolecular polymerization via the carboxylic acid group of NaMN with an accessible OH of another NaMN molecule. Previous methods for forming nicotinamide riboside-based compounds generally rely on the reaction between nicotinamide and peracylated (halo)-D-ribofuranose, resulting in an acylated intermediate that is then converted to nicotinamide riboside. Id.

[0066] The method of the present invention can form nicotinate / nicotinamide riboside based compounds and derivatives starting from NaMN and NaR without cleaving glycosidic bonds. It was discovered that activation of carboxylic acids on NaMN in the presence of nucleophiles containing ester and / or amide forming moieties yielded small molecule novel NaR and NaMN variants. Surprisingly, off-pathway chemistry such as self-dimerization, polymerization, and decomposition did not occur. Unlike previous methods of forming nicotinate / nicotinamide riboside based compounds and derivatives, protecting groups (e.g., acetyl groups) are not required to prevent polymerization of the NaMN molecule, thus reducing the total number of synthetic steps to obtain the product. The method proceeds with yields ranging from 30-80%. This method is an efficient route for late diversification of NaMN and NaR produced from total synthesis to fermentation. The method of the present invention can form novel NAD precursors.

[0067] In one aspect, the disclosure provides a method of making a compound having a structure represented by formula (VI): The present invention provides a nicotinate / nicotinamide riboside compound or derivative of formula (II) or a salt, hydrate, or solvate thereof, comprising: [ka] During the ceremony, R 1’ HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4’ and R 2’ and R 3’ are independently -OH, -C(O)R 4’ 、 -C(O)OR 4’ , -C(O)NHR 4’ 、 or a halogen, R 4’ -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, wherein Ar is aryl or heteroaryl; contacting a compound or derivative of formula (II), or a salt, hydrate, or solvate thereof, with a coupling agent and a compound of formula (III), [ka] During the ceremony, X ’ are O, NH, and NR 7’ , or S, L' is a bond, C 1~20 Alkyl, aryl, heteroaryl, aryl alkyl aryl, aryl alkyl, alkoxy, -R 11’ -SSR 11’ - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)Rb , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; R 4’’ is optionally represented by -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a’ , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a C substituted with one or more groups selected from 1~20 alkyl, and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y' is C 1~20 Alkyl, perfluoroalkyl, -C(O)NH 2 , -C(O)OH, -R 5’ , -C(R 6’ ) 3 , -P(R 7’ ) 3 , -NH 2 , -NHR 5’ 、 [ka] -SH, -OH, R 5’ is -C(O)R 4’’ , [ka] and R 6’ In each occurrence, C 1~6 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, -H, -halogen, -OH, and -NH 2 are individually selected from the group consisting of R 7’ In each occurrence, C 1~6 independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8’ HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4’’ and R 9’ and R 10’ are independently -OH, -C(O)R 4’’ , -C(O)OR 4’’ , -C(O)NHR 4’’ or halogen, R 11” is C 1~10 Alkyl, C 3~10cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Z' is H or C 1~20 is alkyl, G is an anion.

[0068] One aspect of the present invention relates to a method for producing a nicotinate / nicotinamide riboside compound or derivative of formula (I), or a salt, hydrate, or solvate thereof, comprising: [ka] During the ceremony, R 1 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 2 and R 3 are independently -OH, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 4-H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~20 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; X is O, NH, NR 7 , or S, L is a bond, C 1~20 Alkyl, aryl, heteroaryl, aryl alkyl aryl, aryl alkyl, alkoxy, -R 11 -SSR 11 - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R band wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is C 1~20 Alkyl, perfluoroalkyl, -C(O)NH 2 , -C(O)OH, -R 5 , -C(R 6 ) 3 , -P(R 7 ) 3 , -NH 2 , -NHR 5 , [ka] -SH or -OH, R 5 is -C(O)R 4 , [ka] and R 6 In each occurrence, C 1~6 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, -H, -halogen, -OH, and -NH 2 are individually selected from the group consisting of R 7In each occurrence, C 1~6 independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8 HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4 and R 9 and R 10 are independently -H, -C(O)R 4 , -C(O)OR 4 , -C(O)NHR 4 or halogen, R 11 is C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Z is H or C 1~20 or Z and R are alkyl 1 are optionally joined together as a bond to form a macrocycle; under conditions to produce a compound of formula (I) or a derivative, or a salt, hydrate, or solvate thereof, comprising the steps of: The present invention provides a nicotinate / nicotinamide riboside compound or derivative of formula (II) or a salt, hydrate, or solvate thereof, comprising: [ka] During the ceremony, R 1’ HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4’ and R 2’ and R 3’ are independently -OH, -C(O)R 4’ 、 -C(O)OR 4’ , -C(O)NHR 4’ 、 or a halogen, R 4’ -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2Ar, wherein Ar is aryl or heteroaryl; contacting a compound or derivative of formula (II), or a salt, hydrate, or solvate thereof, with a coupling agent and a compound of formula (III), [ka] During the ceremony, X ’ are O, NH, and NR 7’ or S, L' is a bond, C 1~20 Alkyl, aryl, heteroaryl, aryl alkyl aryl, aryl alkyl, alkoxy, -R 11’ -SSR 11’ - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and wherein aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from: -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; R 4’’ is optionally represented by -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a’ , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a C substituted with one or more groups selected from 1~20 alkyl, and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y' is C 1~20 Alkyl, perfluoroalkyl, -C(O)NH 2 , -C(O)OH, -R 5’ , -C(R 6’ ) 3 , -P(R 7’ ) 3 , -NH 2 , -NHR 5’ , [ka] -SH, -OH, R 5’ is -C(O)R 4’’ , [ka] and R 6’ In each occurrence, C1~6 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, -H, -halogen, -OH, and -NH 2 are individually selected from the group consisting of R 7’ In each occurrence, C 1~6 independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R 8’ HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4’’ and R 9’ and R 10’ are independently -OH, -C(O)R 4’’ , -C(O)OR 4’’ , -C(O)NHR 4’’ or halogen, R 11” is C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2Ar, where Ar is aryl or heteroaryl; Z' is H or C 1~20 contacting, And, isolating the compound of formula (I) or a derivative, or a salt, hydrate or solvate thereof.

[0069] In some embodiments, the method yields at least about 30% of the compound or derivative of formula (I), or a salt, hydrate, or solvate thereof. In some embodiments, the method yields at least about 40%, about 50%, about 60%, about 70%, about 80% or more. In some embodiments, the compound or derivative of formula (I), or a salt, hydrate, or solvate thereof, is formed in a yield ranging from about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, or about 75% to about 80%. In some embodiments, the compound or derivative of formula (I), or its salt, hydrate, or solvate, is formed in a yield ranging from about 30% to about 80%. In some embodiments, the method is optimized and the compound or derivative of formula (I), or its salt, hydrate, or solvate, is formed in a yield of at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%.

[0070] In some embodiments of the methods of the invention, the nicotinate / nicotinamide riboside compound or derivative of formula (I) is a compound of formula (Ia) or a salt, hydrate, or solvate thereof: [ka] During the ceremony, R 1 , R 2 , R 3X, L, and Y are as defined in formula (I).

[0071] In some embodiments of the compound of Formula (Ia), R 1 is H 2 PO 4 and R 2 and R 3 is -OH, R 4 is C 1~20 is alkyl, L' is a bond, C 1~20 Alkyl, aryl, aryl alkyl aryl, -R 11 -SSR 11 - and C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO 2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is C 1~20 Alkyl, -C(O)NH 2 , -C(O)OH, -R 5 , -C(R 6 ) 3 , -P(R 7 ) 3 , -NH 2 , -NHR 5 , [ka] -SH or -OH, R 5 is -C(O)R 4 ,or [ka] and R 6 In each occurrence, C 1~6 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, -H, -halogen, -OH, and -NH 2 are individually selected from the group consisting of R 7 is aryl, R 8 is H 2 PO 4 and R 9 and R 10 is -OH, R 11 is C 1~10 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl.

[0072] Exemplary compounds of this embodiment include: [ka] [ka] and combinations thereof, but are not limited to these.

[0073] In some embodiments of the compound of Formula (Ia), L is a bond or C 1~20 is alkyl, X is NH; Y is C 1~20 Alkyl-C(R 6 ) 3 , -P(R 7 ) 3 and R 6 is aryl, R 7 is aryl.

[0074] Exemplary compounds of this embodiment include: [ka] and combinations thereof, but are not limited to these.

[0075] In some embodiments of the compound of Formula (Ia), R 2 and R 3 is -OH, X is O or NH; L' is a bond, C 1~20 Alkyl, or aryl alkyl aryl, C 1~20 Alkyl is optionally a substituent of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R b , -CO2 R b , -OC(O)R b , -NHC(O)R b , -NR b C(O)R b , -NO 2 , -CN, and -SO 2 R b and each R b are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl; Y is C 1~20 Alkyl, perfluoroalkyl, -P(R 7 ) 3 , -NH 2 , or -NHR 5 and R 5 teeth [ka] and R 7 is aryl, R 8 is -OH, R 9 is -OH, R 10 is -OH, Z is -H or C 1~20 Alkyl or Z and R 1 are optionally taken together as bonds to form a macrocycle.

[0076] Exemplary compounds of this embodiment include: [ka] and combinations thereof, but are not limited to these.

[0077] In some embodiments of the process of the present invention, the conditions for producing a compound of formula (I) or derivative include reacting a compound of formula (III) with a compound of formula (II) in the presence of a base and a coupling agent.

[0078] In some embodiments of the method of the present invention, the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-chloro ... fluoroborate (TCTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximide)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU), The coupling agent is selected from the group consisting of 1-(azol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), 1,1'-carbonyldiimidazole (CDI), and combinations thereof. In some embodiments, the coupling agent is a carbodiimide-based coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)).

[0079] In some embodiments, the coupling agent is present in a molar equivalent amount relative to the compound of formula (II) and / or the compound of formula (III). In some embodiments, the coupling agent is present in a molar excess relative to the compound of formula (II) and / or the compound of formula (III). In some embodiments, the coupling agent is present in about 1, about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, or about 3 molar equivalents of the compound of formula (II) and / or the compound of formula (III). The coupling agent may be present in an amount of about 1, about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, or about 2.5 molar equivalents of the compound of formula (II) and / or the compound of formula (III) up to about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, or about 3 molar equivalents of the compound of formula (II) and / or the compound of formula (III). Alternatively, the agent, the coupling agent, may be present in a molar amount less than the compound of formula (II) and / or the compound of formula (III). In some embodiments, the coupling agent is present in about 0.025 molar equivalents, about 0.05 molar equivalents, about 0.1 molar equivalents, about 0.2 molar equivalents, about 0.3 molar equivalents, about 0.4 molar equivalents, about 0.5 molar equivalents, about 0.6 molar equivalents, about 0.7 molar equivalents, about 0.8 molar equivalents, or about 0.9 molar equivalents of the compound of Formula (II) and / or the compound of Formula (III). The coupling agent can be present in an amount from about 0.025, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 molar equivalents to about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 molar equivalents of the compound of Formula (II) and / or the compound of Formula (III).

[0080] In some embodiments of the method of the present invention, the base is an amine base. The amine base may be a sterically hindered base that cannot participate in addition and / or substitution reactions. In some embodiments, the base is selected from the group consisting of triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine, pyridine, 2,6-lutidine, N-methylimidazole, and combinations thereof. In some embodiments, the base is diisopropylethylamine.

[0081] In some embodiments of the method of the present invention, the base may be added in excess relative to the other reagents in the reaction mixture (i.e., the compound of formula (II), the coupling agent, and / or the compound of formula (III)). In some embodiments, the base is present in about 1.1 molar equivalents or more of the coupling agent, the compound of formula (II), and / or the compound of formula (III). The base may be present in about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 7, about 8, about 9, or about 10 molar equivalents of the coupling agent, the compound of formula (II), and / or the compound of formula (III). In some embodiments, the base is present in about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 7, about 8, or about 9 molar equivalents to about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 7, about 8, about 9, or about 10 molar equivalents of the coupling agent, the compound of Formula (II) and / or the compound of Formula (III).

[0082] In some embodiments, the compound of formula (II) can be the limiting reagent (i.e., present in a low molar equivalent amount relative to the base, coupling reagent, and / or compound of formula (III)). In some embodiments, the compound of formula (II) is present in about 0.025, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 molar equivalents of the compound of formula (III) and / or the coupling reagent. The compound of formula (II) may be present in an amount of about 0.025, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 molar equivalents to about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 molar equivalents of the compound of formula (III) and / or the coupling reagent. In some embodiments, the compound of formula (II) is present in a molar equivalent amount with the compound of formula (III) and / or the coupling reagent. Alternatively, the compound of formula (II) may be present in a molar excess relative to the coupling agent and / or the compound of formula (III). In some embodiments, the compound of formula (II) is present in about 1, about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, or about 3 molar equivalents of the compound of formula (III) and / or the coupling reagent. The compound of formula (II) may be present in an amount from about 1, about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, or about 2.5 molar equivalents to about 1.025, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, or about 3 molar equivalents of the compound of formula (III) and / or the coupling reagent.

[0083] In some embodiments, the nicotinic acid / nicotinamide riboside compound or derivative of formula (II) is a compound of formula (IIa) or a salt, hydrate, or solvate thereof: [ka] During the ceremony, R 1’ HPO 4 , H 2 PO 4 , -OH, or -OC(O)R 4’ and R 2’ and R 3’ are independently -OH, -C(O)R 4’ 、 -C(O)OR 4’ , -C(O)NHR 4’ 、 or a halogen, R 4’ -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl.

[0084] In some embodiments of the compound of Formula (IIa), R 1’ is H 2 PO 4 or -OC(O)R 4’ and R 2’ and R 3’are independently -OH, -C(O)R 4’、 -C(O)OR 4’’ and R 4’ -H, C 1~20 Alkyl, C 3~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; C 1~10 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R a , -CO 2 R a , -OC(O)R a , -NHC(O)R a , -NR a C(O)R a , -NO 2 , -CN, and -SO 2 R a and each R a are independently Ar, C 1~6 Alkyl, or CH 2 Ar, where Ar is aryl or heteroaryl.

[0085] In some embodiments of the invention, reacting comprises: (i) dissolving a compound of formula (II) in a solvent or solvent mixture to form a first solution; (ii) adding a base and a coupling agent to the first solution to form a basic solution; (iii) adding a compound of formula (III) to the basic solution; and (iv) isolating the compound of formula (I) or a derivative, or a salt, hydrate, or solvate thereof.

[0086] The base and / or coupling agent may be dissolved in a solvent forming the second solution before adding the base and / or coupling agent to the first solution. Alternatively, the base and / or coupling agent may be added neat to the first solution. The compound of formula (III) may be dissolved in a solvent forming the third solution before adding the compound of formula (III) to the basic solution. The compound of formula (II), the base, the coupling agent, and / or the compound of formula (III) may be dissolved in the same or different solvents or solvent mixtures.

[0087] In some embodiments of the methods of the present invention, the solvent or solvent mixture is selected from the group consisting of water, dimethylformamide (DMF), chloroform, dichloromethane, dichloroethane, acetonitrile, dimethylsulfoxide (DMSO), benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-butanone, hexane, hexane isomers, cyclohexane, ether, diethylene glycol, acetone, ethyl acetate, butanone, 1,4-dioxane, and combinations thereof.

[0088] In some embodiments of the method of the present invention, the compound of formula (II), the base and the coupling agent, and the compound of formula (III) may be dissolved in the respective solvents to form a solution with a concentration ranging from about 0.05 M to about 10 M. For example, the concentration of the solution may be about 0.05 M, about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1.0 M, about 1.5 M, about 2 M, about 2.5 M, about 3 M, about 3.5 M, about 4.0 M, about 4.5 M, about 5.0 M, about 5.5 M, about 6.0 M, about 6.5 M, about 7.0 M, about 7.5 M, about 8 M, about 8.5 M, about 9.0 M, about 9.5 M, or about 10.0 M.

[0089] In some embodiments of the methods of the present invention, reacting is carried out in air. In other embodiments, reacting is carried out under inert conditions (e.g., in a dry nitrogen or argon atmosphere). In some embodiments, the reaction is complete in about 24 to 48 hours. As will be apparent to one of skill in the art, the time required for the reaction to reach completion will vary based on a variety of factors, including the reactivity of the starting materials and the temperature of the reaction. The reaction may last for approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, or 49 hours, up to approximately 2 30 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, or 50 hours. The progress of the reaction may be monitored (e.g., using LCMS) to determine consumption of starting material and / or formation of product.

[0090] In some embodiments of the methods of the invention, the reaction is carried out at a temperature of about 0° C. to about 100° C. For example, the temperature may be from about 0° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., about 80° C., about 85° C., about 90° C., or about 95° C. up to about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., about 80° C., about 85° C., about 90° C., about 95° C., or about 100° C. In some embodiments, the temperature is ambient room temperature (eg, about 25° C.).

[0091] In some embodiments, the compound or derivative of formula (I), or its salt, hydrate, or solvate, may be isolated from the basic solution 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. In one embodiment, the compound or derivative of formula (I), or its salt, hydrate, or solvate, is isolated directly from the basic solution using flash chromatography without the need for any additional workup.

[0092] How NAMN is produced In another aspect, the present disclosure provides a method for preparing compound 1 (NAMN), the method comprising the steps of Scheme I: [ka] The reaction is carried out as shown in R 50 is alkyl, G 1 is an anion, G 2 is a cation.

[0093] In certain embodiments, step 1 is carried out under flow conditions.

[0094] In certain embodiments, step 2 is carried out under flow conditions.

[0095] In certain embodiments, step 3 is carried out under flow conditions.

[0096] In certain embodiments, step 4 is carried out under flow conditions.

[0097] In certain embodiments, base 1 is a hydroxide (eg, sodium hydroxide).

[0098] In certain embodiments, Acid 1 is an inorganic acid (eg, sulfuric acid).

[0099] In certain embodiments, base 2 is a hydroxide (eg, sodium hydroxide).

[0100] In certain embodiments, the method is carried out in acetonitrile.

[0101] In certain embodiments, the process is carried out in a mixture of acetonitrile and ethanol.

[0102] In another aspect, the disclosure is a method for preparing compound 1 (NAMN), the method being carried out as shown in Scheme II: [ka]

[0103] In certain embodiments, step 1 is carried out in a halogenated hydrocarbon solvent (eg, dichloromethane).

[0104] In certain embodiments, acid 3 is a mineral acid (e.g., aqueous hydrochloric acid). In certain embodiments, the mineral acid is the solvent.

[0105] In certain embodiments, base 3 is a hydroxide base (eg, aqueous lithium hydroxide).

[0106] In certain embodiments, step 4 is carried out in a mixture of an organic solvent and water (eg, tetrahydrofuran and water).

[0107] In certain embodiments, R 50 is aralkyl (e.g., benzyl).

[0108] Pharmaceutical Compositions A pharma- ceutically acceptable excipient can be a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, a diluent, a carrier, a manufacturing aid (e.g., a lubricant, magnesium, calcium, or zinc stearate, or steric acid), a solvent or encapsulating material, a bulking agent, a salt, a surfactant, and / or a preservative, which participates in carrying or transporting a therapeutic compound for administration to a subject. Some examples of materials that can function as pharma- ceutically acceptable excipients include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, gelatin, talc, waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as ethylene glycol and propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers, water, isotonic saline, pH buffered solutions, and other non-toxic compatible substances used in pharmaceutical formulations.

[0109] Bulking agents are compounds that add mass to a pharmaceutical formulation and contribute to the physical structure of the formulation in lyophilized form. Suitable bulking agents according to the present invention include mannitol, glycine, polyethylene glycol and sorbitol.

[0110] The use of a surfactant can reduce aggregation of the reconstituted protein and / or reduce the formation of particles in the reconstituted formulation. The amount of surfactant added is such that it reduces aggregation of the reconstituted protein and minimizes the formation of particulates after reconstitution. Suitable surfactants according to the present invention include polysorbates (e.g., polysorbate 20 or 80), poloxamers (e.g., poloxamer 188), triton, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, sodium octyl glycoside, lauryl-, myristyl-, linoleyl-, or stearyl sulfobetaine, lauryl-, myristyl-, linoleyl-, or stearyl sarcosine, linoleyl-, myristyl-, or cetyl-betaine, lauroamidopropyl-, cocamidopropyl-, glyceryl ... -, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl), myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine, sodium methyl cocoyl, or disodium methyl oleyl-taurate, and polyethyl glycol, polypropyl glycol, and copolymers of ethyl and propylene glycol (e.g., Pluronics, PF68, etc.).

[0111] Preservatives may be used in the formulations / compositions provided herein. Suitable preservatives for use in the compositions of the present invention include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyl-dimethylammonium chlorides in which the alkyl group is a long-chain compound), and benzethonium chloride. Other types of preservatives include aromatic alcohols, such as phenol, butyl, and benzyl alcohol, alkyl parabens, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. Other suitable excipients can be found in standard pharmaceutical textbooks, such as "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Pa., (1995).

[0112] Pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. Thus, the compounds described herein can be formulated for administration, for example, by injection, inhalation or insufflation (either oral or nasal), or oral, buccal, parenteral or rectal administration. The agent can also be administered locally at the site where the target cells are present, for example, by using a patch. In some embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a disintegrant, a lubricant, a flavoring agent, a solubilizer, a suspending aid, an emulsifier, a coating agent, a cyclodextrin, and / or a buffer.

[0113] The compounds disclosed herein can be formulated for various administration loads, including systemic administration and local or localized administration. Techniques and formulations are generally found in Remmington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA. For systemic administration, injection is preferred, including intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the agent can be formulated in a liquid solution, for example, a physiologically compatible buffer, such as Hank's solution or Ringer's solution. In addition, the agent can be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms are also included.

[0114] For oral administration, the compositions may take the form of tablets, lozenges, or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared in a conventional manner using pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., ationed oils, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e.g., methyl- or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0115] For administration by inhalation, the compounds of the present invention can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the agent and a suitable powder base, such as lactose or starch.

[0116] The compound of the present invention can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be presented in unit dosage form, for example, in ampoules or multi-dose containers, together with added preservatives.The compound of the present invention can take the form of suspension, solution, or emulsion in oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.Alternatively, the active ingredient can be in powder form for constitution with suitable vehicle, for example, sterile, pyrogen-free water, before use.

[0117] In addition to the above formulations, the compounds of the present invention may be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be formulated in suitable polymeric or hydrophobic materials (e.g., as an emulsion in acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts. Controlled release formulations also include patches, e.g., transdermal patches. Patches can be used with sonic applicators that deploy ultrasound waves with a unique combination of waveforms to introduce drug molecules through the skin that normally could not be effectively delivered through the skin.

[0118] Pharmaceutical compositions (including cosmetic preparations) may contain about 0.00001 to 100% by weight, e.g., 0.001 to 10% by weight or 0.1% to 5% by weight, of one or more of the compounds described herein.

[0119] In some embodiments, the cosmetically acceptable carrier comprises at least one of the group consisting of additives, colorants, emulsifiers, fragrances, humectants, polymerizable monomers, stabilizers, solvents, and surfactants.

[0120] The compounds described herein can be incorporated into topical formulations that contain topical carriers generally suitable for topical drug administration or cosmetic formulations, and include any such materials known in the art.Topical carriers can be selected to provide the composition in the desired form, such as ointments, lotions, creams, microemulsions, gels, oils, solutions, and the like, and can be composed of materials of either natural or synthetic origin.The selected carrier should not adversely affect the active agent or other components of the topical formulation.Examples of suitable topical carriers for use herein include water, alcohol and other non-toxic organic solvents, glycerin, mineral oil, silicone, petrolatum, lanolin, fatty acids, vegetable oils, parabens, waxes, and the like.

[0121] The compounds of the present invention may be incorporated into ointments, which are generally semi-solid preparations typically based on petrolatum or other petroleum derivatives. As will be understood by those skilled in the art, the particular ointment base used is one that provides optimal drug delivery and preferably provides other desired properties, such as emulsification. As with other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing. As described in Remington's, ointment bases can be divided into four classes: oleaginous bases, emulsifiable bases, emulsion bases, and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointments, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Water-soluble ointment bases can be prepared from polyethylene glycols (PEGs) of various molecular weights. Again, reference may be had to Remington's, supra, for further information.

[0122] The compounds of the present invention may be incorporated into lotions, which are preparations that are generally applied to the skin surface without friction, typically liquid or semi-liquid preparations in which solid particles containing active agents are present in a water or alcohol base. Lotions are usually suspensions of solids and may include liquid oily emulsions of the oil-in-water type. Lotions are the preferred preparations for treating large body areas, as it is easier to apply more liquid compositions. In general, it is necessary to finely divide the insoluble matter in the lotion. Lotions typically contain suspending agents to produce better dispersion, as well as compounds that are useful for placing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, and the like. Lotion formulations for use with the present method may include propylene glycol mixed with hydrophilic petrolatum.

[0123] The compounds of the present invention may be incorporated into creams, which are generally viscous liquids or semi-solid emulsions, either oil-in-water or water-in-oil.Cream bases are water-washable and contain an oil phase, an emulsifier and an aqueous phase.The oil phase is generally composed of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol, and the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a moisturizer.As explained in Remington's above, the emulsifier in cream formulations is generally a nonionic, anionic, cationic or amphoteric surfactant.

[0124] The compounds of the present invention may be incorporated into microemulsions, which are generally thermodynamically stable, isotropically transparent dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9). The preparation of a microemulsion requires a surfactant (emulsifier), a co-surfactant (co-emulsifier), an oil phase and an aqueous phase. Suitable surfactants include any surfactant useful in the preparation of emulsions, such as emulsifiers typically used in the preparation of creams. The co-surfactant (or "co-emulsifier") is generally selected from the group of polyglycerol derivatives, glycerol derivatives, and fatty alcohols. Preferred emulsifier / co-emulsifier combinations are generally, but not necessarily, selected from the group consisting of glyceryl monostearate and polyoxyethylene stearate, polyethylene glycol and ethylene glycol palmitostearate, and capric and capric triglycerides, and oleoyl macrogol glycerides.The aqueous phase typically includes not only water, but also buffers, glucose, propylene glycol, polyethylene glycol, preferably low molecular weight polyethylene glycols (e.g., PEG300 and PEG400), and / or glycerol, while the oil phase generally includes, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono-, di-, and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), and the like.

[0125] The compounds of the invention may be incorporated into gel formulations, which are generally semi-solid systems consisting of either a suspension of small inorganic particles (two-phase systems) or large organic molecules distributed substantially uniformly throughout the carrier liquid (single-phase gels). Single-phase gels can be prepared, for example, by combining together the active agent, the carrier liquid, and a suitable gelling agent, such as tragacanth (2-5%), sodium alginate (2-10%), gelatin (2-15%), methylcellulose (3-5%), sodium carboxymethylcellulose (2-5%), carbomer (0.3-5%), or polyvinyl alcohol (10-20%), until a characteristic semi-solid product is produced. Other suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxypropylene, hydroxyethylcellulose, and gelatin. Gels generally use an aqueous carrier liquid, although alcohols and oils can also be used as carrier liquids.

[0126] Various additives known to those skilled in the art may be included in the formulation, e.g., topical formulation. Examples of additives include, but are not limited to, solubilizers, skin permeation enhancers, opacifiers, preservatives (e.g., antioxidants), gelling agents, buffers, surfactants (especially nonionic and amphoteric surfactants), emulsifiers, emollients, thickeners, stabilizers, moisturizers, colorants, fragrances, and the like. It is particularly preferred to include a solubilizer and / or skin permeation enhancer along with an emulsifier, emollient, and preservative. An optimal topical formulation will include about 2% to 60% by weight, preferably 2% to 50% by weight, solubilizer and / or skin permeation enhancer, 2% to 50% by weight, preferably 2% to 20% by weight, emulsifier, 2% to 20% by weight, emollient, and 0.01 to 0.2% by weight, preservative, with the active agent and carrier (e.g., water) making up the remainder of the formulation.

[0127] Skin permeation enhancers serve to facilitate the passage of therapeutic levels of an active agent through a reasonably sized area of ​​unbroken skin. Suitable accelerators are well known in the art and include, for example, lower alkanols such as methanol, ethanol, and 2-propanol; alkyl sulfoxides such as dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (C.sub.10 MSO), and tetradecyl methyl sulfoxide; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, and N-(hydroxyethyl)pyrrolidone; urea; N,N-diethyl-m-toluamide; C.sub.2-C.sub.6 alkanediols; various solvents such as dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydrofurfuryl alcohol; and 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcycloazacycloheptan-2-one (laurocapram, available under the trademark Azone R™ from Whitby Research Incorporated, Richmond, Va.).

[0128] Examples of solubilizers include, but are not limited to, hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, commercially available as Transcutol™) and diethylene glycol monoethyl ether oleate (commercially available as Softcutol™); polyethylene castor oil derivatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil; polyethylene glycols, particularly low molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol derivatives such as PEG-8 caprylic / capric glyceride (commercially available as Labrasol™); alkylmethylsulfoxidones such as DMSO; pyrrolidones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers. A single solubilizer may be incorporated into the formulation, or a mixture of solubilizers may be incorporated therein.

[0129] Suitable emulsifiers and co-emulsifiers include, but are not limited to, those described for microemulsion formulations. Emollients include, for example, propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) myristyl ether propionate, and the like.

[0130] Other active agents may also be included in the formulation, such as, for example, anti-inflammatory agents, analgesics, antibacterial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunscreen formulations include, but are not limited to, anthranilates, benzophenones (especially benzophenone-3), camphor derivatives, cinnamates (e.g., octyl methoxycinnamate), dibenzoylmethanes (e.g., butyl methoxydibenzoylmethane), p-aminobenzoic acid (PABA) and its derivatives, and salicylic acid (e.g., octyl salioylate).

[0131] In certain topical formulations, the compounds of the present invention are present in an amount ranging from about 0.25% to 75% by weight of the formulation, preferably from about 0.25% to 30% by weight of the formulation, more preferably from about 0.5% to 15% by weight of the formulation, and most preferably from about 1.0% to 10% by weight of the formulation.

[0132] The topical skin treatment composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer.For example, a lotion or cream can be packaged in a bottle or a roll-ball applicator, or a propellant-driven aerosol device, or a container equipped with a pump suitable for finger operation.If the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a jar with a lid.The composition can also be included in a capsule.

[0133] kit Also described herein are kits for therapeutic purposes, such as kits, including those described herein, for regulating aging and treating disease.The kits can include one or more compounds described herein, and optionally devices for contacting cells with the compounds of the present invention.Devices include syringes, stents, and other devices for introducing drugs into subjects or applying them to the skin of subjects.

[0134] Additionally, the kit may also include components for measuring factors, such as components for measuring levels of NAD+, NADH, or nicotinamide in a tissue sample.

[0135] The kits may include kits for diagnosing the likelihood of having or developing an aging-related disease, weight gain, obesity, insulin resistance, diabetes, cancer, precursors thereof, or secondary conditions thereof. The kits may include agents for measuring activity and / or expression levels of NAD+, NADH, nicotinamide, and / or other intermediate compounds in the NAD+ salvage pathway.

[0136] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In general, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0137] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0138] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0139] All of the above, as well as any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0140] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The use of "or" or "and" means "and / or" unless specifically stated otherwise.

[0141] The term "about" as used herein when referring to a measurable value, such as an amount, a temporal duration, and the like, is inclusive of the value itself and includes up to ±10% variation from the specified value. Unless otherwise indicated, all numbers expressing properties such as amounts of ingredients, molecular weights, reaction conditions, and the like, used herein should be understood to be modified by the term "about."

[0142] The term "agent" is used herein to denote a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., nucleic acids, antibodies including portions thereof, as well as humanized, chimeric and human antibodies, and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract made from biological material such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Agents include, for example, agents of known structure and agents of unknown structure.

[0143] The term "alkyl" refers to an aliphatic hydrocarbon group that may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0144] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0145] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0146] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0147] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0148] The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight-chained or branched having about 2 to about 6 carbon atoms in the chain. Particular alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. The term "alkenyl" may also refer to a hydrocarbon chain having 2 to 6 carbons containing at least one double bond and at least one triple bond.

[0149] The term "alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight chained or branched having about 2 to about 6 carbon atoms in the chain. Particular alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.

[0150] The term "alkoxy" refers to groups of 1 to 8 carbon atoms of a configuration including linear, branched, or cyclic and combinations thereof, attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower alkoxy refers to groups containing 1 to 4 carbons. For purposes of this application, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is attached to an atom, chain, or ring to which a methylenedioxy or ethylenedioxy group is pendant to form a ring. Thus, for example, a phenyl substituted with an alkoxy may be, for example, [ka]

[0151] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0152] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0153] As used herein, the term "amide" means [ka] In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0154] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] (In the formula, R 9 , R 10 , and R 10 ' each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 which, together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure.

[0155] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0156] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system of about 3 to about 8 carbon atoms, preferably about 5 to about 7 carbon atoms, which may contain at least one double bond. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclophenyl, anti-bicyclopropane, and syn-tricyclopropane.

[0157] The term "cycloalkylalkyl" refers to a cycloalkyl-alkyl group, where cycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, and cyclopentylethyl. The alkyl and cycloalkyl radicals can be optionally substituted as defined herein.

[0158] The term "aryl" refers to an aromatic monocyclic or polycyclic (multicyclic) ring system of 6 to about 19 carbon atoms, or 6 to about 10 carbon atoms, including arylalkyl groups. The ring system of the aryl group can be optionally substituted. Representative aryl groups include, but are not limited to, groups such as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

[0159] The term "arylalkyl" refers to an alkyl substituted with one or more aryl groups, where the alkyl and aryl groups are as described herein. One particular example is an arylmethyl or arylethyl group, where a single or double carbon spacer unit is attached to the aryl group, and the carbon spacer and aryl groups can be optionally substituted as described herein. Representative arylalkyl groups include: [ka] Examples include:

[0160] The term "arylalkylaryl" refers to a group of aryl groups substituted with one or more arylalkyl groups, where the aryl and alkyl groups are as described herein. One particular example is an arylmethyl or arylethyl group in which a methyl or ethyl group is attached to an additional aryl group. Representative arylalkylaryl groups include: [ka] In some embodiments, an arylalkylaryl group can be optionally substituted, where either the alkyl group, the aryl group, or any combination thereof can be substituted as described herein.

[0161] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more atoms in the ring system is an element(s) other than carbon, such as nitrogen, oxygen, or sulfur. In the case of polycyclic ring systems, only one of the rings must be aromatic for the ring system to be defined as a "heteroaryl". Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinolin ... Noxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazinyl azolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5] These include oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, etc.

[0162] As used herein, "heterocyclyl" or "heterocycle" refers to a stable 3- to 18-membered ring (radical) that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For purposes of this application, a heterocycle can be a monocyclic or polycyclic ring system which can include fused, bridged, or spiro ring systems, the nitrogen, carbon, or sulfur atoms in the heterocycle can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the ring can be partially or fully saturated. Examples of such heterocycles include, but are not limited to, azepinyl, azocanyl, pyranyldioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfolinyloxide, and thiamorpholinylsulfonylsulfone. Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, NY (1984), which is incorporated herein by reference in its entirety.

[0163] In some embodiments, the heterocycle is a non-aromatic heterocycle. The term "non-aromatic heterocycle" refers to a non-aromatic monocyclic ring system containing 3 to 10 atoms, preferably 4 to about 7 carbon atoms, in which one or more of the atoms in the ring system is an element(s) other than carbon, such as nitrogen, oxygen, or sulfur. Representative non-aromatic heterocyclic groups include pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, tetrahydro-2H-oxazinyl, and the like.

[0164] The term "monocyclic" as used herein refers to a molecular structure having one ring.

[0165] The terms "polycyclic" or "multi-cyclic" as used herein refer to molecular structures having two or more rings, including, but not limited to, fused, bridged, or spiro rings.

[0166] The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo.

[0167] The term "sulfate" is art-recognized and includes the term -OSO 3 H group, or a pharma- ceutically acceptable salt thereof.

[0168] The term "sulfonamide" is art recognized and refers to a group that can be represented by the general formula: [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0169] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0170] The term "sulfonate" is art-recognized and refers to a group consisting of sulfonates, such as aryl, aryl, and aryl. 3 H group, or a pharma- ceutically acceptable salt thereof.

[0171] The term "sulfone" is art-recognized and refers to the radical -S(O) 2 - refers to the group.

[0172] The term "substituted" or "substitution" of an atom means that one or more hydrogens on the specified atom are replaced with a selection from the indicated group, provided that the normal valence of the specified atom is not exceeded. "Substituted" or "substituted with" will be understood to include the implicit condition that such substitution is in accordance with the permitted valences of the substituted atom and substituents, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, where appropriate.

[0173] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0174] As used herein, the term "thioester" refers to the group -C(O)SR 9 Or -SC(O)R 9 Refers to... In the formula, R 9 represents hydrocarbyl.

[0175] As used herein, the term "thioether" is the equivalent of an ether where the oxygen is replaced with a sulfur.

[0176] The term "urea" is art-recognized and may be represented by the general formula: [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0177] As used herein, the term "amino acid side chain" or "side chain" refers to a substituent that characterizes an amino acid. The term refers to a substituent attached to the α-carbon of either a natural or unnatural α-amino acid. For example, the characterizing substituents of some natural amino acids are shown in Table 1. [Table 1]

[0178] Another naturally occurring amino acid is proline, where the alpha side chain terminates in a bond to the amino acid amine nitrogen atom. [ka]

[0179] Some non-limiting examples characterizing substituents of unnatural amino acids are shown in Table 2. [Table 2]

[0180] An "unsubstituted" atom carries all hydrogen atoms as determined by its valency. When a substituent is keto (i.e., =0), two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds, and a "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0181] The term "optionally substituted" is used to indicate that a group may have a substituent at each substitutable atom of the group (including two or more substituents on a single atom), provided that the normal valence of the designated atom is not exceeded and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, carboxy, carboalkoxy (aka alkoxycarbonyl), carboxamido (aka alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy. "Unsubstituted" atoms carry all hydrogen atoms as determined by their valence. If the substituent is keto (i.e., =0), two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds, and a "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0182] The terms "protection", "deprotection", and "protected" functional groups occur throughout this application. Such terms are well understood by those skilled in the art and are used in the context of processes involving sequential treatment with a series of reagents. In that context, a protecting group refers to a group used to mask a functionality during a process step that would otherwise react, but where that reaction is undesirable. The protecting group prevents reaction at that step, but may subsequently be removed to expose the original functionality. Removal or "deprotection" occurs after completion of one or more reactions in which the functionality interferes. Thus, when a sequence of reagents is specified, as is the process described herein, one of skill in the art can readily envision those groups that would be suitable as "protecting groups". Groups suitable for that purpose are described in standard textbooks in chemistry, such as Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991), which are incorporated herein by reference in their entirety.

[0183] The term "compounds of the invention" and equivalent expressions are intended to include compounds of general formula (I), formula (Ia), formula (IV), formula (IVa), formula (V), and formula (Va) as described herein, and the expressions include prodrugs, pharma- ceutically acceptable salts, and solvates, such as hydrates, if the context permits. Similarly, references to intermediates, whether or not they are themselves claimed, are intended to include their salts and solvates, if the context permits. For clarity, specific cases are often given in the text, if the context permits, but these cases are purely illustrative and are not intended to exclude other cases, if the context permits.

[0184] The compounds of the present invention are nicotinate / nicotinamide riboside-based compounds and derivatives. Exemplary compounds include nicotinamide (Nam), nicotinic acid (NA), nicotinamide ribose (NR), nicotinic mononucleotide (NMN), and nicotinic acid mononucleotide (NaMN) derivatives.

[0185] In some embodiments, the compounds of the present invention are zwitterions. As used herein, the term "zwitterion" or "zwitterionic" refers to a neutral molecule that has both positive and negative charges. Zwitterions are also called dipolar ions or internal salts, which are different from molecules that have dipoles at different positions within the molecule. Alternatively, the compounds of the present invention may be ionic compounds with one or more counterions. Exemplary counterions include, but are not limited to, 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 trifluoroacetate. The compounds of the present invention may exist in a variety of different forms, such as compounds associated with a counterion (e.g., a dry salt), but may also exist in a form that is not associated with a counterion (e.g., an aqueous or organic solution).

[0186] The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic acid addition salts, as well as base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. Specifically, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamate, malonate, salicylate, propionate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluyltartrate, methane-sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinateslaurylsulphonate, and the like (see, e.g., Berge et al., J. Am. Soc. Soc., 1999, 143:131-132, 1999). al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-9 (1977) and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, which are incorporated herein by reference in their entireties. Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharma- ceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. Suitable inorganic base addition salts are prepared, for example, from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide.Suitable amine base addition salts are prepared from amines which are sufficiently basic to form stable salts, and preferably include amines which are frequently used in pharmaceutical chemistry due to their low toxicity and acceptability for medical use, such as ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, dicyclohexylamine, and the like.

[0187] As used herein, the term "pharmaceutically acceptable prodrugs" refers to prodrugs of the compounds formed by the processes of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and sub-animals having undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, and where possible, zwitterionic forms of the compounds of the present invention.

[0188] The term "prodrug" refers to a compound that is rapidly converted in vivo, for example by hydrolysis in blood, to obtain the parent compound of the above formula. Functional groups that can be rapidly converted in vivo by metabolic cleavage form a class of groups that are reactive with the compounds of the present application. These include, but are not limited to, groups such as alkanoyl (acetyl, propionyl, butyryl, etc.), unsubstituted and substituted aroyl (benzoyl and substituted benzoyl, etc.), alkoxycarbonyl (ethoxycarbonyl, etc.), trialkylsilyl (trimethyl- and triethylsilyl, etc.), monoesters formed with dicarboxylic acids (succinyl, etc.). Because the metabolically cleavable groups of compounds useful according to the present application are easy to cleave in vivo, compounds bearing such groups act as prodrugs. Compounds bearing metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of the enhanced solubility and / or absorption rate imparted to the parent compound by the presence of the metabolically cleavable group.A thorough discussion of prodrugs is provided in: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs” p. 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1-38 (1992); J. Pharm. Sci., 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated by reference in their entireties. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.

[0189] The term "solvate" refers to a compound of the invention in the solid state, in which molecules of a suitable solvent are incorporated into the crystal lattice. Solvents suitable for therapeutic administration are physiologically acceptable at the dose administered. Examples of solvents suitable for therapeutic administration are ethanol and water. When water is the solvent, the solvate is called a hydrate. Pharmaceutically acceptable solvates and hydrates may include compounds with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent or water molecules. In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped under ambient conditions.

[0190] The compounds described herein may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present technology is intended to include all such possible isomers, including racemic and optically pure forms, as well as mixtures thereof. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using prior art techniques. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0191] This technique also contemplates the "quaternization" of any basic nitrogen-containing group of the compounds disclosed herein. Basic nitrogen can be quaternized with any agent known to those skilled in the art, including, for example, lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates including dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate, long chain halides such as decyl chloride, bromide, iodide, lauryl, myristyl, and stearyl, and aralkyl halides including benzyl bromide and phenethyl bromide. Water or oil soluble or dispersible products can be obtained by such quaternization.

[0192] In some characterizations of substituents, it is recited that certain substituents may be linked to form a ring. Unless otherwise indicated, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may contain heteroatoms, and may be substituted with lower alkyl or alkoxy.

[0193] As used herein, the term "subject" includes any human or non-human animal. For example, the methods and compositions described herein can be used to treat a subject (e.g., a human patient) in need of treatment for a skin affliction or skin condition. The subject can be a human in need of treatment for inflammation, sun damage, or natural aging.

[0194] "Therapeutically effective amount" means an amount of a compound disclosed herein, or other active agent described herein, that is effective to produce a therapeutic effect when administered to a subject.

[0195] As used herein, "administering" refers to physically introducing a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Preferred routes of administration of the therapeutic agents described herein include topical, oral, intravenous, intraperitoneal, intramuscular, subcutaneous, spinal, or other parenteral routes of administration. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0196] As used herein, the terms "treatment", "treating", "treat" and the like refer to alleviating or reducing the severity of at least one symptom or indication, eliminating the cause of a symptom, either temporarily or permanently, or obtaining a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of the severity of a symptom, condition, disorder or disease, stabilization (i.e., not worsening) of the condition, disorder or disease state, delaying or slowing the onset of the progression of the condition, disorder or disease, amelioration of the condition, disorder or disease state, and remission (partial or complete), whether detectable or undetectable, or enhancement or amelioration of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival in the absence of treatment. Treatment may result in a partial response (PR) or a complete response (CR).

[0197] As used herein, the term "prevent" includes prophylactic treatment or treatment that prevents one or more symptoms or conditions of a disease, disorder, or condition described herein (e.g., skin aging). Treatment can be initiated, for example, before ("pre-exposure prophylaxis") or after ("post-exposure prophylaxis") an event that precedes the onset of a disease, disorder, or condition. Treatment involving administration of a compound of the present invention or a pharmaceutical composition thereof can be acute, short-term, or chronic. The dose administered can vary during the course of prophylactic treatment.

[0198] The term "treatment method" refers to the amelioration or alleviation of the symptoms and / or effects associated with the disorders described herein. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

[0199] The various aspects described herein are described in further detail in the following subsections. EXAMPLES

[0200] Having now generally described the invention, the specification will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0201] Example 1: Preparation of exemplary compounds of the present disclosure Materials and Methods All commercially available chemicals and reagent grade solvents were used without further purification unless otherwise stated. Thin layer chromatography (TLC) was performed on silica gel plates using UV light (254 and 365 nm) detection or visualization. HPLC chromatography was performed on a porous graphite carbon HPLC column using an Agilent 1269 Infinity11 coupled to an InfinityLab LC / MSD. NMR spectra were acquired at room temperature using a 400 MHz Bruker spectrometer using individually identified solvents. Chemical shifts (δ) are expressed as the mean ± SEM of the solvent signal [ 1 H-NMR:CDCl 3 (7.26ppm), CD 3 OD(3.30ppm), DMSO-d 6(2.49 ppm)]. Signal patterns are reported as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sex (sexlet), sep (septet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), td (triplet of triplets), and tt (triplet of triplets). Coupling constants (J) are given in Hz. LCMS analysis was performed on an Agilent 1269 Infinity11 coupled to an InfinityLab LC / MSD mass spectrometer. Samples were ionized by electrospray ionization (ESI) in positive mode and reported as m / z (relative intensity) to the molecular ion [M].

[0202] Synthesis of nicotinate / nicotinamide riboside compounds and derivatives. ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((phenylthio)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl phosphate (6) [ka] To a solution of nicotinic acid (1, 5 g, 40.61 mmol, 3.40 mL, 1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (10.12 g, 52.80 mmol, 1.3 equiv.) in dichloromethane (DCM) (50 mL) was added hydroxybenzotriazole (HOBt) (7.13 g, 52.80 mmol, 1.3 equiv.) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 10 min, followed by dropwise addition of benzenethiol (2, 6.180 g, 56.09 mmol, 5.72 mL, 1.38 equiv.) at 0 °C. The resulting mixture was stirred at 20 °C for 5 h. LCMS (0-60AB / 1.5 min, RT=1.033 min, 216.1 [M+H] + , ESI pos) showed that a major peak with the desired product was detected.

[0203] The mixture was diluted with ice water (150 mL) and extracted with DCM (150 mL). The combined organic layers were washed with brine (210 mL) and sodium sulfate (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give a residue. The aqueous phase was quenched with aqueous sodium hypochlorite (NaClO). The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:0-5:1) to give S-phenylpyridine-3-carbothioate (3, 7 g, 32.19 mmol, 79.26% yield) as a colorless oil. LCMS:t R =0.861 min, m / z=216.3(M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 9.25 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.26 (br d, J = 8.1 Hz, 1H), 7.54 (br s, 5H), 7.45 - 7.41 (m, 1H).

[0204] To a solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3, 4.69 g, 14.73 mmol, 1.2 equiv.) and tert-butyl nicotinate (2.2 g, 12.28 mmol, 1 equiv.) in DCM (30 mL) was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.36 g, 6.14 mmol, 1.11 mL, 0.5 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 h. LCMS (0-60AB / 1.5 min, RT=0.915 min, 474.1 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The mixture was diluted with ice water (200 mL) and then saturated aqueous sodium bicarbonate (NaHCO 3 The mixture was neutralized with 1,2-dichloromethane (1.2 mL) to pH 6-7. The residue was extracted with DCM (50 mL). The combined organic layers were washed with brine (250 mL) and diluted with Na 2 SO 4The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 0:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (4, 6 g, 12.64 mmol, 90.74% yield) as a white solid. LCMS:t R =0.915 min, m / z=474.1(M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.58 - 9.50 (m, 2H), 9.09 (d, J = 8.2 Hz, 1H), 8.50 - 8.40 (m, 1H), 7.51 (s, 5H), 6.69 (d, J = 3.8 Hz, 1H), 5.55 - 5.48 (m, 1H), 5.36 (t, J = 5.6 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.60 - 4.41 (m, 2H), 2.20 - 2.12 (m, 9H).

[0205] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (4, 1 g, 2.11 mmol, 1 equiv.) was suspended in hydrochloric acid (HClaq) (3 M, 10 mL, 14.24 equiv.) at 0° C. The mixture was stirred at 20° C. for 16 h. LCMS (0-60AB / 1.5 min, RT=0.741 min, 348.0 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue at 0° C. The crude product was purified by reverse phase HPLC (MeCN / H 20, neutral) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (5,300 mg, 809.43 μmol, 38.41% yield) as a white solid. LCMS: R =0.727min, m / z=348.0(M+H) + . 1 H NMR (400 MHz, D 2 O) δ 9.75 (s, 1H), 9.29 (d, J = 6.2 Hz, 1H), 9.11 (br d, J = 8.2 Hz, 1H), 8.35 - 8.23 ​​(m, 1H), 7.63 - 7.50 (m, 5H), 6.25 (d, J = 3.9 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.36 - 4.29 (m, 1H), 4.08 - 3.99 (m, 1H), 3.90 - 3.82 (m, 1H).

[0206] Trimethyl phosphate (PO(OMe) 3 To a solution of 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (5, 100 mg, 287.03 umol, 1 equiv.) in 1 mL of phosphoryl chloride (POCl) at 0 °C. 3 ) (0.6 mL) was added. The mixture was stirred at 0° C. for 3 h. LCMS (0-6CD / 2 min, RT=0.412 min, 427.9 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The mixture was cooled to 0 °C with NaHCO 3 The pH was adjusted to about 7 with aqueous solution and filtered to give a residue. The crude product was purified by reverse phase HPLC (MeCN / H 2 0, neutral) to give (2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((phenylthio)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl phosphate (6) as a white solid. LCMS: R=0.412 min, m / z=427.9(M+H) + .

[0207] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (7) [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 mmol) was dissolved in a 1M, 50:50 deionized water:DMF solution and diisopropylethylamine (5 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 eq.) were added sequentially. The mixture was stirred at ambient temperature for 15 minutes. To this solution was slowly added (6-aminohexyl)triphenylphosphonium bromide hydrobromide (1 eq., 1M) in DMF and stirred at 25° C. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 2 The purified fraction was directly purified by HPLC. The purified fraction was lyophilized to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (7) as a white solid (about 45% yield).

[0208] LCMS:LCMS(1~99ABmL / min, RT=5.757min, 679.2[M+H] + , ESI pos) showed that a major peak with the desired product was detected.

[0209] A general synthetic method for the formation of analogs of 7 is shown in Scheme 1 below. [ka]

[0210] ((2R,3S,4R,5R)-5-(3-(tert-butoxycarbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate (8) [ka] ((2R,3S,4R,5R)-5-(3-(tert-butoxycarbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (8) was formed using the method described for compound 7. LCMS: R =0.660 min, m / z=392.2(M+H) + . 1 H NMR (400 MHz, D 2 O) δ 9.41 (s, 1H), 9.33 (d, J = 6.5 Hz, 1H), 9.05 (d, J = 8.1 Hz, 1H), 8.31 - 8.24 (m, 1H), 6.19 (d, J = 5.3 Hz, 1H), 4.63 - 4.59 (m, 1H), 4.52 (t, J = 5.1 Hz, 1H), 4.44 - 4.39 (m, 1H), 4.31 - 4.24 (m, 1H), 4.17 - 4.10 (m, 1H), 1.61 (s, 9H).

[0211] 3-((4-(4-aminobenzyl)phenyl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (9) [ka] 3-((4-(4-aminobenzyl)phenyl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (9) was formed using the method described for compound 7. LCMS: R=16.34 min, m / z=516.15(M+H) + .

[0212] 6-(Nicotinamido)hexyl)triphenylphosphonium(10) [ka] Nicotinoyl chloride (1 eq.) was dissolved in DMF (1M) and diisopropylethylamine (5 eq.) and (6-aminohexyl)triphenylphosphonium bromide hydrobromide (1 eq.) were added sequentially. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction was quenched with 1M HCl and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (MeCN / H 2 0), to give 6-(nicotinamido)hexyl)triphenylphosphonium (10) as a white solid in approximately 70% yield. LCMS: LCMS (1-99AB, 1.0 mL / min, RT=5.902 min, 467.1 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. 1 H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 8.22 (s, 1H), 7.81 (m, 15H), 7.54 (s, 1H), 3.39 (m, 4H), 1.65 (m, 6H), 1.43 (m, 2H).

[0213] A general synthetic method for the formation of analogs of 10 is shown in Scheme 2 below. [ka]

[0214] 3-(tert-butoxycarbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (11) [ka] To a solution of nicotinic acid (1 equiv.) in DMF (50 mL), 2 1,1'-carbonyldiimidazole (CDI) (1 eq.) was added under reduced pressure. After the addition, the mixture was stirred at 40°C for 1 h, followed by the addition of t-BuOH (2 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (61 eq.). The resulting mixture was stirred at 40°C for 16 h. TLC (petroleum ether:ethyl acetate=0:1) showed that a new spot was detected (R f EA (100 mL) was added to the mixture, and the solution was diluted with 10% acetic acid (20 mL), H 2 O (50 mL), and 10% K 2 CO 3 Wash with aqueous solution (50 mL) and add Na 2 SO 4 The mixture was dried at rt, filtered and concentrated under reduced pressure to give tert-butyl nicotinate (5 g, 27.90 mmol, 68.69% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 9.11 - 8.97 (m, 1H), 8.85 - 8.73 (m, 1H), 8.29 - 8.16 (m, 1H), 7.62 - 7.47 (m, 1H), 1.55 (s, 9H).

[0215] To a solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.2 eq.) in DCM (30 mL) containing TMSOTf (10.5 eq.) was added at 0° C. The mixture was stirred at 25° C. for 16 h. LCMS (0-60AB / 1.5 min, RT=0.879 min, 438.2 [M+H] + , ESI pos) showed that a major peak with the desired product was detected.

[0216] The residue was diluted with ice water (50 mL) and the mixture was diluted with saturated NaHCO 3The mixture was neutralized with aqueous solution (~15 mL) to pH 6-7. The residue was extracted with DCM (50 mL). The combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2、 Purification with petroleum ether:ethyl acetate = 1:0 to 0:1) gave 3-(tert-butoxycarbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (11) (N-2-INT4, 3 g, 6.76 mmol, 40.38% yield) as a white solid. 1 H NMR (400 MHz, D2O) δ 9.44 (s, 1H), 9.30 (d, J = 6.2 Hz, 1H), 9.05 (d, J = 8.1 Hz, 1H), 8.42 - 8.33 (m, 1H), 6.70 (d, J = 3.4 Hz, 1H), 5.66 - 5.57 (m, 1H), 5.41 (t, J = 5.9 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.52 - 4.40 (m, 2H), 2.15 (s, 3H), 2.10 (d, J = 7.1 Hz, 6H), 1.61 (s, 9H).

[0217] A general synthetic method for the formation of analogs of 11 is shown in Scheme 3 below. [ka]

[0218] Synthesis of additional nicotinate / nicotinamide riboside compounds and derivatives 3-(((S)-1-Carboxy-2-(1H-indol-3-yl)ethyl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 mmol) is dissolved in deionized water:DMF solution (1M, 50:50) and diisopropylethylamine (5 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 eq.) is added. The mixture is stirred at ambient temperature for 15 minutes. L-tryptophan in DMF (1 eq., 1M) is then slowly added to the solution and stirred at 25° C. The progress of the reaction is monitored by LCMS. After the reaction is complete, the crude product is directly purified by reverse phase HPLC. The purified fractions are lyophilized to give 3-(((S)-1-carboxy-2-(1H-indol-3-yl)ethyl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium.

[0219] 3-((R)-1-amino-4-methyl-1-oxopentan-2-yl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 mmol) is dissolved in a deionized water:DMF solution (1M, 50:50) and diisopropylethylamine (5 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 eq.) is added. The mixture is stirred at ambient temperature for 15 minutes. (R)-2-amino-4-methylpentanamide (1 eq., 1M) in DMF is then slowly added to the solution and stirred at 25° C. The progress of the reaction is monitored by LCMS. After the reaction is complete, the crude product is directly purified by reverse phase HPLC. The purified fractions are lyophilized to give 3-(((R)-1-amino-4-methyl-1-oxopentan-2-yl)carbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium.

[0220] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 mmol) is dissolved in deionized water:DMF solution (1M, 50:50) and diisopropylethylamine (5 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 eq.) is added. The mixture is stirred at ambient temperature for 15 minutes. Menthol in DMF (1 eq., 1M) is then slowly added to the solution and stirred at 25° C. The progress of the reaction is monitored by LCMS. After the reaction is complete, the crude product is directly purified by reverse phase HPLC. The purified fractions are lyophilized to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium.

[0221] intermediate formation Without being bound by any theory, the proposed reaction mechanism of the new procedure is outlined in Scheme 4. The conversion of NaMN to compound 9 is believed to occur via intermediate 9'. This was confirmed by treating NaMN with EDCI and N,N-diisopropylethylamine (DIPEA) alone (following the new procedure), which gave intermediate 9'. HPLC data showed that t R The NAMN peak at t = 14.8 min R = 18.5 min, suggesting the formation of intermediate 9'. By treating this mixture with 4,4'-methylenedianiline, R = 18.5 for the new amide (9) peak t R = Shift to 16.34 minutes. [ka]

[0222] Example 2: Further preparation of exemplary compounds of the present disclosure 2-Isopropyl-5-methylcyclohexyl nicotinate [ka] One equivalent of nicotinoyl chloride hydrochloride was dissolved in 0.1 M DMF and treated with one equivalent of menthol at 0° C. The reaction was stirred for 24 h. The crude product was purified by reverse phase HPLC (MeCN / H2O, 0.1% TFA) to give 2-isopropyl-5-methylcyclohexyl nicotinate as a white solid in 94% yield. LCMS:t R =0.727min, m / z=262.0(M+H) + .

[0223] 8-Hydroxy-6-oxo-6H-benzo[c]chromen-3-yl nicotinate [ka] To a solution of 3,8-dihydroxy-6H-benzo[c]chromen-6-one (1, 330 mg, 1.45 mmol, 1 equiv), nicotinoyl chloride (2, 1.29 g, 7.23 mmol, 73.40 uL, 5 equiv, HCl) in MeCN (10 mL) was added DMAP (88.34 mg, 723.05 umol, 0.5 equiv) and EDCI (554.43 mg, 2.89 mmol, 2 equiv), TEA (585.32 mg, 5.78 mmol, 805.12 uL, 4 equiv). The mixture was stirred at 25 °C for 48 h. LCMS (5-95 AB / 1 min, RT = 0.456 min, 334.1 [M+H] + , ESI pos) showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C8 250×50mm×10um; mobile phase: [water (HCl)-ACN]; B%: 20%~50%, 20min) to obtain 8-hydroxy-6-oxo-6H-benzo[c]chromen-3-yl nicotinate (N-16, 11.2mg, 32.26umol, 2.23% yield, 96% purity) as a white solid. LCMS:t R =0.461 min, m / z=334.1(M+H) + .

[0224] tert-Butyl 18-((2-(nicotinamido)ethyl)amino)-18-oxooctadecanoate [ka] To a solution of nicotinic acid (1, 10 g, 81.23 mmol, 6.80 mL, 1 equiv.) in DCM (50 mL), DMF (593.73 mg, 8.12 mmol, 624.98 uL, 0.1 equiv.) was added oxalyl dichloride (20.62 g, 162.46 mmol, 14.22 mL, 2 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 h. TLC (petroleum ether:ethyl acetate=0:1) showed that the material was consumed (R f =0.0), new spots were detected (R f =0.26). The reaction mixture was filtered and concentrated under reduced pressure to give nicotinoyl chloride (2, 10 g, 70.64 mmol, 86.97% yield) as a white solid. To a solution of nicotinoyl chloride (2, 1 g, 5.62 mmol, 6.80 mL, 1 equiv, HCl), tert-butyl (2-aminoethyl)carbamate (3, 900.00 mg, 5.62 mmol, 882.35 uL, 1 equiv) in DCM (10 mL) was added Et 3 N (1.14 g, 11.23 mmol, 1.56 mL, 2 equiv.) was added. The mixture was stirred at 25 °C for 2 h. LCMS (5-95AB / 1.5 min, RT = 0.319 min, 266.2, [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The reaction mixture was diluted with 80 mL of H 2 Dilute with 50 mL of DCM and extract with NaCl. 2 SO 4Drying over 100° C., filtering and concentrating under reduced pressure gave tert-butyl (2-(nicotinamido)ethyl)carbamate (4, 1.5 g, crude) as a yellow oil. To this tert-butyl (2-(nicotinamido)ethyl)carbamate (4, 1.5 g, 5.65 mmol, 1 equiv.) in DCM (20 mL) was added TFA (3.22 g, 28.27 mmol, 2.09 mL, 5 equiv.). The mixture was stirred at 25° C. for 1 h. LCMS (0-6° C. D / 1.5 min, RT=0.338 min, 166.4, [M+H] + , ESI pos) showed that the main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to give N-(2-aminoethyl)nicotinamide (5, 900 mg, 5.45 mmol, 96.36% yield) as a yellow oil. To this 18-(tert-butoxy)-18-oxooctadecanoic acid (6, 471.08 mg, 1.27 mmol, 1.05 equiv) in DCM (5 mL) was added dropwise HATU (552.42 mg, 1.45 mmol, 1.2 equiv), DIEA (469.43 mg, 3.63 mmol, 632.65 uL, 3 equiv). After addition, the mixture was stirred at 25 °C for 30 min, then N-(2-aminoethyl)nicotinamide (5, 200 mg, 1.21 mmol, 1 equiv) in DCM (1 mL) was added. The resulting mixture was stirred at 25° C. for 16 h. LCMS (5-95AB / 1.5 min, RT=0.726 min, 518.4, [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The residue was purified by H 2 The mixture was diluted with 200 mL of 2H2O (60 mL) and extracted with 100 mL of DCM (60 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (0.225% FA)-ACN]; B%: 80%-100%, 15 min) to give tert-butyl 18-((2-(nicotinamido)ethyl)amino)-18-oxooctadecanoate (N-10, 185 mg, 352.03 umol, 29.08% yield, 98.52% purity) as a white solid. LCMS: tR =0.724 min, m / z=518.5(M+H) + 1 H NMR (400 MHz, CDCl 3 ) δ 9.08 (s, 1H), 8.70 (br d, J = 3.9 Hz, 1H), 8.16 (br d, J = 8.1 Hz, 1H), 7.98 (br s, 1H), 7.42 - 7.35 (m, 1H), 6.51 (br t, J = 5.3 Hz, 1H), 3.63 - 3.49 (m, 4H), 2.19 (t, J = 7.5 Hz, 4H), 1.61 - 1.51 (m, 4H), 1.43 (s, 9H), 1.23 (br t, J = 13.3 Hz, 24H).

[0225] (E)-5-(4-(nicotinoyloxy)styryl)-1,3-phenylenediacetate [ka] To a solution of (E)-5-(4-hydroxystyryl)benzene-1,3-diol (1, 1 g, 4.38 mmol, 1 equiv.) in Py (5 mL) was added Ac2O (2.68 g, 26.29 mmol, 2.47 mL, 6 equiv.). The mixture was stirred at 80 °C for 1 h. LCMS (5-95 AB / 1 min, RT = 0.570 min, 355.0 [M+H] +, ESI pos) showed a major peak at the desired ms. The product was precipitated in 50 mL of water, filtered, and washed twice successively with water to give (E)-5-(4-acetoxystyryl)-1,3-phenylenediacetate (2, 1.5 g, 4.23 mmol, 96.62% yield) as a yellow solid. To a solution of this (E)-5-(4-acetoxystyryl)-1,3-phenylenediacetate (2, 3 g, 8.47 mmol, 1 equiv.), (E)-5-(4-hydroxystyryl)benzene-1,3-diol (1, 966.17 mg, 4.23 mmol, 0.5 equiv.) in DMSO (20 mL) was added K2CO3 (1.17 g, 8.47 mmol, 1 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS (5~95AB / 1min, RT=0.519min, 312.2[M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was diluted with H2O (150 mL), extracted with EA (150 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 0:1) to give (E)-5-(4-hydroxystyryl)-1,3-phenylenediacetate (3, 2.6 g, 8.32 mmol, 98.33% yield) as a white solid.

[0226] LCMS: RT=0.519 min, m / z=312.2[M+H] + To a solution of this (E)-5-(4-hydroxystyryl)-1,3-phenylenediacetate (3, 3 g, 9.61 mmol, 1 equiv.), nicotinoyl chloride (4, 1.71 g, 9.61 mmol, 1 equiv., HCl) in DCM (50 mL) was added TEA (2.92 g, 28.82 mmol, 4.01 mL, 3 equiv.). The mixture was stirred at 25 °C for 1 h. LCMS (5-95AB / 1 min, RT = 0.548 min, 418.2 [M+H] +, ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 1:1) to give (E)-5-(4-(nicotinoyloxy)styryl)-1,3-phenylenediacetate (N-39-INT4, 1 g, 2.34 mmol, 24.33% yield, 97.54% purity) as a white solid. QC of N-39-INT4. LCMS: RT=0.556 min, m / z=418.3 (M+H) + 1H NMR (400 MHz, MeOD) δ 9.34 - 9.24 (m, 1H), 8.89 - 8.79 (m, 1H), 8.61 - 8.50 (m, 1H), 7.66 - 7.56 (m, 3H), 7.38 (s, 1H), 7.28 - 7.01 (m, 6H), 2.32 - 2.26 (m, 6H)

[0227] (E)-5-(4-(nicotinoyloxy)styryl)-1,3-phenylenedicotinate [ka] Three equivalents of nicotinoyl chloride hydrochloride were dissolved in 0.1 M DMF and treated with one equivalent of resveratol at 0° C. The reaction was stirred for 24 h. The crude product was purified by reverse phase HPLC (MeCN / H2O, 0.1% TFA) to give 91% of (E)-5-(4-(nicotinoyloxy)styryl)-1,3-phenylenedinicotinate) as a white solid. LCMS:t R =0.9 min, m / z=544.0(M+H) + .

[0228] N-(2-aminoethyl)nicotinamide [ka] To a solution of nicotinoyl chloride (1, 5 g, 28.09 mmol, 6.80 mL, 1 equiv, HCl), tert-butyl (2-aminoethyl)carbamate (2, 4.50 g, 28.09 mmol, 4.41 mL, 1 equiv) in DCM (50 mL) was added Et3N (5.68 g, 56.17 mmol, 7.82 mL, 2 equiv). The mixture was stirred at 25 °C for 2 h. LCMS (5-95AB / 1.5 min, RT = 0.311 min, 266.1 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was diluted with 200 mL of H2O, extracted with 150 mL of DCM, dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (2-(nicotinamido)ethyl)carbamate (3,7 g, crude) as a yellow solid. To this solution of tert-butyl (2-(nicotinamido)ethyl)carbamate (3,7 g, 26.38 mmol, 1 equiv.) in DCM (20 mL) was added TFA (15.04 g, 131.92 mmol, 9.77 mL, 5 equiv.). The mixture was stirred at 25 °C for 5 h. LCMS (0-6 °C D / 1.5 min, RT = 0.309 min, 166.4 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (0.1% TFA condition) to give N-(2-aminoethyl)nicotinamide (N-13, 4 g, 14.30 mmol, 54.22% yield, 99.85% purity, TFA) as a yellow solid. LCMS: tR=0.331 min, m / z=166.4 (M+H) + 1 H NMR (400 MHz, DMSO) δ 9.07 (br s, 1H), 8.93 (br s, 1H), 8.78 (br d, J = 4.4 Hz, 1H), 8.37 - 8.27 (m, 1H), 7.94 (br s, 2H), 7.68 - 7.58 (m, 1H), 3.59 - 3.49 (m, 2H), 3.07 - 2.98 (m, 2H)

[0229] Ethyl 2-aminonicotinate [ka] To a solution of nicotinoyl chloride (1, 2 g, 11.23 mmol, 1 equiv., HCl) in DCM (50 mL) was added tert-butyl (2-hydroxyethyl)carbamate (1A, 1.81 g, 11.23 mmol, 1.74 mL, 1 equiv.) and TEA (2.27 g, 22.47 mmol, 3.13 mL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1.5 min, RT = 0.448 min, 267.1 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give ethyl 2-((tert-butoxycarbonyl)amino)nicotinate (2, 2.7 g, 10.14 mmol, 90.25% yield) as a yellow solid. To this solution of ethyl 2-((tert-butoxycarbonyl)amino)nicotinate (2, 2.7 g, 10.14 mmol, 1 equiv) in dioxane (12 mL) was added HCl / dioxane (4 M, 12 mL, 4.73 equiv) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS (0-6 °C D / 1.5 min, RT = 0.436 min, 167.2 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 (250 x 70 mm, 10 um); mobile phase: [water (HCl)-ACN]; gradient: 0% to 20% B in 12 min) to give ethyl 2-aminonicotinate (N-28-IN3, 2.8 g, 16.12 mmol, 95.7% purity) as a white solid. LCMS: RT=0.388 min, m / z=167.2 (M+H) + . 1 H NMR (400 MHz, MeOD) δ 9.46 (s, 1H), 9.07 - 8.95 (m, 2H), 8.07 (br s, 1H), 4.73 - 4.63 (m, 2H), 3.49 - 3.40 (m, 2H)

[0230] Nicotinic acid 2-hydroxyethyl [ka] To a solution of nicotinic acid (5 g, 40.61 mmol, 3.40 mL, 1 equiv.), ethane-1,2-diol (2, 5.04 g, 81.23 mmol, 4.54 mL, 2 equiv.) in DCM (10 mL), EDCI (11.68 g, 60.92 mmol, 1.5 equiv.), DMAP (992.35 mg, 8.12 mmol, 0.2 equiv.), TEA (4.11 g, 40.61 mmol, 5.65 mL, 1 equiv.) were added. The mixture was stirred at 25 °C for 16 h. LCMS (0-60 AB / 1 min, RT = 0.327 min, 168.1 [M+H] + , ESI pos) showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 0:1). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10um; mobile phase: [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain ethyl 2-hydroxynicotinate (N-20-INT3, 3.8g, 22.41mmol, 55.17% yield, 98.56% purity) as a white solid. LCMS:t R =0.326 min, m / z=168.1(M+H) + ; 1 H NMR (400 MHz, MeOD) 9.32 (d, J = 0.9 Hz, 1H), 8.97 - 8.89 (m, 1H), 8.87 - 8.77 (m, 1H), 7.97 - 7.87 (m, 1H), 4.52 - 4.42 (m, 2H), 3.96 - 3.85 (m, 2H).

[0231] 2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl nicotinate [ka] To a solution of diclofenac (1 eq.), ethyl 2-hydroxynicotinate (2 eq.) in DCM (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25°C for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 0:1). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 um, mobile phase: [water (HCl)-ACN], B%: 0% to 25%, 13 min), to obtain ethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)nicotinate (yield 81%, purity 98%) as a white solid. LCMS:t R =0.82 min, m / z=467(M+23) + .

[0232] N-(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetamido)ethyl)nicotinamide [ka] To a solution of diclofenac (1 eq.), N-(2-aminoethyl)nicotinamide (2 eq.) in DCM (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25°C for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 0:1). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 um; mobile phase: [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain N-(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetamido)ethyl)nicotinamide (yield 88%, purity 99%) as a white solid. LCMS:t R =8.1 min, m / z=444(M+H)+ .

[0233] N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)nicotinamide [ka] To a solution of ibuprofen (1 eq.), N-(2-aminoethyl)nicotinamide (2 eq.) in DMF (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to give N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)nicotinamide (82% yield, 98% purity) as a white solid. LCMS:t R =9.8 min, m / z=354(M+H) + .

[0234] 2-Methyl-2-(4-methylpent-3-en-1-yl)-7-pentyl-2h-chromen-5-yl nicotinate [ka] To a solution of cannabichromene (1 eq.), nicotinic acid (2 eq.) in DCM (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25°C for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 0:1). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 um; mobile phase: [water(HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain 2-methyl-2-(4-methylpent-3-en-1-yl)-7-pentyl-2H-chromen-5-yl nicotinate (84% yield, 99% purity) as a white solid. LCMS:t R =12.7 min, m / z=420(M+H) + .

[0235] N-(2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethyl)nicotinamide [ka] To a solution of retinoic acid (1 eq.), N-(2-aminoethyl)nicotinamide (2 eq.) in DMF (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain N-(2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethyl)nicotinamide (yield 86%, purity 99%) as a white solid. LCMS:t R =7.1 min, m / z=450(M+H) + .

[0236] 2-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoyl)oxy)ethyl nicotinate [ka] To a solution of retinoic acid (1 eq.), ethyl 2-hydroxynicotinate (2 eq.) in DMF (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain N-(2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethyl)nicotinamide (yield 86%, purity 99%) as a white solid. LCMS:t R =12.7 min, m / z=449(M+H) + .

[0237] 2-(3,4-bis(nicotinoyloxy)phenyl)-3-hydroxy-4-oxo-4H-chromene-5,7-diyldinicotinate [ka] To a solution of gallocatechol (1 eq.), nicotinic acid (5 eq.) in DMF (10 mL), EDCI (6 eq.), DMAP (0.2 eq.), TEA (10 eq.) were added. The mixture was stirred at 25° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to obtain 2-(3,4-bis(nicotinoyloxy)phenyl)-3-hydroxy-4-oxo-4H-chromene-5,7-diyldinicotinate (76% yield, 96% purity) as a white solid. LCMS:t R =0.5 min, m / z=723(M+H) + .

[0238] 2-((2-(4-isobutylphenyl)propanoyl)oxy)ethyl nicotinate [ka] To a solution of ibuprofen (1 eq.), ethyl 2-hydroxynicotinate (2 eq.) in DMF (10 mL), EDCI (1.5 eq.), DMAP (0.2 eq.), TEA (1 eq.) were added. The mixture was stirred at 25° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC [water (HCl)-ACN]; B%: 0% to 25%, 13 min) to give ethyl 2-((2-(4-isobutylphenyl)propanoyl)oxy)nicotinate (86% yield, 99% purity) as a white solid. LCMS:t R =9.5 minutes, m / z=356(M+H) + .

[0239] (Nicotinamidomethyl)triphenylphosphonium [ka] To a solution of N-(hydroxymethyl)nicotinamide (1, 200 mg, 1.31 mmol, 2 equiv.) in toluene (5 mL) and HCl (12 M, 54.77 μL, 1 equiv.), PPh 3 (189.62 mg, 722.97 μmol, 1.1 equiv) was added in one portion. The mixture was stirred at 110 °C for 2 h. LCMS (5-95AB / 1 min, RT = 0.402 min, 397.2 [M] + , ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water(HCl)-ACN]; B%: 10%-40%, 8 min) to give (nicotinamidomethyl)triphenylphosphonium (N-22, 13.9mg, 33.48μmol, 5.09% yield, 95.72% purity) as a white solid. LCMS:t R =0.402 min, m / z=397.2(M) + 1 H NMR (400 MHz, MeOD) 9.11 (d, J = 1.9 Hz, 1H), 9.00 (d, J = 5.6 Hz, 1H), 8.82 - 8.76 (m, 1H), 8.20 - 8.12 (m, 1H), 7.97 - 7.86 (m, 9H), 7.81 - 7.73 (m, 6H), 5.55 (d, J = 4.6 Hz, 2H).

[0240] ((nicotinoyloxy)methyl)triphenylphosphonium [ka] To a solution of nicotinoyl chloride (1, 200 mg, 1.41 mmol, 487.46 uL, 2 equiv.) and (hydroxymethyl)triphenylphosphonium chloride (2, 232.26 mg, 706.44 umol, 1 equiv.) in MeCN (10 mL), Py (279.40 mg, 3.53 mmol, 285.10 uL, 5 equiv.) was added. The mixture was stirred at 50 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.427 min, 398.2 [M] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 18%-48%, 8 min) to obtain ((nicotinoyloxy)methyl)triphenylphosphonium (N-23, 38.10mg, 89.54μmol, 12.67% yield, 93.63% purity) as a colorless oil. LCMS:t R =0.441 min, m / z=398.2(M) + 1 H NMR (400 MHz, MeOD) 9.24 (s, 1H), 9.12 (d, J = 5.6 Hz, 1H), 8.95 - 8.88 (m, 1H), 8.25 - 8.19 (m, 1H), 8.02 - 7.91 (m, 9H), 7.87 - 7.81 (m, 6H), 6.49 (d, J = 4.6 Hz, 2H).

[0241] (2-(nicotinamido)benzyl)triphenylphosphonium [ka] One equivalent of nicotinoyl chloride hydrochloride was dissolved in 0.1M MMF and treated with one equivalent of (2-aminobenzyl)triphenylphosphonium bromide at 0° C. The reaction was stirred for 24 h. The crude product was purified by reverse phase HPLC (MeCN / H2O, 0.1% TFA) to give (2-(nicotinamido)benzyl)triphenylphosphonium as a white solid in 94% yield. LCMS:t R =5.0 min, m / z=473(M+).

[0242] (6-(nicotinamide-2,4,5,6-D4)hexyl)triphenylphosphonium [ka] To a solution of 2,4,5,6-tetradeuteriopyridine-3-carboxylic acid (4,200 mg, 1.57 mmol, 1 equiv) in DCM (5 mL) was added DIEA (609.94 mg, 4.72 mmol, 822.02 uL, 3 equiv) and HATU (717.79 mg, 1.89 mmol, 1.2 equiv) and the mixture was stirred at 25 °C for 30 min. Then (6-aminohexyl)triphenylphosphonium (3, 570.21 mg, 1.57 mmol, 1 equiv) in DCM (1 mL) was added. The mixture was stirred at 25 °C for 1 h. LCMS (5-95AB / 1.5 min, RT=0.576 min, 471.3, [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The reaction mixture was diluted with 1M HCl (100 mL), extracted with DCM (100 mL), and washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 10 min) to give triphenyl-[6-[(2,4,5,6-tetradeuteriopyridine-3-carbonyl)amino]hexyl]phosphonium (420 mg, 890.61 umol, 56.62% yield) as a yellow solid. LCMS:t R =0.433 min, m / z=471.2(M+H) + .

[0243] (2-(nicotinamide)ethyl)triphenylphosphonium chloride [ka] To a solution of tert-butyl (2-bromoethyl)carbamate (1 g, 4.46 mmol, 1 equiv.) in MeCN (10 mL) was added PPh 3 (1.23 g, 4.69 mmol, 1.05 equiv.) was added. The mixture was stirred at 85 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.353 min, 306.3 [M] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition, 100% water) to give (2-aminoethyl)triphenylphosphonium (300 mg, 705.05 umol, 15.80% yield, 72% purity) as a yellow oil. To this solution of nicotinic acid (40.18 mg, 326.41 umol, 27.34 uL, 1 eq) in DCM (2 mL) was added HATU (148.93 mg, 391.70 umol, 1.2 eq), DIEA (126.56 mg, 979.24 umol, 170.57 uL, 3 eq). The mixture was stirred at 25°C for 30 minutes. Then, (2-aminoethyl)triphenylphosphonium (3, 100 mg, 326.41 umol, 1 eq.) was added. The mixture was stirred at 25° C. for 2 h. LCMS (5-95 AB / 1 min, RT=0.404 min, 411.2 [M] + , ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water(HCl)-ACN]; B%: 10%~40%, 8 min) to give (2-(nicotinamido)ethyl)triphenylphosphonium chloride (22.8mg, 54.86μmol, 16.81% yield, 99% purity) as a yellow solid. LCMS:t R =0397min, m / z=411.3(M) + 1 H NMR (400 MHz, MeOD) 9.16 (br s, 1H), 8.98 (br d, J = 4.8 Hz, 1H), 8.86 - 8.78 (m, 1H), 8.17 - 8.08 (m, 1H), 7.96 - 7.86 (m, 10H), 7.82 - 7.78 (m, 5H), 3.88 - 3.79 (m, 4H).

[0244] (2-(nicotinoyloxy)ethyl)triphenylphosphonium trifluoroacetate [ka] One equivalent of nicotinoyl chloride hydrochloride was dissolved in 0.1 M DMF and treated with one equivalent of (2-hydroxyethyl)triphenylphosphonium bromide at 0° C. The reaction was stirred for 24 h. The crude product was purified by reverse phase HPLC (MeCN / H2O, 0.1% TFA) to give 56% yield of (2-(nicotinoyloxy)ethyl)triphenylphosphonium trifluoroacetate as a white solid. LCMS:t R =11.344 min, m / z=412(M+).

[0245] (5-((2-(nicotinamido)ethyl)amino)-5-oxopentyl)triphenylphosphonium [ka] To a solution of N-(2-aminoethyl)nicotinamide (1, 200 mg, 1.21 mmol, 1 equiv.) in MeCN (5 mL) was added EDCI (696.29 mg, 3.63 mmol, 3 equiv.), HOBt (490.79 mg, 3.63 mmol, 3 equiv.) and (4-carboxybutyl)triphenylphosphonium (2, 439.98 mg, 1.21 mmol, 1 equiv.). The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1 min, RT = 0.408 min, 510.2 [M+H] + , ESI pos) showed a major peak at the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 10% to 40% B in 8 min) to give (5-((2-(nicotinamido)ethyl)amino)-5-oxopentyl)triphenylphosphonium (N-40, 65.7 mg, 126.36 μmol, 10.44% yield, 98.2% purity) as a yellow solid. LCMS: RT=0.408 min, m / z=510.2 (M+H) + 1 H NMR (400 MHz, CD 3OD) δ 9.26 (s, 1H), 9.01 - 8.99 (m, 2H), 8.22 - 8.20 (m, 1H), 7.89 - 7.81 (m, 3H), 7.77 - 7.75 (m, 12H), 3.51-3.31 (m, 6H), 2.29 - 2.25 (m, 2H), 1.86 - 1.83 (m, 2H), 1.71 - 1.69 (m, 2H)

[0246] (5-((2-(nicotinoyloxy)ethyl)amino)-5-oxopentyl)triphenylphosphonium [ka] To a solution of ethyl 2-aminonicotinate (200 mg, 1.20 mmol, 1 equiv) in DCM (5 mL) was added EDCI (346.08 mg, 1.81 mmol, 1.5 equiv), HOBt (243.94 mg, 1.81 mmol, 1.5 equiv) and (4-carboxybutyl)triphenylphosphonium (437.38 mg, 1.20 mmol, 1 equiv). The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1 min, RT = 0.427 min, 511.4 [M+H] + , ESI pos) showed a major peak with the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 15% to 45% B in 8 min) to give (5-((2-(nicotinoyloxy)ethyl)amino)-5-oxopentyl)triphenylphosphonium (123.1 mg, 217.41 μmol, 18.06% yield, 90.349% purity) as a yellow solid. LCMS: RT=0.427 min, m / z=511.4 (M+H) + 1H NMR (400 MHz, MeOD) δ 9.17 (s, 1H), 8.86 - 8.85 (m, 1H), 8.66 - 8.65 (m, 1H), 7.90 - 7.88 (m, 3H), 7.77 - 7.76 (m, 1H), 7.75 - 7.73 (m, 12H), 4.41 - 4.38 (m, 2H), 3.57-3.54 (m, 2H), 3.36 - 3.31 (m, 2H), 2.29 - 2.25 (m, 2H), 1.85 - 1.79 (m, 2H), 1.70 - 1.66 (m, 2H).

[0247] (2-(nicotinamide)ethyl)triphenylphosphonium chloride [ka] To a solution of nicotinic acid (4, 50 mg, 406.14 umol, 34.01 uL, 1 equiv) in DCM (2 mL) was added HATU (185.31 mg, 487.37 umol, 1.2 equiv), DIEA (209.96 mg, 1.62 mmol, 282.96 uL, 4 equiv). The mixture was stirred at 25 °C for 30 min. Then, (3-aminopropyl)triphenylphosphonium (3, 144.93 mg, 406.14 umol, 1 equiv, HCl) was added. The mixture was stirred at 25 °C for 2 h. LCMS (5-95AB / 1 min, RT=0.401 min, 425.1 [M] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 12%~42%, 8 min) to obtain (2-(nicotinamido)ethyl)triphenylphosphonium chloride (N-26, 63.8mg, 148.84μmol, 36.65% yield, 99.26% purity) as a white solid. LCMS:t R =0.401 min, m / z=425.3(M) + 1H NMR (400 MHz, MeOD) 9.21 (s, 1H), 8.99 - 8.89 (m, 2H), 8.17 - 8.09 (m, 1H), 7.93 - 7.88 (m, 3H), 7.87 - 7.75 (m, 12H), 3.65 (t, J = 6.8 Hz, 2H), 3.56 - 3.46 (m, 2H), 2.11 - 1.99 (m, 2H).

[0248] (3-(nicotinoyloxy)propyl)triphenylphosphonium chloride [ka] To a solution of nicotinic acid (1 g, 8.12 mmol, 680.27 uL, 1 equiv.), 3-bromopropan-1-ol (1.35 g, 9.75 mmol, 879.74 uL, 1.2 equiv.) in DCM (10 mL), EDCI (2.34 g, 12.18 mmol, 1.5 equiv.), DMAP (198.47 mg, 1.62 mmol, 0.2 equiv.), TEA (821.95 mg, 8.12 mmol, 1.13 mL, 1 equiv.) were added. The mixture was stirred at 25 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.442 min, 244.0 [M+H] + , ESI pos) showed a major peak at the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 3:1) to give 3-bromopropyl nicotinate (1.1 g, 4.51 mmol, 55.48% yield) as a white solid. To this solution of 3-bromopropyl nicotinate (500 mg, 2.05 mmol, 1 equiv.) in MeCN (10 mL), PPh 3 (564.15 mg, 2.15 mmol, 1.05 equiv) was added. The mixture was stirred at 80 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.428 min, 426.1 [M+H] +, ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 18%-48%, 8 min) to give (3-(nicotinoyloxy)propyl)triphenylphosphonium (116mg, 259.46umol, 12.67% yield, 95.39% purity) as a yellow oil. LCMS:t R =0.447min, m / z=426.1(M+H) + 1 H NMR (400 MHz, MeOD) 9.48 - 9.43 (m, 1H), 9.19 - 9.07 (m, 2H), 8.29 - 8.22 (m, 1H), 7.94 - 7.77 (m, 15H), 4.62 (t, J = 5.9 Hz, 2H), 3.74 - 3.62 (m, 2H), 2.29 - 2.17 (m, 2H).

[0249] (6-((2-(nicotinamido)ethyl)amino)-6-oxohexyl)triphenylphosphonium [ka] To a solution of N-(2-aminoethyl)nicotinamide (200 mg, 716.29 umol, 1 eq., TFA), (5-carboxypentyl)triphenylphosphonium (327.59 mg, 716.29 umol, 1 eq.) in MeCN (5 mL) was added EDCI (411.94 mg, 2.15 mmol, 3 eq.) and HOBt (290.36 mg, 2.15 mmol, 3 eq.). The mixture was stirred at 25° C. for 1 h. LCMS (5-95 AB / 1 min, RT=0.409 min, 524.3 [M] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 15%-45%, 8 min) to give (6-((2-(nicotinamido)ethyl)amino)-6-oxohexyl)triphenylphosphonium (111.5mg, 208.14μmol, yield 29.06%, purity 97.93%) as a colorless oil. LCMS:t R =0.400min, m / z=524.4(M) + 1 H NMR (400 MHz, MeOD) 9.28 (s, 1H), 9.06 - 8.99 (m, 2H), 8.26 - 8.20 (m, 1H), 7.94 - 7.76 (m, 15H), 3.59 - 3.40 (m, 6H), 2.21 (t, J = 7.1 Hz, 2H), 1.77 - 1.54 (m, 6H).

[0250] (6-((2-(nicotinoyloxy)ethyl)amino)-6-oxohexyl)triphenylphosphonium [ka] To a solution of ethyl 2-aminonicotinate (200 mg, 1.20 mmol, 1 equiv) in DCM (10 mL) was added EDCI (346.08 mg, 1.81 mmol, 1.5 equiv), (5-carboxypentyl)triphenylphosphonium (454.26 mg, 1.20 mmol, 1 equiv), and HOBt (243.94 mg, 1.81 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1.5 min, RT = 0.412 min, 525.2 [M+H] +, ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 18%-48% B in 8 min) to give (6-((2-(nicotinoyloxy)ethyl)amino)-6-oxohexyl)triphenylphosphonium (75.4 mg, 129.45 μmol, 10.76% yield, 90.23% purity) as a yellow solid. LCMS: t R =0.412 min, m / z=525.2(M+H) + 1 H NMR (400 MHz, MeOD) δ 9.41 (s, 1H), 9.16 - 8.99 (m, 2H), 8.22 (dd, J = 6.3, 8.1 Hz, 1H), 7.95 - 7.85 (m, 3H), 7.83 - 7.74 (m, 12H), 4.48 (t, J = 5.4 Hz, 2H), 3.63 - 3.54 (m, 2H), 3.48 - 3.36 (m, 2H), 2.24 - 2.15 (m, 2H), 1.73 - 1.53 (m, 6H).

[0251] (6-(nicotinamide)hexyl)triphenylphosphonium chloride [ka] To a solution of nicotinic acid (2, 249.64 mg, 2.03 mmol, 169.82 uL, 1.05 equiv) in THF (8 mL) was added DIEA (748.79 mg, 5.79 mmol, 1.01 mL, 3 equiv) and HATU (881.17 mg, 2.32 mmol, 1.2 equiv). Then, (6-(nicotinamido)hexyl)triphenylphosphonium chloride (700 mg, 1.93 mmol, 1 equiv) was added. The mixture was stirred at 20° C. for 16 hours. LCMS showed that reactant 1 was completely consumed and the desired mass was detected. The reaction mixture was filtered to obtain a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to obtain (6-(nicotinamido)hexyl)triphenylphosphonium chloride (100 mg, 213.88 umol, 42.66% yield) as a yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ 8.93 (d, J = 1.7 Hz, 1H), 8.71 - 8.66 (m, 1H), 8.23 ​​- 8.18 (m, 1H), 7.92 - 7.86 (m, 3H), 7.82 - 7.74 (m, 12H), 7.57 - 7.51 (m, 1H), 3.44 - 3.35 (m, 4H), 1.72 - 1.58 (m, 6H), 1.47 - 1.39 (m, 2H).

[0252] (6-(nicotinoyloxy)hexyl)triphenylphosphonium [ka] Nicotinic acid (173.25 mg, 1.41 mmol, 117.86 uL, 1.2 equiv) in MeCN (5 mL), K 2 CO 3 To a solution of (324.16 mg, 2.35 mmol, 2 equiv.) was added (6-bromohexyl)triphenylphosphonium (500 mg, 1.17 mmol, 1 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.458 min, 468.4, [M+H] +, ESI pos) showed a major peak at the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 22%~52%, 7min) to give (6-(nicotinoyloxy)hexyl)triphenylphosphonium (43.6mg, 89.53umol, 7.63% yield, 96.21% purity) as a yellow oil. LCMS:t R =0.468 min, m / z=468.3(M+H) + 1 H NMR (400 MHz, MeOD) δ 9.09 (d, J = 1.6 Hz, 1H), 8.78 - 8.72 (m, 1H), 8.54 (s, 1H), 8.41 - 8.33 (m, 1H), 7.92 - 7.86 (m, 3H), 7.83 - 7.74 (m, 11H), 7.59 - 7.55 (m, 1H), 4.35 (t, J = 6.6 Hz, 2H), 3.45 - 3.38 (m, 2H), 1.82 - 1.61 (m, 6H), 1.55 - 1.47 (m, 2H).

[0253] (9-((2-(nicotinamido)ethyl)amino)nonyl)triphenylphosphonium [ka] A mixture of (9-bromononyl)triphenylphosphonium (HBr salt, 100 mg, 213.48 μmol, 1 equiv.), N-(2-aminoethyl)nicotinamide (298.03 mg, 1.07 mmol, 5 equiv., TFA) in MeOH (2 mL), then the mixture was stirred at 80 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.395 min, 276.8 [1 / 2M+H] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 5% to 35% B in 10 min) to give (9-((2-(nicotinamido)ethyl)amino)nonyl)triphenylphosphonium (, HCl salt, 23.7 mg, 42.49 μmol, yield 19.90%, purity 99.09%) as a yellow gum. 1 H NMR (400 MHz, CD 3 OD) 9.60 (s, 1H), 9.16 (d, J = 6.3 Hz, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.29 - 8.21 (m, 1H), 7.94 - 7.89 (m, 3H), 7.85 - 7.75 (m, 12H), 4.75 - 4.68 (m, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.46 - 3.39 (m, 2H), 3.26 (t, J = 5.9 Hz, 2H), 2.13 - 2.04 (m, 2H), 1.73 - 1.54 (m, 4H), 1.46 - 1.32 (m, 8H).

[0254] (9-(2-(nicotinoyloxy)ethoxy)nonyl)triphenylphosphonium [ka] To a solution of ethyl 2-((9-bromononyl)oxy)nicotinate (90 mg, 241.74 μmol, 1 equiv.) in MeCN (3 mL), PPh 3 (66.58 mg, 253.83 μmol, 1.05 equiv.) was added. The mixture was stirred at 85° C. for 1 h. LCMS (5-95AB / 1.5 min, RT=0.518 min, 554.3 [M+H] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 32% to 62% B, 9 min) to give (9-(2-(nicotinoyloxy)ethoxy)nonyl)triphenylphosphonium (HCl salt, 12.8 mg, 22.37 μmol, 24.82% yield, 96.94% purity) as a yellow solid. QC of N-42 LCMS: RT=0.537 min, m / z=554.4 (M+H) + 1 H NMR (400 MHz, CD 3 OD) δ 9.39 (br s, 1H), 9.14 - 9.07 (m, 2H), 8.24 (br t, J = 6.5 Hz, 1H), 7.93 - 7.89 (m, 3H), 7.85 - 7.77 (m, 12H), 4.65 - 4.57 (m, 2H), 3.88 - 3.79 (m, 2H), 3.54 (br t, J = 6.5 Hz, 2H), 3.40 (br d, J = 9.1 Hz, 2H), 1.74 - 1.56 (m, 6H), 1.32 (br d, J = 2.9 Hz, 8H).

[0255] (3-((2-(nicotinamido)ethyl)amino)propyl)triphenylphosphonium chloride [ka] A mixture of (3-bromopropyl)triphenylphosphonium (100 mg, 260.23 umol, 1 equiv.), N-(2-aminoethyl)nicotinamide (363.31 mg, 1.30 mmol, 5 equiv., TFA) in MeOH (2 mL) was degassed and cooled with N 2 The mixture was then purged with 500 mL of ethyl acetate three times and then stirred at 80° C. for 32 h. LCMS (5-95AB / 1.5 min, RT=0.301 min, 468.2 [M+H] +, ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC Triart C18 150×25mm×5um; mobile phase: [water(HCl)-ACN]; B%: 6%~36%, 10min) to give (3-((2(nicotinamido)ethyl)amino)propyl)triphenylphosphonium chloride (25.21mg, 53.55umol, yield 20.58%, purity 99.53%) as a white solid. LCMS:t R =0.309min, m / z=468.2(M+H) + 1 H NMR (400 MHz, MeOD) δ 9.72 (s, 1H), 9.19 (d, J = 6.1 Hz, 1H), 9.00 (d, J = 8.2 Hz, 1H), 8.27 - 8.18 (m, 1H), 7.94 - 7.75 (m, 15H), 4.98 (t, J = 7.5 Hz, 2H), 3.78 - 3.67 (m, 4H), 3.24 (t, J = 5.7 Hz, 2H), 2.56 - 2.44 (m, 2H).

[0256] (3-(2-(nicotinoyloxy)ethoxy)propyl)triphenylphosphonium [ka] To a solution of oxirane (950.83 mg, 21.58 mmol, 1.08 mL, 1 equiv.) in phosphoric acid (634.54 mg, 6.48 mmol, 377.70 μL, 0.3 equiv.) was added 3-bromopropan-1-ol (3 g, 21.58 mmol, 1.95 mL, 1 equiv.). The mixture was stirred at 5° C. for 16 h. The reaction mixture was diluted with 150 mL of H 2 Dilute with 150 mL of EA and extract with NaCl. 2 SO 4The mixture was dried over 100° C., filtered and concentrated under reduced pressure to give a residue giving 2-(3-bromopropoxy)ethan-1-ol (3.9 g, crude) as a colorless oil. To a solution of 2-(3-bromopropoxy)ethan-1-ol (646.54 mg, 3.53 mmol, 1 equiv.) in DCM (10 mL) was added TEA (714.84 mg, 7.06 mmol, 983.27 μL, 2 equiv.) dropwise followed by nicotinoyl chloride (500 mg, 3.53 mmol, 1 equiv.). The mixture was stirred at 25° C. for 2 h. LCMS (5-95 AB / 1 min, RT=0.444 min, 290.1 ​​[M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=2:1) ​​to give ethyl 2-(3-bromopropoxy)nicotinate (150 mg, 400.85 μmol, 11.35% yield, 77% purity) as a yellow oil. To this solution of ethyl 2-(3-bromopropoxy)nicotinate (5, 100 mg, 347.06 μmol, 1 equiv.) in MeCN (1 mL) was added PPh 3 (95.58 mg, 364.41 μmol, 1.05 equiv.) was added. The mixture was stirred at 85° C. for 1 h. LCMS (5-95AB / 1 min, RT=0.452 min, 470.2 [M] + , ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water(HCl)-ACN]; B%: 18%-48%, 8 min) to give (3-(2-(nicotinoyloxy)ethoxy)propyl)triphenylphosphonium (20.2mg, 40.54μmol, yield 11.68%, purity 94.42%) as a red gum. LCMS:t R =0.450 min, m / z=470.3(M+H) + 1H NMR (400 MHz, MeOD) 9.39 (s, 1H), 9.12 - 9.07 (m, 2H), 8.26 - 8.19 (m, 1H), 7.91 - 7.87 (m, 3H), 7.83 - 7.74 (m, 12H), 4.66 - 4.59 (m, 2H), 3.88 - 3.81 (m, 2H), 3.70 (t, J = 5.3 Hz, 2H), 3.53 - 3.43 (m, 2H), 2.00 - 1.88 (m, 2H).

[0257] (3-((2-(nicotinoyloxy)ethyl)amino)-3-oxopropyl)triphenylphosphonium [ka] To a solution of ethyl 2-aminonicotinate (200 mg, 986.98 μmol, 1 equiv, HCl), (2-carboxyethyl)triphenylphosphonium (330.99 mg, 986.98 μmol, 1 equiv) in DCM (10 mL) was added EDCI (283.81 mg, 1.48 mmol, 1.5 equiv) and HOBt (200.05 mg, 1.48 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.419 min, 438.3 [M] + , ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water(HCl)-ACN]; B%: 15%-45%, 8 min) to give (3-((2-(nicotinoyloxy)ethyl)amino)-3-oxopropyl)triphenylphosphonium (87.1mg, 173.94μmol, yield 17.62%, purity 96.56%) as a colorless gum. LCMS:t R =0.419 min, m / z=483.3(M+H )+ 1H NMR (400 MHz, MeOD) 9.48 - 9.43 (m, 1H), 9.18 - 9.07 (m, 2H), 8.29 - 8.23 ​​(m, 1H), 7.92 (br s, 3H), 7.85 - 7.75 (m, 12H), 4.42 (t, J = 5.3 Hz, 2H), 3.76 - 3.70 (m, 2H), 3.54 (t, J = 5.3 Hz, 2H), 2.76 - 2.69 (m, 2H).

[0258] (3-((2-(nicotinamido)ethyl)amino)-3-oxopropyl)triphenylphosphonium [ka] To a solution of N-(2-aminoethyl)nicotinamide (200 mg, 716.29 umol, 1 eq., TFA), (2-carboxyethyl)triphenylphosphonium (240.21 mg, 716.29 umol, 1 eq.) in MeCN (5 mL) was added EDCI (411.94 mg, 2.15 mmol, 3 eq.) and HOBt (290.36 mg, 2.15 mmol, 3 eq.). The mixture was stirred at 25° C. for 1 h. LCMS (5-95 AB / 1 min, RT=0.395 min, 482.2 [M] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 12%~42%, 8 min) to obtain (3-((2-(nicotinamido)ethyl)amino)-3-oxopropyl)triphenylphosphonium (100.5mg, 203.38μmol, yield 28.39%, purity 97.65%) as a colorless oil. LCMS:t R =0.383min, m / z=482.3(M) + 1H NMR (400 MHz, MeOD) 9.28 (br s, 1H), 9.05 - 8.93 (m, 2H), 8.19 (br d, J = 4.4 Hz, 1H), 7.93 - 7.75 (m, 15H), 3.78 - 3.69 (m, 2H), 3.55 - 3.48 (m, 2H), 3.42 - 3.35 (m, 2H), 2.74 - 2.63 (m, 2H).

[0259] (6-((2-(nicotinamido)ethyl)amino)hexyl)triphenylphosphonium [ka] To a solution of N-(2-aminoethyl)nicotinamide (3.27 g, 11.73 mmol, 5 equiv., TFA) in MeOH (25 mL) was added (6-bromohexyl)triphenylphosphonium (1 g, 2.35 mmol, 1 equiv.). The mixture was stirred at 80 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.361 min, 510.3 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 0%~30%, 8 min) to obtain (6-((2-(nicotinamido)ethyl)amino)hexyl)triphenylphosphonium (8.2mg, 15.90umol, 6.78e-1% yield, 99% purity) as a yellow oil. LCMS:t R =0.363min, m / z=510.3(M+H) + 1H NMR (400 MHz, MeOD) δ 9.63 (s, 1H), 9.16 (br d, J = 5.3 Hz, 1H), 9.02 (br d, J = 7.6 Hz, 1H), 8.24 (br t, J = 6.3 Hz, 1H), 7.93 - 7.76 (m, 15H), 4.73 (br t, J = 6.4 Hz, 2H), 3.77 (br t, J = 5.5 Hz, 2H), 3.52 - 3.40 (m, 2H), 3.27 (br t, J = 5.2 Hz, 2H), 2.10 (br s, 2H), 1.71 (br s, 4H), 1.50 (br s, 2H).

[0260] (6-(2-(nicotinoyloxy)ethoxy)hexyl)triphenylphosphonium [ka] To a solution of oxirane (1.90 g, 43.17 mmol, 2.16 mL, 2 equiv.) in phosphoric acid (634.54 mg, 6.48 mmol, 377.70 μL, 0.3 equiv.) was added 6-bromohexan-1-ol (3.91 g, 21.58 mmol, 2.82 mL, 1 equiv.). The resulting mixture was stirred at 5° C. for 16 h. The reaction mixture was cooled to 5° C. and cooled to 5° C. for 1 h. 2 Dilute with O (150 mL), extract with EA (150 mL), and add Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated under reduced pressure to give a residue giving 2-((6-bromohexyl)oxy)ethan-1-ol (4.8 g, crude) as a colorless oil. To this solution of 2-((6-bromohexyl)oxy)ethan-1-ol (795.18 mg, 3.53 mmol, 1 equiv.) in DCM (2 mL) was added dropwise TEA (714.85 mg, 7.06 mmol, 983.28 μL, 2 equiv.) followed by nicotinoyl chloride (500 mg, 3.53 mmol, 1 equiv.). The resulting mixture was stirred at 25° C. for 1 h. LCMS (5-95 AB / 1 min, RT=0.541 min, 330.1 [M+H] +, ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=3:1) to give ethyl 2-((6-bromohexyl)oxy)nicotinate (300 mg, 708.63 μmol, 20.06% yield, 78% purity) as a colorless oil. To this solution of ethyl 2-((6-bromohexyl)oxy)nicotinate (170 mg, 514.81 μmol, 1 equiv.) in MeCN (3 mL) was added PPh 3 (141.78 mg, 540.55 μmol, 1.05 equiv.) was added dropwise. The resulting mixture was stirred at 85° C. for 1 h. LCMS (5-95 AB / 1 min, RT=0.502 min, 512.4 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 24%~54%, 8 min) to give (6-(2-(nicotinoyloxy)ethoxy)hexyl)triphenylphosphonium (21.2mg, 39.29μmol, yield 7.63%, purity 95%) as a colorless gum. LCMS:t R =0.474 min, m / z=512.3(M+H) + 1 H NMR (400 MHz, MeOD) 9.41 (d, J = 1.0 Hz, 1H), 9.15 - 9.07 (m, 2H), 8.27 - 8.21 (m, 1H), 7.93 - 7.86 (m, 3H), 7.83 - 7.73 (m, 12H), 4.60 - 4.55 (m, 2H), 3.83 - 3.77 (m, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.45 - 3.36 (m, 2H), 1.69 - 1.53 (m, 6H), 1.45 - 1.38 (m, 2H).

[0261] 1-((2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium [ka] To a solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium (1, 100 mg, 172.80 μmol, 1 equiv.) was added HCl (3M, 5 mL). The mixture was stirred at 25 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.580 min, 452.2 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 45%-75%, 8 min) to obtain 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium (, 14.1mg, 29.23μmol, 16.92% yield, 93.84% purity) as a white solid. LCMS:t R =0.596 min, m / z=452.4(M+H) + . 1 H NMR (400 MHz, MeOD) 9.85 (s, 1H), 9.45 (br d, J = 6.3 Hz, 1H), 9.12 (br d, J = 8.0 Hz, 1H), 8.29 (t, J = 7.1 Hz, 1H), 6.20 (d, J = 4.9 Hz, 1H), 4.50 - 4.39 (m, 4H), 4.31 (br d, J = 3.1 Hz, 1H), 4.05 - 3.82 (m, 2H), 1.88 - 1.80 (m, 2H), 1.51 - 1.44 (m, 2H), 1.29 (s, 20H), 0.90 (br t, J = 6.5 Hz, 3H).

[0262] 1-((2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-(tetradecylcarbamoyl)pyridin-1-ium [ka] To a solution of nicotinoyl chloride (3 g, 16.85 mmol, 1 equiv, HCl) in DCM (50 mL) was added TEA (3.41 g, 33.70 mmol, 4.69 mL, 2 equiv) and tetradecan-1-ol (2, 3.61 g, 16.85 mmol, 1 equiv) at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.857 min, 320.3 [M+H] + , ESI pos) showed a major peak for the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 1:1) to give tetradecyl nicotinate (5 g, 15.53 mmol, 92.17% yield, 99.25% purity) as a yellow solid. LCMS:t R =0.867 min, m / z=320.4(M+H) + 1H NMR (400 MHz, MeOD) 9.11 (d, J = 1.9 Hz, 1H), 8.78 - 8.68 (m, 1H), 8.44 - 8.34 (m, 1H), 7.61 - 7.50 (m, 1H), 4.37 (br t, J = 6.6 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.45 (br d, J = 7.8 Hz, 4H), 1.28 (br s, 18H), 0.89 (br t, J = 6.4 Hz, 3H).To this solution of tetradecyl nicotinate (1 g, 3.13 mmol, 1 equiv.), (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.20 g, 3.76 mmol, 1.2 equiv.) in DCM (20 mL) was added TMSOTf (1.04 g, 4.70 mmol, 848.40 μL, 1.5 equiv.) at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.632 min, 578.5 [M+H] + , ESI pos) showed a major peak for the desired product. The reaction mixture was diluted with 50 mL of 1 M NaHCO 3 Dilute with 50 mL of DCM and extract with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 The residue was purified by prep-HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 51%-81%, 8 min) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium (1g, 1.71mmol, 54.50% yield, 98.72% purity) as a colorless oil. LCMS:t R =0.642min, m / z=578.5(M+H) + 1H NMR (400 MHz, MeOD) 9.66 (s, 1H), 9.36 (d, J = 6.4 Hz, 1H), 9.22 - 9.16 (m, 1H), 8.41 - 8.34 (m, 1H), 6.62 (d, J = 3.5 Hz, 1H), 5.63 - 5.54 (m, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.85 - 4.82 (m, 1H), 4.64 - 4.48 (m, 4H), 2.21 - 2.14 (m, 9H), 1.88 - 1.80 (m, 2H), 1.52 - 1.45 (m, 2H), 1.29 (s, 20H), 0.93 - 0.88 (m, 3H). To this solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium, 100 mg, 172.80 μmol, 1 equiv., was added HCl (3M, 5 mL). The mixture was stirred at 25° C. for 16 h. LCMS (5-95AB / 1 min, RT=0.580 min, 452.2 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 45%-75%, 8 min) to obtain 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium (14.1mg, 29.23μmol, 16.92% yield, 93.84% purity) as a white solid. LCMS:t R =0.596 min, m / z=452.4(M+H) + . 1H NMR (400 MHz, MeOD) 9.85 (s, 1H), 9.45 (br d, J = 6.3 Hz, 1H), 9.12 (br d, J = 8.0 Hz, 1H), 8.29 (t, J = 7.1 Hz, 1H), 6.20 (d, J = 4.9 Hz, 1H), 4.50 - 4.39 (m, 4H), 4.31 (br d, J = 3.1 Hz, 1H), 4.05 - 3.82 (m, 2H), 1.88 - 1.80 (m, 2H), 1.51 - 1.44 (m, 2H), 1.29 (s, 20H), 0.90 (br t, J = 6.5 Hz, 3H).

[0263] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((4-((E)-3,5-dihydroxystyryl)phenoxy)carbonyl)pyridin-1-ium [ka] A solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((4-((E)-3,5-diacetoxystyryl)phenoxy)carbonyl)pyridin-1-ium (400 mg, 591.15 μmol, 1 equiv.) in HCl (3M, 5 mL, 25.37 equiv.) was stirred at 25° C. for 16 h. LCMS (5-95AB / 1 min, RT=0.382 min, 466.4 [M+H] +, ESI pos) showed a major peak at the desired ms. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (0.1% HCl condition). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (HCl)-ACN]; gradient: 5% to 35% B for 10 min) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((4-((E)-3,5-dihydroxystyryl)phenoxy)carbonyl)pyridin-1-ium (13.1 mg, 26.83 μmol, 4.54% yield, 95.54% purity, HCl salt) as a yellow solid. LCMS: RT=0.378 min, m / z=466.1(M+H) + 1 H NMR (400 MHz, CD 3 OD) δ 10.07 (s, 1H), 9.53 (d, J = 6.3 Hz, 1H), 9.32 - 9.24 (m, 1H), 8.42 - 8.33 (m, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.11 - 6.96 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.65 (t, J = 1.8 Hz, 1H), 6.26 (d, J = 4.8 Hz, 1H), 4.50 - 4.44 (m, 2H), 4.36 - 4.32 (m, 1H), 4.06 (s, 1H), 3.90 - 3.84 (m, 1H).

[0264] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((4-((E)-3,5-diacetoxystyryl)phenoxy)carbonyl)pyridin-1-ium [ka] To a solution of (E)-5-(4-(nicotinoyloxy)styryl)-1,3-phenylenediacetate (1 g, 2.40 mmol, 1 equiv.), (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (915.00 mg, 2.87 mmol, 1.2 equiv.) in DCM (20 mL) was added TMSOTf (1.06 g, 4.79 mmol, 865.80 μL, 2 equiv.). The mixture was stirred at 25 °C for 2 h. LCMS (5-95 AB / 1 min, RT = 0.509 min, 676.3 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was diluted with 1M NaHCO 3 (150 mL), extracted with DCM (150 mL), and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:0 to 0:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((4-((E)-3,5-diacetoxystyryl)phenoxy)carbonyl)pyridin-1-ium (1 g, 2.34 mmol, 24.33% yield, 97.54% purity, TfOH salt) as a yellow solid. LCMS: RT=0.509 min, m / z=676.3 (M+H) + . 1 H NMR (400 MHz, CD 3OD) δ 9.85 (s, 1H), 9.51 - 9.37 (m, 2H), 8.54 - 8.45 (m, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.49 (t, J = 1.6 Hz, 1H), 7.38 - 7.19 (m, 3H), 7.17 - 7.10 (m, 3H), 6.69 (d, J = 3.5 Hz, 1H), 5.69 - 5.62 (m, 1H), 5.48 (t, J = 5.8 Hz, 1H), 4.88 - 4.85 (m, 1H), 4.68 - 4.51 (m, 2H), 2.32 (d, J = 15.8 Hz, 6H), 2.23 - 2.15 (m, 9H).

[0265] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium [ka] To a solution of tetradecyl nicotinate (1 g, 3.13 mmol, 1 equiv.), (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (2, 1.20 g, 3.76 mmol, 1.2 equiv.) in DCM (20 mL) was added TMSOTf (1.04 g, 4.70 mmol, 848.40 μL, 1.5 equiv.) at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.632 min, 578.5 [M+H] + , ESI pos) showed a major peak for the desired product. The reaction mixture was diluted with 50 mL of 1 M NaHCO 3 Dilute with 50 mL of DCM and extract with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2The mixture was purified by prep-HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water (HCl)-ACN]; B%: 51%-81%, 8 min) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((tetradecyloxy)carbonyl)pyridin-1-ium (1g, 1.71mmol, 54.50% yield, 98.72% purity) as a colorless oil. LCMS:t R =0.642 min, m / z=578.5(M+H) + . 1 H NMR (400 MHz, MeOD) 9.66 (s, 1H), 9.36 (d, J = 6.4 Hz, 1H), 9.22 - 9.16 (m, 1H), 8.41 - 8.34 (m, 1H), 6.62 (d, J = 3.5 Hz, 1H), 5.63 - 5.54 (m, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.85 - 4.82 (m, 1H), 4.64 - 4.48 (m, 4H), 2.21 - 2.14 (m, 9H), 1.88 - 1.80 (m, 2H), 1.52 - 1.45 (m, 2H), 1.29 (s, 20H), 0.93 - 0.88 (m, 3H).

[0266] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(tetradecylcarbamoyl)pyridin-1-ium [ka] To a solution of N-tetradecylnicotinamide (3 g, 9.42 mmol, 1 equiv.), (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3.00 g, 9.42 mmol, 1 equiv.) in DCM (50 mL) was added TMSOTf (4.19 g, 18.84 mmol, 3.40 mL, 2 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.611 min, 577.5 [M+H] + , ESI pos) showed a major peak for the desired product. The reaction mixture was diluted with 50 mL of 1 M NaHCO 3 Dilute with 50 mL of DCM and extract with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:0, ethyl acetate:MeOH=10:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(tetradecylcarbamoyl)pyridin-1-ium (2.7 g, 4.51 mmol, 47.93% yield, 96.6% purity) as a colorless gum. LCMS:t R =0.625 min, m / z=577.5(M+H) + . 1 H NMR (400 MHz, MeOD) 9.59 (s, 1H), 9.29 (d, J = 6.2 Hz, 1H), 9.06 (d, J = 8.1 Hz, 1H), 8.39 - 8.31 (m, 1H), 6.59 (d, J = 3.8 Hz, 1H), 5.63 - 5.58 (m, 1H), 5.45 (t, J = 5.6 Hz, 1H), 4.85 - 4.81 (m, 1H), 4.66 - 4.48 (m, 2H), 3.51 - 3.44 (m, 2H), 2.23 - 2.15 (m, 9H), 1.74 - 1.64 (m, 2H), 1.31 (s, 22H), 0.92 (t, J = 6.8 Hz, 3H).

[0267] 1-((2R,3R,4R,5R)-3,4-bis(propionyloxy)-5-((propionyloxy)methyl)tetrahydrofuran-2-yl)-3-carboxypyridin-1-ium [ka] To a solution of nicotinic acid (10 g, 81.23 mmol, 6.80 mL, 1 equiv.) in HMDS (39.33 g, 243.69 mmol, 51.08 mL, 3 equiv.) was added (NH 4 ) 2 SO 4 (536.68 mg, 4.06 mmol, 303.21 uL, 0.05 equiv) was added in one portion. The mixture was stirred at 110° C. for 1 h. TLC (petroleum ether:ethyl acetate=0:1) showed that the material was consumed (R f =0.01), new spots were detected (R f =0.26). The reaction mixture was filtered and concentrated under reduced pressure to give trimethylsilyl nicotinate (2, 14 g, 71.69 mmol, 88.25% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 9.07 (dd, J = 0.6, 2.1 Hz, 1H), 8.79 (dd, J = 1.7, 4.8 Hz, 1H), 8.26 (td, J = 2.0, 7.9 Hz, 1H), 7.54 (ddd, J = 0.6, 4.8, 7.9 Hz, 1H), 0.36 (s, 6H), 0.03 (s, 3H).To this solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (23.31 g, 73.22 mmol, 1.1 equiv.) and trimethylsilyl nicotinate (13 g, 66.57 mmol, 1 equiv.) in DCM (300 mL) was added TMSOTf (17.75 g, 79.88 mmol, 14.43 mL, 1.2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS (0-60 AB / 1.5 min, RT = 0.289 min, 382.1 [M+H] +, ESI pos) showed that a major peak with the desired product was detected. The product was dissolved in about 100 mL of DCM and the solution was poured into ice water. The mixture was washed with saturated NaHCO 3 The mixture was neutralized to pH 6-7 with aqueous solution, and the colorless aqueous phase was separated from the yellowish organic phase. The aqueous phase was evaporated under reduced pressure at <40 °C to give a white solid product. The crude product was purified by reverse phase HPLC (MeCN / H 2 0) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (13.5 g, 35.40 mmol, 53.18% yield) as a white solid. 1 H NMR (400 MHz, D 2 O) δ 9.38 (s, 1H), 9.07 (d, J = 6.2 Hz, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.24 - 8.09 (m, 1H), 6.55 (d, J = 4.0 Hz, 1H), 5.61 - 5.43 (m, 2H), 4.93 - 4.82 (m, 1H), 4.52 (d, J = 2.2 Hz, 2H), 2.20 - 2.04 (m, 9H).To this solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (1 g, 2.62 mmol, 1 equiv.) in MeOH (10 mL) was added NH 3 / MeOH (7M, 10.00 mL, 26.69 equiv.) was added. The mixture was stirred at 0° C. for 2 h. LCMS (0-60AB / 1.5 min, RT=0.127 min, 256.1 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure at 0° C. to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydrofuran-2-yl)pyridin-1-ium-3-carboxylate (650 mg, 2.55 mmol, 97.12% yield) as a white solid. 1 H NMR (400 MHz, D 2O) δ 9.38 (s, 1H), 9.07 (d, J = 6.2 Hz, 1H), 8.87 (d, J = 8.1 Hz, 1H), 8.18 - 8.04 (m, 1H), 6.15 (d, J = 4.6 Hz, 1H), 4.46 - 4.37 (m, 2H), 4.32 - 4.25 (m, 1H), 4.03 - 3.92 (m, 1H), 3.89 - 3.79 (m, 1H). 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (200 mg, 783.63 μmol, 1 equiv.) in a solution of Py (1.24 g, 15.67 mmol, 1.26 mL, 20 equiv.) was added to H 2 HO (0.2 mL) was added and propionic anhydride (1.53 g, 11.75 mmol, 1.51 mL, 15 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. LCMS (0-60AB / 1.5 min, RT = 0.874 min, 424.2 [M+H] + , ESI pos) showed that the main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75×30mm×3um; mobile phase: [water (FA)-ACN]; B%: 12%~42%, 7min) to obtain 1-((2R,3R,4R,5R)-3,4-bis(propionyloxy)-5-((propionyloxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (92.84mg, 215.42umol, 27.49% yield, 98.48% purity) as a yellow solid. LCMS:t R =0.726 min, m / z=424.2(M+H )+ 1 H NMR (400 MHz, D 2O) δ 9.38 (s, 1H), 9.09 (br d, J = 6.1 Hz, 1H), 8.97 (br d, J = 7.9 Hz, 1H), 8.20 (t, J = 7.0 Hz, 1H), 6.58 (d, J = 4.3 Hz, 1H), 5.61 - 5.50 (m, 2H), 4.92 (br d, J = 1.5 Hz, 1H), 4.56 (br s, 2H), 2.53 - 2.39 (m, 6H), 1.13 - 1.01 (m, 9H).

[0268] 1-((2R,3R,4R,5R)-3,4-bis(butyryloxy)-5-((butyryloxy)methyl)tetrahydrofuran-2-yl)-3-carboxypyridin-1-ium [ka] A solution of 3-carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (1, 240 mg, 940.35 μmol, 1 equiv.) in Py (30 mL) and H 2 To the O solution (6 mL) was added butyric anhydride (2.23 g, 14.11 mmol, 2.31 mL, 15 equiv) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS (5-95AB / 1.5 min, RT = 0.467 min, 466.4 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 20% to 50% B over 10 min) to give 1-((2R,3R,4R,5R)-3,4-bis(butyryloxy)-5-((butyryloxy)methyl)tetrahydrofuran-2-yl)-3-carboxypyridin-1-ium (14.3 mg, 28.72 μmol, 3.05% yield, 93.7% purity) as a yellow solid. LCMS: RT=0.468 min, m / z=466.0 (M+H) + 1H NMR (400 MHz, MeOD) δ 9.52 (s, 1H), 9.13 (d, J = 6.4 Hz, 1H), 9.05 (d, J = 7.8 Hz, 1H), 8.21 (dd, J = 6.5, 7.6 Hz, 1H), 6.53 (d, J = 4.4 Hz, 1H), 5.57 (t, J = 4.9 Hz, 1H), 5.46 (t, J = 5.3 Hz, 1H), 4.64 - 4.56 (m, 2H), 4.52 - 4.44 (m, 1H), 2.48 - 2.38 (m, 6H), 1.70 - 1.62 (m, 6H), 1.00 - 0.93 (m, 9H).

[0269] 3-((benzyloxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of benzyl nicotinate (1, 1 g, 4.69 mmol, 1 equiv.) in DCM (20 mL) was added TMSOTf (1.25 g, 5.63 mmol, 1.02 mL, 1.2 equiv.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.64 g, 5.16 mmol, 1.1 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1.5 min, RT=0.402 min, 472.2 [M+H] +, ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (2, 3.5 g, 4.67 mmol, 99.50% yield, 62.993% purity) as a white solid. To a solution of 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (2.5 g, 5.29 mmol, 1 equiv.) was added HCl (3 M, 25.00 mL). The mixture was stirred at 25 °C for 12 h. LCMS (5~95AB / 1min, RT=0.352min, 346.2[M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 2% to 32% B, 9 min) to give 3-((benzyloxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (N-53, 150 mg, 433.08 μmol, 8.18% yield, HCl salt) as a white solid. LCMS: Rt=0.369 min, m / z=346.2 (M+H) + . 1 H NMR (400 MHz, CD 3OD) δ 9.85 (s, 1H), 9.46 (d, J = 6.4 Hz, 1H), 9.14 (d, J = 8.0 Hz, 1H), 8.28 (dd, J = 6.3, 7.8 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.43 - 7.36 (m, 3H), 6.19 (d, J = 5.0 Hz, 1H), 5.51 (s, 2H), 4.46 - 4.37 (m, 2H), 4.29 (dd, J = 3.0, 4.8 Hz, 1H), 4.00 (dd, J = 2.6, 12.3 Hz, 1H), 3.85 (dd, J = 2.1, 12.3 Hz, 1H).

[0270] 3-(Benzylcarbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of 3-(benzylcarbamoyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (100 mg, 212.10 μmol, 1 equiv.) in MeOH (3 mL) was added NH 3 / MeOH (7M, 3 mL, 99.01 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 2 h. LCMS (5-95AB / 1 min, RT=0.349 min, 344.9 [M+H] +, ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (HCl)-ACN]; gradient: 0% to 30% B, 8 min) to give 3-(benzylcarbamoyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (15.8 mg, 44.08 μmol, 20.79% yield, 96.364% purity) as a yellow solid. LCMS: RT=0.349 min, m / z=344.9 (M+H) + . 1 H NMR (400 MHz, MeOD) δ 9.69 (s, 1H), 9.42 - 9.40 (m, 1H), 9.02 - 9.00 (m, 1H), 8.29 - 8.27 (m, 1H), 7.42 - 7.29 (m, 5H), 6.17 - 6.16 (m, 1H), 4.66 - 4.65 (m, 2H), 4.44 - 4.41 (m, 2H), 4.31 - 4.30 (m, 1H), 4.00 - 3.87 (m, 1H), 3.31 - 3.30 (m, 1H).

[0271] 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of benzyl nicotinate (1 g, 4.69 mmol, 1 equiv.) in DCM (20 mL) was added TMSOTf (5 equiv.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.64 g, 5.16 mmol, 1.1 equiv.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (0.1% FA conditions) to give 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (3.5 g, 4.67 mmol, 60% yield, 99% purity) as a white solid. LCMS: Rt=5.14 min, m / z=472 M. + .

[0272] 3-(Benzylcarbamoyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of nicotinoyl chloride (2 g, 11.23 mmol, 1 equiv., HCl) in DCM (50 mL) was added BnNH 2 (1.20 g, 11.23 mmol, 1.22 mL, 1 equiv.) and TEA (2.27 g, 22.47 mmol, 3.13 mL, 2 equiv.) were added at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1.5 min, RT=0.376 min, 213.2 [M+H]+, ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give N-benzylnicotinamide (2 g, 9.32 mmol, 82.95% yield, 98.9% purity) as a white solid. LCMS: Rt = 0.362 min, m / z = 213.2 (M+H) +To this solution of N-benzylnicotinamide (2, 500 mg, 2.36 mmol, 1 equiv.) in DCM (15 mL) was added TMSOTf (1.05 g, 4.71 mmol, 851.36 μL, 2 equiv.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (749.78 mg, 2.36 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS (5-95AB / 1.5 min, RT=0.410 min, 471.2 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 3-(benzylcarbamoyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (350 mg, 727.50 μmol, 30.88% yield, 98% purity) as a white solid. LCMS: RT = 0.416 min, m / z = 471.1 (M+H). + . 1 H NMR (400 MHz, CD 3 OD) δ 9.60 (s, 1H), 9.28 (d, J = 6.1 Hz, 1H), 9.07 (d, J = 8.1 Hz, 1H), 8.37 - 8.28 (m, 1H), 7.41 - 7.27 (m, 5H), 6.57 (d, J = 3.6 Hz, 1H), 5.61 - 5.55 (m, 1H), 5.42 (t, J = 5.7 Hz, 1H), 4.83 - 4.79 (m, 1H), 4.65 (d, J = 3.1 Hz, 2H), 4.62 - 4.46 (m, 2H), 2.19 - 2.09 (m, 9H)

[0273] 1-((2R,3R,4R,5R)-3,4-bis(nicotinoyloxy)-5-((nicotinoyloxy)methyl)tetrahydrofuran-2-yl)-3-carboxypyridin-1-ium [ka] A mixture of (3R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol (1, 10.00 g, 66.61 mmol, 1 equiv.) in MeOH (80 mL) was added to H 2 SO 4 (1.96 g, 19.98 mmol, 1.07 mL, 0.3 equiv) was added and the mixture was then stirred at 25° C. for 16 h. TLC (dichloromethane:methanol=3:1) showed that the material was consumed (R f =0.5), new spots were detected (R f =0.7). The mixture was cooled to 0°C and then cooled to 0°C. 2 CO 3 After neutralization to pH 9 with aqueous solution, the mixture was then filtered and concentrated under reduced pressure to give (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3,4-diol (8 g, 48.73 mmol, 73.16% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 4.62 (s, 1H), 3.70 (d, J = 4.8 Hz, 1H), 3.53 - 3.48 (m, 1H), 3.45 - 3.39 (m, 1H), 3.35 - 3.27 (m, 2H), 3.22 (s, 3H).To this solution of (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3,4-diol (2, 1 g, 6.09 mmol, 1 equiv) in DCM (30 mL) was added Py (4.82 g, 60.92 mmol, 4.92 mL, 10 equiv) and nicotinoyl chloride (5.42 g, 30.46 mmol, 5 equiv, HCl) at 0 °C. The mixture was stirred at 25° C. for 16 h. LCMS (5-95AB / 1.5 min, RT=0.588 min, 480.2 [M+H] + , ESI pos) showed that a major peak with the desired ms was detected. The residue was purified by H 2 The mixture was diluted with 200 mL of O (100 mL) and extracted with 100 mL of DCM (100 mL x 3). The combined organic layers were washed with Na 2 SO 4The crude product was purified by column chromatography (SiO 2 , DCM:MeOH=1:0-10:1) to give (3R,4R,5R)-2-methoxy-5-((nicotinoyloxy)methyl)tetrahydrofuran-3,4-diyldinicotinate (2.5 g, 5.21 mmol, 85.60% yield) as a colorless oil. LCMS: Rt=0.588 min, m / z=480.2 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 9.18 - 8.90 (m, 3H), 8.86 - 8.74 (m, 3H), 8.39 - 8.13 (m, 3H), 7.62 - 7.47 (m, 3H), 5.84 - 5.74 (m, 1H), 5.61 - 5.50 (m, 1H), 5.42 - 5.25 (m, 1H), 4.89 - 4.62 (m, 2H), 4.59 - 4.48 (m, 1H), 3.32 (s, 3H).To this solution of (3R,4R,5R)-2-methoxy-5-((nicotinoyloxy)methyl)tetrahydrofuran-3,4-diyldinicotinate (200 mg, 417.16 umol, 1 equiv.) in AcOH (2 mL), 2 O (127.76mg, 1.25mmol, 117.21uL, 3eq), H 2 SO 4 (40.91 mg, 417.16 umol, 22.24 uL, 1 eq) was added. The mixture was stirred at 25°C for 1 h. LCMS (5-95AB / 1.5 min, RT=0.718 min, 508.2 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The product was dissolved in about 50 mL of DCM and the solution was poured onto ice. The mixture was washed with saturated NaHCO 3 Neutralize to pH 6-7 with aqueous solution, and add Na 2 SO 4The mixture was dried over 100 ml, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give (2S,3R,4R,5R)-2-acetoxy-5-((nicotinoyloxy)methyl)tetrahydrofuran-3,4-diyldinicotinate (100 mg, 197.06 umol, 47.24% yield) as a yellow oil. LCMS: Rt=0.718 min, m / z=508.2 (M+H + ). 1 H NMR (400 MHz, CDCl 3 ) δ 9.34 - 9.05 (m, 3H), 8.88 - 8.75 (m, 3H), 8.40 - 8.13 (m, 3H), 7.51 - 7.33 (m, 3H), 6.78 - 6.40 (m, 1H), 5.95 - 5.65 (m, 2H), 4.88 - 4.71 (m, 2H), 4.69 - 4.57 (m, 1H), 2.20 - 2.08 (m, 3H).To this nicotinic acid solution (5g, 40.61mmol, 3.40mL, 1eq) was added HMDS (19.66g, 121.84mmol, 25.54mL, 3eq) and (NH 4 ) 2 SO 4 (268.34 mg, 2.03 mmol, 151.60 uL, 0.05 equiv) was added. The mixture was stirred at 110 °C for 1 h. TLC (petroleum ether:ethyl acetate = 0:1) showed that reactant 1 was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue that afforded trimethylsilyl nicotinate (4 g, 20.48 mmol, 50.43% yield) as a colorless oil. To a solution of (2S,3R,4R,5R)-2-acetoxy-5-((nicotinoyloxy)methyl)tetrahydrofuran-3,4-diyldinicotinate (500 mg, 985.32 μmol, 1 equiv.), trimethylsilylnicotinate (230.91 mg, 1.18 mmol, 1.2 equiv.) in DCM (10 mL) was added TMSOTf (262.79 mg, 1.18 mmol, 213.65 uL, 1.2 equiv.). The mixture was stirred at 25 °C for 1 h. LCMS (5-95AB / 1.5 min, RT = 0.363 min, 571.3, [M+H] +, ESI pos) showed that a main peak with the desired ms was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase HPLC (0.1% FA condition). The residue was then purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 4%-34%, 10min) to obtain 1-((2R,3R,4R,5R)-3,4-bis(nicotinoyloxy)-5-((nicotinoyloxy)methyl)tetrahydrofuran-2-yl)-3-carboxypyridin-1-ium (20mg, 34.99umol, 3.55% yield) as a yellow solid. LCMS:t R =0.363 min, m / z=571.2(M+H) + . 1 H NMR (400 MHz, MeOD) δ 9.62 (s, 1H), 9.29 (d, J = 6.1 Hz, 1H), 9.20 - 9.12 (m, 3H), 9.06 (br d, J = 7.9 Hz, 1H), 8.80 - 8.73 (m, 3H), 8.53 - 8.39 (m, 3H), 8.25 - 8.16 (m, 1H), 7.63 - 7.52 (m, 3H), 6.94 (d, J = 3.2 Hz, 1H), 6.12 - 6.04 (m, 2H), 5.33 - 5.26 (m, 1H), 5.05 - 4.97 (m, 2H)

[0274] 3,3'-((ethane-1,2-diylbis(azanediyl))bis(carbonyl))bis(1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium) [ka] To a solution of N,N'-(ethane-1,2-diyl)dinicotinamide (1 eq.) in DMF (0.1 M) was added TMSOTf (5 eq.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.64 g, 5.16 mmol, 4 eq.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (0.1% TFA conditions) to give 3,3'-((ethane-1,2-diylbis(azanediyl))bis(carbonyl))bis(1-((2R,3R,4R,5R)-3,4-diacetoxy-5(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium) (52% yield, 98% purity) as a white gummy solid. LCMS: Rt = 10.35 min, m / z = 788 (M + ).

[0275] 3,3'-((ethane-1,2-diylbis(oxy))bis(carbonyl))bis(1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium) [ka] To a solution of ethane-1,2-diyldinicotinate (1 equiv.) in DMF (0.1 M) was added TMSOTf (5 equiv.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.64 g, 5.16 mmol, 4 equiv.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure and purified by reverse phase HPLC (0.1% TFA conditions) to give 3,3'-((ethane-1,2-diylbis(oxy))bis(carbonyl))bis(1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium) (32% yield, 96% purity) as a white solid. LCMS: Rt=4.6 min, m / z=791 (M+H) + .

[0276] 3-(tert-butoxycarbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of nicotinic acid (1, 5 g, 40.61 mmol, 3.40 mL, 1 equiv.) in DMF (50 mL), 2 CDI (6.59 g, 40.61 mmol, 1 equiv.) was added under reduced pressure. After the addition, the mixture was stirred at 40° C. for 1 h, and then t-BuOH (6.02 g, 81.23 mmol, 7.77 mL, 2 equiv.), DBU (6.18 g, 40.61 mmol, 6.12 mL, 1 equiv.) were added. The resulting mixture was stirred at 40° C. for 16 h. TLC (petroleum ether:ethyl acetate=0:1) showed that a new spot was detected (R f EA (100 mL) was added to the mixture, and the solution was diluted with 10% acetic acid (20 mL), H 2 O (50 mL) and 10% K 2 CO 3 Wash with aqueous solution (50 mL) and add Na 2 SO 4 Drying at rt, filtering and concentrating under reduced pressure gave tert-butyl nicotinate (2, 5 g, 27.90 mmol, 68.69% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 9.11 - 8.97 (m, 1H), 8.85 - 8.73 (m, 1H), 8.29 - 8.16 (m, 1H), 7.62 - 7.47 (m, 1H), 1.55 (s, 9H).To this solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3, 6.39 g, 20.09 mmol, 1.2 equiv.), tert-butyl nicotinate (2, 3 g, 16.74 mmol, 1 equiv.) in DCM (30 mL) was added TMSOTf (1.86 g, 8.37 mmol, 1.51 mL, 0.5 equiv.) at 0° C. The mixture was stirred at 25° C. for 16 h. LCMS (0~60AB / 1.5min, RT=0.879min, 438.2[M+H]+ , ESI pos) showed that a major peak with the desired product was detected. The residue was washed with ice-H 2 Dilute the mixture with 200 mL of saturated NaHCO 3 The mixture was neutralized with aqueous solution (~15 mL) to pH 6-7. The residue was extracted with DCM (50 mL). The combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:0 to 0:1) to give 3-(tert-butoxycarbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (3 g, 6.76 mmol, 40.38% yield) as a white solid. LCMS:t R =0.829min, m / z=438.3(M+H) + 1 H NMR (400 MHz, D2O) δ 9.44 (s, 1H), 9.30 (d, J = 6.2 Hz, 1H), 9.05 (d, J = 8.1 Hz, 1H), 8.42 - 8.33 (m, 1H), 6.70 (d, J = 3.4 Hz, 1H), 5.66 - 5.57 (m, 1H), 5.41 (t, J = 5.9 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.52 - 4.40 (m, 2H), 2.15 (s, 3H), 2.10 (d, J = 7.1 Hz, 6H), 1.61 (s, 9H).

[0277] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(ethoxycarbonyl)pyridin-1-ium [ka] Ethyl nicotinate (1 eq.) and β-D-ribofuranose tetraacetate were dissolved in 0.1 M DMF and treated with 5 eq. TMSOTf. The mixture was stirred at 50° C. for 12 h. LCMS: The reaction mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (0.1% TFA condition) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(ethoxycarbonyl)pyridin-1-ium (82% yield, 97% purity) as a white solid. LCMS: Rt=6.2 min, m / z=411.14 (M+H). + .

[0278] 3-(tert-butoxycarbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] To a solution of 3-(tert-butoxycarbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 g, 2.28 mmol, 1 equiv.) in MeOH (2 mL) was added NH 3 / MeOH (7M, 10.00 mL, 30.69 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 1 h. LCMS (0-60AB / 1.5 min, RT=0.678 min, 312.2 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue at 0° C. The crude residue was purified by HPLC (MeCN / H 2 Purification by reverse phase eluting with O gave 3-(tert-butoxycarbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (5, 200 mg, 601.91 umol, 26.39% yield) as a yellow oil. LCMS: R =0.616 min, m / z=312.2(M+H) + . 1H NMR (400 MHz, D 2 O) δ 9.62 (s, 1H), 9.25 (d, J = 6.4 Hz, 1H), 9.06 (d, J = 8.2 Hz, 1H), 8.28 - 8.19 (m, 1H), 6.24 (d, J = 4.2 Hz, 1H), 4.49 - 4.43 (m, 2H), 4.37 - 4.31 (m, 1H), 4.06 - 4.00 (m, 1H), 3.90 - 3.85 (m, 1H), 1.61 (s, 9H).

[0279] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(methoxycarbonyl)pyridin-1-ium [ka] To a solution of (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.39 g, 4.38 mmol, 1.2 equiv.) and methyl nicotinate (500 mg, 3.65 mmol, 1 equiv.) in DCM (10 mL) was added TMSOTf (810.37 mg, 3.65 mmol, 658.83 μL, 1 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS (5-95AB / 1 min, RT = 0.348 min, 396.2 [M+H] + , ESI pos) showed a major peak at the desired MS. The reaction mixture was cooled to ice H 2 Dilute the mixture with 200 mL of saturated NaHCO 3 The mixture was neutralized with aqueous solution (~15 mL) to pH 6-7. The residue was extracted with DCM (50 mL). The combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether:ethyl acetate = 1:0 to 0:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(methoxycarbonyl)pyridin-1-ium (284.20 mg, 689.03 μmol, 27.31% yield, 96.097% purity, TfOH salt) as a yellow solid. LCMS: RT = 0.358 min, m / z = 396.3 (M+H) + 1 H NMR (400 MHz, CD 3 OD) δ 9.66 (s, 1H), 9.37 (d, J = 6.4 Hz, 1H), 9.24 - 9.16 (m, 1H), 8.38 (dd, J = 6.4, 7.9 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1H), 5.58 (dd, J = 3.7, 5.6 Hz, 1H), 5.44 (t, J = 5.8 Hz, 1H), 4.82 (td, J = 3.0, 5.8 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.08 (s, 3H), 2.18 (d, J = 5.5 Hz, 6H), 2.15 (s, 3H).

[0280] 3-Carboxy-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium [ka] A solution of nicotinic acid (10 g, 81.23 mmol, 6.80 mL, 1 equiv.) was added to HMDS (39.33 g, 243.69 mmol, 51.08 mL, 3 equiv.) and (NH 4 ) 2 SO 4 (536.68 mg, 4.06 mmol, 303.21 uL, 0.05 equiv.) was added. The mixture was stirred at 110° C. for 1 h. TLC (petroleum ether:ethyl acetate=0:1) showed that the material was consumed (R f =0.01), new spots were detected (R f=0.26). The reaction mixture was filtered and concentrated under reduced pressure to give trimethylsilyl nicotinate (2, 14 g, 71.69 mmol, 88.25% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 9.07 (dd, J = 0.6, 2.1 Hz, 1H), 8.79 (dd, J = 1.7, 4.8 Hz, 1H), 8.26 (td, J = 2.0, 7.9 Hz, 1H), 7.54 (ddd, J = 0.6, 4.8, 7.9 Hz, 1H), 0.36 (s, 6H), 0.03 (s, 3H).To this solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (23.31 g, 73.22 mmol, 1.1 equiv.), trimethylsilyl nicotinate (2,13 g, 66.57 mmol, 1 equiv.) in DCM (300 mL) was added TMSOTf (17.75 g, 79.88 mmol, 14.43 mL, 1.2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS (0-60AB / 1.5 min, RT=0.289 min, 382.1 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The mixture was dissolved in about 100 mL of DCM and the solution was poured into ice water. The mixture was washed with saturated NaHCO 3 The mixture was neutralized to pH 6-7 with aqueous solution and the colorless aqueous phase was separated from the yellowish organic phase. The aqueous phase was evaporated under reduced pressure at <40° C. to give a white solid product. The crude product was purified by reverse phase HPLC (MeCN / H 2 0) to give 3-carboxy-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (13.5 g, 35.40 mmol, 53.18% yield) as a white solid. LCMS: Rt=0.697 min, m / z=382.0 (M+H + ). 1 H NMR (400 MHz, D 2O) δ 9.38 (s, 1H), 9.07 (d, J = 6.2 Hz, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.24 - 8.09 (m, 1H), 6.55 (d, J = 4.0 Hz, 1H), 5.61 - 5.43 (m, 2H), 4.93 - 4.82 (m, 1H), 4.52 (d, J = 2.2 Hz, 2H), 2.20 - 2.04 (m, 9H).

[0281] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium [ka] To a solution of nicotinoyl chloride (2 g, 11.23 mmol, 1 equiv, HCl) in DCM (50 mL) was added TEA (2.27 g, 22.47 mmol, 3.13 mL, 2 equiv) and 2-isopropyl-5-methylcyclohexan-1-ol (2, 1.76 g, 11.23 mmol, 1.97 mL, 1 equiv) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS (5-95AB / 1 min, RT = 0.644 min, 261.9 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:0 to 0:1) to give 2-isopropyl-5-methylcyclohexyl nicotinate (3, 1 g, 3.82 mmol, 33.99% yield, 99.8% purity) as a yellow solid. LCMS:t R =0.544 min, m / z=330.1(M+H) +To this solution of 2-isopropyl-5-methylcyclohexylnicotinate (466 mg, 1.78 mmol, 1 equiv.), (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (680.98 mg, 2.14 mmol, 1.2 equiv.) in MeCN (10 mL) was added TMSOTf (792.57 mg, 3.57 mmol, 644.36 μL, 2 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS (5-95 AB / 1 min, RT = 0.536 min, 520.4 [M] + , ESI pos) showed that a major peak with the desired product was detected. The reaction mixture was diluted with 1M NaHCO 3 water (50 mL), extracted with DCM (50 mL), and added Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 0:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium (TfOH salt, 600 mg, 1.12 mmol, 62.86% yield, 97.25% purity) as a yellow solid. LCMS:t R =0.536 min, m / z=520.4(M+H) + 1H NMR (400 MHz, MeOD) 9.66 (br s, 1H), 9.36 (d, J = 6.1 Hz, 1H), 9.23 - 9.16 (m, 1H), 8.43 - 8.33 (m, 1H), 6.62 (d, J = 3.4 Hz, 1H), 5.62 - 5.55 (m, 1H), 5.47 - 5.40 (m, 1H), 5.15 - 5.06 (m, 1H), 4.85 - 4.81 (m, 1H), 4.63 - 4.48 (m, 2H), 2.20 (d, J = 2.4 Hz, 3H), 2.16 (d, J = 8.6 Hz, 6H), 2.09 - 2.06 (m, 1H), 2.03 - 1.92 (m, 2H), 1.84 - 1.76 (m, 2H), 1.71 - 1.56 (m, 2H), 1.30 - 1.19 (m, 2H), 0.99 - 0.94 (m, 6H), 0.84 - 0.79 (m, 3H).

[0282] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium [ka] To a solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium (1, 430 mg, 825.99 μmol, 1 equiv.) was added aqueous HCl (3 M, 18 mL, 65.38 equiv.). The mixture was stirred at 25° C. for 12 h. LCMS (5-95AB / 1 min, RT=0.456 min, 394.2 [M+H] + , ESI pos) showed a major peak at the desired ms. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (H 20 / MeCN) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-ium (105 mg, 257.87 μmol, 31.22% yield, 96.88% purity, HCl salt) as a yellow solid. LCMS: RT=0.477 min, m / z=394.3 (M+H). + 1 H NMR (400 MHz, CD 3 OD) δ 9.93 - 9.78 (m, 1H), 9.44 (t, J = 6.6 Hz, 1H), 9.13 (d, J = 8.1 Hz, 1H), 8.35 - 8.23 ​​(m, 1H), 6.20 (t, J = 4.3 Hz, 1H), 5.17 - 4.96 (m, 1H), 4.47 - 4.37 (m, 2H), 4.33 - 4.26 (m, 1H), 4.00 (dd, J = 2.7, 12.3 Hz, 1H), 3.91 - 3.81 (m, 1H), 2.20 - 2.08 (m, 1H), 2.03 - 1.91 (m, 1H), 1.85 - 1.73 (m, 2H), 1.73 - 1.53 (m, 2H), 1.30 - 1.13 (m, 2H), 1.01 - 0.94 (m, 6H), 0.82 (dd, J = 1.6, 6.9 Hz, 3H).

[0283] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium [ka] To a solution of nicotinic acid (5 g, 40.61 mmol, 3.40 mL, 1 equiv), EDCI (10.12 g, 52.80 mmol, 1.3 equiv) in DCM (50 mL) was added HOBt (7.13 g, 52.80 mmol, 1.3 equiv) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 10 min, then benzenethiol (6.180 g, 56.09 mmol, 5.72 mL, 1.38 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 5 h. LCMS (0-60AB / 1.5 min, RT=1.033 min, 216.1 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The residue was cooled to ice H 2 The mixture was diluted with 200 mL of O (150 mL) and the residue was extracted with DCM (150 mL). The combined organic layers were washed with brine (210 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was quenched with aqueous NaClO. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 5:1) to give S-phenylpyridine-3-carbothioate (7 g, 32.19 mmol, yield 79.26%) as a colorless oil. LCMS:t R =0.861 min, m / z=216.3(M+H) + 1 H NMR (400 MHz, CDCl 3) δ (ppm) = 9.25 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.26 (br d, J = 8.1 Hz, 1H), 7.54 (br s, 5H), 7.45 - 7.41 (m, 1H).To this solution of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (4.69 g, 14.73 mmol, 1.2 equiv.), tert-butyl nicotinate (2, 2.2 g, 12.28 mmol, 1 equiv.) in DCM (30 mL) was added TMSOTf (1.36 g, 6.14 mmol, 1.11 mL, 0.5 equiv.) at 0 °C. The mixture was stirred at 25° C. for 2 h. LCMS (0-60AB / 1.5 min, RT=0.915 min, 474.1 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The residue was cooled to ice H 2 Dilute the mixture with 200 mL of saturated NaHCO 3 The mixture was neutralized to pH 6-7 with aqueous solution of DCM (50 mL). The residue was extracted with DCM (50 mL). The combined organic layer was washed with brine (250 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 0:1) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (6 g, 12.64 mmol, yield 90.74%) as a white solid. LCMS:t R =0.915min, m / z=474.1(M+H) + 1 H NMR (400 MHz, CDCl 3) δ 9.58 - 9.50 (m, 2H), 9.09 (d, J = 8.2 Hz, 1H), 8.50 - 8.40 (m, 1H), 7.51 (s, 5H), 6.69 (d, J = 3.8 Hz, 1H), 5.55 - 5.48 (m, 1H), 5.36 (t, J = 5.6 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.60 - 4.41 (m, 2H), 2.20 - 2.12 (m, 9H).

[0284] 1-(3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((((R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl)oxy)carbonyl)pyridin-1-ium [ka] To a solution of ethane-(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl nicotinate (1 eq.) in DMF (0.1 M) was added TMSOTf (5 eq.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1.64 g, 5.16 mmol, 3 eq.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure and purified by reverse phase HPLC (0.1% TFA condition) to give 1-(3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((((R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl)oxy)carbonyl)pyridin-1-ium (22% yield, 96% purity) as a white solid. LCMS: Rt=6.9 min, m / z=794 (M). + .

[0285] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium [ka] A solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (1 g, 2.11 mmol, 1 equiv.) was stirred in aqueous HCl (3 M, 10 mL, 14.24 equiv.) at 0° C. The mixture was stirred at 20° C. for 16 h. LCMS (0-60AB / 1.5 min, RT=0.741 min, 348.0 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue at 0° C. The crude product was purified by reverse phase HPLC (MeCN / H 2 0, neutral) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((phenylthio)carbonyl)pyridin-1-ium (300 mg, 809.43 umol, 38.41% yield) as a white solid. LCMS: R =0.727min, m / z=348.0(M+H) + 1 H NMR (400 MHz, D 2 O) δ 9.75 (s, 1H), 9.29 (d, J = 6.2 Hz, 1H), 9.11 (br d, J = 8.2 Hz, 1H), 8.35 - 8.23 ​​(m, 1H), 7.63 - 7.50 (m, 5H), 6.25 (d, J = 3.9 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.36 - 4.29 (m, 1H), 4.08 - 3.99 (m, 1H), 3.90 - 3.82 (m, 1H).

[0286] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium [ka] To a solution of (6-(nicotinamido)hexyl)triphenylphosphonium (1 eq.) in DMF (0.1 M) was added TMSOTf (5 eq.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3 eq.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (0.1% TFA condition) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (28% yield, 97% purity) as a white solid. LCMS: Rt=10.81 min, m / z=726 (M). + .

[0287] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium [ka] A solution of 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (1 eq.) was added to aqueous HCl (3M, 10 mL, 14.24 eq.) at 0° C. The mixture was stirred at 20° C. for 16 h. LCMS showed that the main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue at 0° C. The crude product was purified by reverse phase HPLC (MeCN / H 20, neutral) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (38% yield) as a white solid. LCMS: R =4.7 min, m / z=601(M+H) + .

[0288] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(triphenylphosphonio)propyl)carbamoyl)pyridin-1-ium [ka] To a solution of (3-(nicotinamido)propyl)triphenylphosphonium (1 eq.) in DMF (0.1 M) was added TMSOTf (5 eq.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3 eq.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (0.1% TFA condition) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((3-(triphenylphosphonio)propyl)carbamoyl)pyridin-1-ium (18% yield, 96% purity) as a white solid. LCMS: Rt=5.3 min, m / z=684 (M). + .

[0289] 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(6-(triphenylphosphonio)hexanamido)ethyl)carbamoyl)pyridin-1-ium [ka] To a solution of (6-((2-(nicotinamido)ethyl)amino)-6-oxohexyl)triphenylphosphonium (1 eq.) in DMF (0.1 M) was added TMSOTf (5 eq.) and (2S,3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (3 eq.) at 0° C. The mixture was stirred at 50° C. for 12 h. LCMS (. The reaction mixture was filtered, concentrated under reduced pressure and purified by reverse phase HPLC (0.1% TFA condition) to give 1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-3-((2-(6-(triphenylphosphonio)hexanamido)ethyl)carbamoyl)pyridin-1-ium (55% yield, 97% purity) as a white solid. LCMS: Rt=6.503 min, m / z=783 (M). + .

[0290] ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-yl-1-tetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M solution of deionized water:DMF (50:50) and diisopropylethylamine (5 equiv.) was added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added 2-isopropyl-5-methylcyclohexan-1-ol (1 equiv.) dissolved in a 1M solution of DMF at 25° C. and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 20, 0.01% TFA) to give (2R,3S,4R,5R)-3,4-dihydroxy-5-(3-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)pyridin-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: RT=0.338 min, m / z=474.1 (M+H). + . 1 H NMR (400 MHz, CD 3 OD) δ 9.63 - 9.55 (m, 1H), 9.48 (d, J = 5.4 Hz, 1H), 9.16 - 9.08 (m, 1H), 8.37 - 8.29 (m, 1H), 6.19 (t, J = 5.0 Hz, 1H), 5.15 - 5.01 (m, 1H), 4.55 - 4.45 (m, 2H), 4.39 - 4.33 (m, 1H), 4.29 - 4.10 (m, 2H), 2.18 - 2.10 (m, 1H), 2.01 - 1.92 (m, 1H), 1.83 - 1.76 (m, 2H), 1.71 - 1.56 (m, 2H), 1.29 - 1.16 (m, 2H), 1.02 - 0.99 (m, 1H), 0.99 - 0.94 (m, 6H), 0.84 - 0.81 (m, 3H).

[0291] ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((tetradecyloxy)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M, 50:50 solution of deionized water:DMF, followed by the addition of diisopropylethylamine (5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). Tetradecan-1-ol (1 equiv.) dissolved in a 1M solution of DMF at 25° C. was added to this solution and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 2 0, 0.01% TFA) to give ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((tetradecyloxy)carbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: R =0.641 min, m / z=532.4(M+H) + . 1 H NMR (400 MHz, MeOD) 9.58 - 9.50 (m, 2H), 9.13 - 9.08 (m, 1H), 8.37 - 8.29 (m, 1H), 6.18 (d, J = 5.6 Hz, 1H), 4.54 - 4.46 (m, 4H), 4.38 - 4.35 (m, 1H), 4.29 - 4.10 (m, 2H), 1.88 - 1.81 (m, 2H), 1.50 - 1.45 (m, 2H), 1.29 (s, 20H), 0.92 - 0.88 (m, 3H).

[0292] ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-(tetradecylcarbamoyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M 50:50 solution of deionized water:DMF, followed by the addition of diisopropylethylamine (5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added tetradecan-1-amine (1 equiv.) dissolved in a 1M solution of DMF at 25° C. and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 2 0, 0.01% TFA) to give ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-(tetradecylcarbamoyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: R =0.566 min, m / z=531.5(M+H) + 1 H NMR (400 MHz, MeOD) 9.65 (s, 1H), 9.28 (d, J = 6.3 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.34 - 8.20 (m, 1H), 6.11 (d, J = 6.1 Hz, 1H), 4.57 - 4.43 (m, 2H), 4.37 - 4.05 (m, 3H), 3.44 (t, J = 7.3 Hz, 2H), 1.73 - 1.64 (m, 2H), 1.38 (br s, 2H), 1.29 (s, 20H), 0.90 (t, J = 6.8 Hz, 3H).

[0293] ((2R,3S,4R,5R)-5-(3-(tert-butoxycarbonyl)pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M solution of deionized water:DMF (50:50) and diisopropylethylamine (5 equiv.) was added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added 2-methylpropan-2-ol (1 equiv.) dissolved in a 1M solution of DMF at 25° C. and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 2 0, 0.01% TFA) to give ((2R,3S,4R,5R)-5-(3-(tert-butoxycarbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: R =0.660 min, m / z=392.2(M+H) + . 1 H NMR (400 MHz, D 2 O) δ 9.41 (s, 1H), 9.33 (d, J = 6.5 Hz, 1H), 9.05 (d, J = 8.1 Hz, 1H), 8.31 - 8.24 (m, 1H), 6.19 (d, J = 5.3 Hz, 1H), 4.63 - 4.59 (m, 1H), 4.52 (t, J = 5.1 Hz, 1H), 4.44 - 4.39 (m, 1H), 4.31 - 4.24 (m, 1H), 4.17 - 4.10 (m, 1H), 1.61 (s, 9H).

[0294] ((2R,3S,4R,5R)-5-(3-((6-bromohexyl)carbamoyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M 50:50 solution of deionized water:DMF, followed by the addition of diisopropylethylamine (5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added 6-bromohexan-1-amine (1 equiv.) dissolved in a 1M solution of DMF at 25° C. and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 2 0, 0.01% TFA) to give ((2R,3S,4R,5R)-5-(3-((6-bromohexyl)carbamoyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: R =0.56 min, m / z=497,2(M+H) + .

[0295] ((2R,3S,4R,5R)-5-(3-((benzyloxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (NAMN) (1 mmol) was dissolved in a 5M 50:50 solution of deionized water:DMF, followed by the addition of diisopropylethylamine (5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added phenylmethanol (1 equiv.) dissolved in a 1M solution of DMF at 25° C. and stirred vigorously. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 20, 0.01% TFA) to give ((2R,3S,4R,5R)-5-(3-((benzyloxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate as a white solid. LCMS: Rt = 0.181 min, m / z = 426.1 (M+H + ). 1 H NMR (400 MHz, D 2 O) δ 9.40 (s, 1H), 9.26 (d, J = 6.2 Hz, 1H), 8.97 (br d, J = 8.1 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.42 - 7.31 (m, 5H), 6.08 (d, J = 5.3 Hz, 1H), 5.37 (s, 2H), 4.51 (br d, J = 2.1 Hz, 1H), 4.44 (t, J = 5.1 Hz, 1H), 4.35 - 4.30 (m, 1H), 4.20 - 3.99 (m, 2H).

[0296] ((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)hydrogen methyl phosphate [ka] 3-Carboxy-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium (1 mmol) was dissolved in a 5M, 50:50 solution of deionized water:DMF, and diisopropylethylamine (5 equiv.) was added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 equiv.). To this solution was added (6-aminohexyl)triphenylphosphonium bromide hydrobromide (1 equiv.) dissolved in a 1M solution in DMF at 25° C. The progress of the reaction was monitored by LCMS. After completion of the reaction, the crude product was purified by reverse phase HPLC (MeCN / H 20) to give 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-(tetradecylcarbamoyl)pyridin-1-ium as a white solid. LCMS: (1-99H 2 O / ACN mL / min, RT=5.757 min, 679.2[M+H] + , ESI pos) showed that a major peak with the desired product was detected.

[0297] Example 3: Exemplary Biological Activities of Compounds of the Present Disclosure General NAD assay procedure NHDF cells (Lonza Cat#CC-2511) were plated in 12-well tissue culture plates at a density of 200,000 cells per well in 0.75 mL growth medium (Lonza FGM-2 cat#CC-3132; cat#CC-4126 containing growth factors). The plates were then incubated at 4°C for 24 hours at 37°C for 12 h at 5% CO. 2 The cells were incubated overnight at 37°C in a humidified atmosphere. The following day, dilutions of each test sample were prepared in growth medium at 4x the desired final concentration. 250 μL of each dilution was added to each well to obtain the desired concentration in each well. The cells were incubated for the desired length of time.

[0298] After incubation, the cell monolayer in each well was washed with cold PBS. 400 μL of extraction buffer (provided in the NAD assay kit) was added and triturated 5-6 times. The cell lysates were collected in Eppendorf tubes and then flash frozen in a dry ice-methanol bath for 20 min and then thawed at room temperature. The freeze-thaw cycle was repeated once more. The cell lysates were centrifuged and the collected supernatants were stored at -80°C until use.

[0299] An aliquot of the extract was used to determine total protein concentration using the Pierce BCA kit (Thermo Fisher Cat#23225). The total volume of each sample was adjusted to ensure the same total protein concentration in all samples.

[0300] 50 μL of standards and each sample were added to the appropriate wells of a 96-well plate and NAD assayed according to the kit manufacturer's instructions (NAD / NADH quantification kit; Sigma-Aldrich; Cat. No. MAK037). Absorbance at 450 nm was measured using an Envision plate reader (Perkin Elmer) with default settings. Data was normalized to blank. A standard curve was plotted and used to determine the total NAD level in each test sample.

[0301] Nicotinic acid mononucleotide (NaMN) [ka] Nicotinic acid mononucleotide (NaMN) was analyzed using the general NAD assay procedure described above. NaNM ("Sample 1") was compared to nicotinamide mononucleotide (NMN) at various concentrations and times. The results are shown in Figure 1, as well as in the table below. TIFF2025505975000161.tif57165

[0302] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (7) [ka] 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)-3-((6-(triphenylphosphonio)hexyl)carbamoyl)pyridin-1-ium (7) was analyzed using the general NAD assay procedure described above. 7 ("Sample 2") was compared to nicotinamide mononucleotide (NMN) at various concentrations and times. The results are shown in FIG. 2, as well as in Table 3 below. At the 6 hour time point, compound 7 causes a greater increase in NAD levels than NMN at all concentrations. [Table 3]

[0303] 6-(Nicotinamido)hexyl)triphenylphosphonium(10) [ka] 6-(Nicotinamido)hexyl)triphenylphosphonium (10) was analyzed using the general NAD assay procedure described above. 10 ("Sample 5") was compared to nicotinamide mononucleotide (NMN) at various concentrations and times. The results are shown in FIG. 3, as well as in Table 4 below. At the 6 hour time point, compound 10 caused a greater increase in NAD levels than NMN at all concentrations. [Table 4]

[0304] Example 4: Further exemplary biological activities of compounds of the present disclosure The biological activity of certain compounds disclosed herein was determined using the following methods: 1. Plate HaCaT cells in 12-well tissue culture plates at a density of 200,000 cells per well in 0.75 mL of DMEM growth medium. Incubate at 5% CO. 2 Incubate overnight at 37 °C in a 37 °C incubator. 2. The next day, prepare dilutions of each compound in growth medium at the desired final concentration. 3. Incubate the cells as above for 4 hours. 4. After incubation, wash the cell monolayer in each well with 200 uL of PBS and add 200 uL of 0.25% trypsin. Allow cells to lift for 15 minutes. 5. Once the cells have lifted, collect the cells into a sterile 1.5 mL Eppendorf tube containing 400 μL of DMEM with 2% HIFBS. 6. Centrifuge the tubes at 500 x g for 5 minutes. 7. Aspirate the supernatant and wash the cells with 200uL of cold PBS. 8. Centrifuge the tube at 500xg for 5 minutes. 9. Aspirate the supernatant and add 400 μL of cold extraction buffer (provided in the NAD assay kit) and vortex each tube for 10 seconds. 10. Centrifuge the sample at 13,000 x g for 10 minutes to remove insoluble material. 11. Use a small aliquot of the extract to determine the total protein concentration by BCA protein assay kit. 12. Deproteinize the samples by filtering them through a 10 kDa cutoff spin filter. Centrifuge at 13,000 x g for 10 min. 13. After filtering the cell lysates, load 25 μL of sample into a 96-well plate for NAD assay. 14. Add 25uL of Extraction Buffer with sample to each well, diluting 1:2. Add 50uL of standard to appropriate wells. 15. Set up a master reaction mix of cycling buffer and NAD cycling enzyme mix. Add 100uL of mix to each well and incubate for 5 minutes. 16. Add 10uL of developer to each well. 17. Incubate the plate at room temperature for 1 hour. 18. Stop the reaction by adding 10 uL of Stop Solution to each well and mix well. 19. Using a plate reader, measure absorbance at 450 nm. 20. Plot the standard curve and normalize the data to determine total NAD levels.

[0305] TIFF2025505975000166.tif234165TIFF2025505975000167.tif232165TIFF2025505975000168.tif23216 5TIFF2025505975000169.tif239165TIFF2025505975000170.tif237165TIFF2025505975000171.tif24016 5TIFF2025505975000172.tif240165TIFF2025505975000173.tif231165TIFF2025505975000174.tif23416 5TIFF2025505975000175.tif204165TIFF2025505975000176.tif233165TIFF2025505975000177.tif70165

[0306] Example 5: Exemplary preparation of nicotinic acid mononucleosides NAMN was prepared under flow chemistry conditions using the route illustrated in Scheme 5. First, the ribose material was alkylated using ethyl nicotinate in the presence of trimethylsilyl triflate (TMSOTf) in acetonitrile. The resulting triacetate product was then deacetylated using sodium ethoxide in ethanol, followed by reprotonation using sulfuric acid, and then purified via liquid-liquid extraction. Water was then removed from the resulting triol by lyophilization, and the resulting purified triol was phosphorylated using phosphoryl chloride to obtain the ethyl ester form of NAMN. The ester group was then saponified using aqueous sodium hydroxide to obtain the final product. [ka]

[0307] An exemplary flow setup is shown in FIG.

[0308] Briefly, β-D-ribofuranose 3 (105.3 g, 330.8 mmol) was dissolved in 5 volumes of acetonitrile (413.8 g, 526.4 mL). Ethyl nicotinate (75 g, 496.2 mmol) was then added to the solution. The KF of the acetonitrile was kept low (<300 ppm). The density of the solution was measured to be 0.883 g / mL.

[0309] The starting material 3 solution was pumped at a flow rate of 4.4 g / min using a diaphragm pump and mass flow meter. TMSOTf was pumped from a stainless steel syringe at a flow rate of 0.667 mL / min (or 0.817 g / min) using a syringe pump. The two solutions were mixed using a static mixer and the heat of reaction was measured using a thermocouple. The crude solution then entered the PFR (30 mL) into the CASCADE reactor at 40° C. for a residence time of 5 min. After exiting the CASCADE reactor, the resulting reaction product was collected in a collection flask and stored under nitrogen until further use.

[0310] The oil containing triacetate 2 (67.9 w / w%) was used in its concentrated form from the alkylation step.

[0311] A solution of sodium ethoxide in ethanol (21 w / w%, Sigma Aldrich) (332.1 g, 382.6 mL) was added to 81.1 g of ethanol to produce a 16.9 w / w% NaOEt solution. A solution of sulfuric acid (98 w / w%) (202.4 g, 2.02 mol, 110 mL) was slowly dissolved in water (540 g) to make a 3M H2O solution with stoichiometry. 2 SO 4 The crude solution was concentrated by rotary evaporator at 20-25°C. 2 Quantitative analysis using dimethyl sulfone as an internal standard 1 H-NMR was taken to obtain the potency. The total mass of the oil was 222.4g (67.9w / w% 2) with a yield of 99.9%. This step was carried out in batches.

[0312] A portion of the oil (151.3 g, 67.9 w / w% 2) was dissolved in ethanol (400.4 g, 507.5 mL, 5 vol) and added to a cooled (-5°C) solution of NaOEt in EtOH (16.9 w / w%) (410.9 g, 480.6 mL, 5.55 eq) to give a homogeneous dark brown solution. Deprotection was complete within 7 min. Dilute sulfuric acid (261.1 g, 142.7 mL, 2.3 eq wrt 2) was added slowly, maintaining the temperature below 0°C, until a pH of 7 was obtained. If the pH is below 7, sodium bicarbonate can be added. The quench is carried out for a minimum of time to prevent nicotinic acid from forming.

[0313] The heterogeneous solution was then filtered. Ethanol (4 volumes to 4) was used to wash the solid. The filtrate was then concentrated to a crude weight of 139.7 g (48.3 w / w% 4) (1.75 times the theoretical mass of triol 4) by rotary evaporation at 20-30 °C. 2 Quantitative analysis was performed to obtain efficacy by using dimethylsulfone as an internal standard in O. 1 H-NMR showed a yield of 85% of that before freeze-drying.

[0314] The oil was dissolved in water (279.4 mL) and washed with toluene (x3, 116 mL). The resulting aqueous solution containing triol 4 was lyophilized in portions over 2-4 days.

[0315] After freeze-drying, D 2 Quantitative analysis was performed to obtain potency using dimethyl sulfone as an internal standard in O. 1 H-NMR was taken. The potency of each lyophilized lot of triol 4 can be seen in the table below. The yield after lyophilization was 72.3%.

[0316] Lyophilized triol 4 solid (5.11 g, 7.2 mmol, 61.0 w / w% 4 Lot #JS17-47-6-B-lyo) was dissolved in trimethyl phosphate (18.7 g, 15.6 mL, 5 vol) to give a homogenous brown solution. The triol 4 solution (23.2 g, 13.5 w / w%) was assayed against an HPLC calibration curve to obtain potency. 2,6-lutidine (0.78 g, 7.23 mmol, 1 equiv) was added to the solution to give a total concentration of 13.0 w / w%. The density of the solution was measured to be 1.27 g / mL. The solution was filled into a plastic syringe. POCl 3 was used neat from the bottle and filled into an airtight glass syringe.

[0317] The triol 4 solution was pumped using a syringe pump at a flow rate of 0.079 mL / min. 3 was pumped from a glass syringe using a syringe pump at a flow rate of 0.023 g / min. A check valve was included to ensure there was no backflow. Once both streams entered a dry ice / IPA bath controlled at 0 °C, the triol 4 solution was pre-cooled through a 3 mL pre-cooled PFR before being poured into the POCl 3 Tailored to the feed.

[0318] The two solutions were mixed using a static mixer and the heat of reaction was measured using a thermocouple. The reaction had a residence time of 60 minutes in a 20 mL PFR at 0° C. and was 95% converted to NAMN ethyl ester. After leaving the cold bath, the crude product stream was collected in a collection flask held at −10° C. The product was collected for 63 minutes.

[0319] The crude phosphoryl containing NAMN ethyl ester was used directly from the phosphorylation step. Sodium hydroxide (40 g, 1 mol) was dissolved in water (960 g) to prepare a 1 M NaOH solution. This step was carried out in batches.

[0320] The crude NAMN ethyl ester solution was saponified at 18° C. by the addition of 1 M aqueous NaOH (107 mL, 107 mmol, 59.5 equiv.). Saponification occurred over a period of 24 h with reaction monitoring by HPLC and pH monitoring by a digital pH probe. The final pH of the solution was 9. Once saponification was complete as indicated by HPLC, a portion of the material was lyophilized and quantitatively analyzed. 1 Assayed by H-NMR. The overall yield of phosphorylation and saponification is 66%.

[0321] A comparison of different routes for preparing NAMN is shown in Table 5. [Table 5]

[0322] In summary, disclosed herein is an alternative route for the synthesis of NAMN ethyl nicotinate and β-D-ribofuranose 1,2,3,5-tetraacetate by forming an ethyl ester intermediate. Additionally, analytical methods were carefully constructed to efficiently monitor the reaction progress and product purity throughout the synthesis. Process development and intensification in batches significantly improved the reaction cost and performance at each step. Reported reaction times at each step were reduced from days to hours / minutes. Screening studies were performed to evaluate the optimal reagents / solvents required to increase the reaction rate, solubility, and concentration of each step. Each step was evaluated for continuous flow and proof-of-concept runs were demonstrated where necessary. Additionally, a cost model for the process demonstrated herein was developed with a feasible route where raw material costs were significantly less than $800 / kg.

[0323] Example 6: Further exemplary preparations of nicotinic acid mononucleosides [ka]

[0324] General procedure for the preparation of compound 3. [ka] To a mixture of (3R,4R,5R)-5-(acetoxymethyl)tetrahydrofuran-2,3,4-triyl triacetate (1, 50 g, 157.10 mmol, 1 equiv.), benzyl nicotinate (2, 35.17 g, 164.95 mmol, 1.05 equiv.) in DCM (500 mL) was added TMSOTf (52.37 g, 235.64 mmol, 42.58 mL, 1.5 equiv.) and the mixture was then cooled to 50° C. for 2 h. 2 The mixture was stirred at 20°C for 2 hours under atmospheric pressure. LCMS (5-95AB / 1.5 min, RT=0.653 min, 472.3 [M+H] + , ESI pos) showed that a major peak with the desired product was detected. The residue was cooled to ice H 2 Dilute the mixture with 400 mL of saturated NaHCO 3 The mixture was neutralized to pH 6-7 with aqueous solution of DCM (100 mL) and the residue was extracted with DCM (100 mL). The combined organic layers were washed with brine (350 mL) and added Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 0:1) to give 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (3, 70 g, 148.16 mmol, 94.31% yield) as a yellow oil. LCMS: Rt = 0.653 min, m / z = 472.3 (M+H + ); 1H NMR (400 MHz) δ 9.58 (s, 1H), 9.46 (br d, J = 6.2 Hz, 1H), 9.03 (d, J = 8.1 Hz, 1H), 8.37 - 8.30 (m, 1H), 7.47 - 7.37 (m, 5H), 6.63 (d, J = 3.8 Hz, 1H), 5.50 - 5.44 (m, 3H), 5.33 (t, J = 5.6 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.57 - 4.41 (m, 2H), 2.14 - 2.07 (m, 9H).

[0325] General procedure for the preparation of compound 4. [ka] A mixture of 3-((benzyloxy)carbonyl)-1-((2R,3R,4R,5R)-3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (3, 70 g, 148.16 mmol, 1 equiv.), HCl (3 M, 700.00 mL, 14.17 equiv.) was then added and the mixture was stirred at 25 °C for 16 h. LCMS (0-60AB / 1.5 min, RT = 0.689 min, 346.0 [M+H] + , ESI pos) showed that a main peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to remove HCl at 25°C. The residue was purified by H 2 The mixture was diluted with 2H2O (500 mL) and extracted with DCM (300 mL). The aqueous phase was lyophilized to give 3-((benzyloxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (4.50 g, crude, HCl) as a yellow solid. LCMS: Rt=0.689 min, m / z=346.0 (M+H). + ).

[0326] General procedure for the preparation of compound 5. [ka] PO(OMe)3 To a solution of 3-((benzyloxy)carbonyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (4, 40 g, 115.49 mmol, 1 equiv.) in POCl (200 mL) was added 3 (80 mL) was added dropwise at 0° C. for 0.5 h. The mixture was stirred at 0° C. for 4 h. LCMS (ice H 2 quenched with O) (0-60AB / 1.5 min, RT = 0.256 min, 426.1 [M+H] + , ESI pos) showed that a major peak with the desired MS was detected. The reaction mixture was cooled to 0° C. with H 2 200 mL) was slowly added and the mixture was then stirred at 0° C. for 1.5 h. The solution was purified by reverse-phase HPLC (neutral conditions, 0.5 h H 2 Purification by O washing as is, mobile phase: [water-ACN]; B%: 0%-30% gave ((2R,3S,4R,5R)-5-(3-((benzyloxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate (5.15 g, 28.56 mmol, 30.53% yield, 81% purity) as a yellow solid. LCMS: Rt=0.181 min, m / z=426.1(M+H + ); 1 H NMR (400 MHz, D 2 O) δ 9.40 (s, 1H), 9.26 (d, J = 6.2 Hz, 1H), 8.97 (br d, J = 8.1 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.42 - 7.31 (m, 5H), 6.08 (d, J = 5.3 Hz, 1H), 5.37 (s, 2H), 4.51 (br d, J = 2.1 Hz, 1H), 4.44 (t, J = 5.1 Hz, 1H), 4.35 - 4.30 (m, 1H), 4.20 - 3.99 (m, 2H).

[0327] General procedure for the preparation of N-1. [ka] To a solution of ((2R,3S,4R,5R)-5-(3-((benzyloxy)carbonyl)pyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate (5, 8 g, 18.81 mmol, 1 equiv.) in THF (60 mL), 2 2H2O (60 mL) was added. 2 0 (955.05 mg, 22.76 mmol, 1.2 equiv). The mixture was stirred at 25 °C for 16 h. Special LCMS (0-30AB_7min_T3_5cm, RT = 0.790 min, 336.0 [M+H] + , ESI pos) showed that the main peak with the desired product was detected. The reaction mixture was purified by ion exchange resin (H) form to obtain ((2R,3S,4R,5R)-5-(3-carboxypyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl) methyl hydrogen phosphate (N-1, 2 g, 5.55 mmol, 29.50% yield, 93% purity) as a yellow solid. LCMS:t R =0.814 min, m / z=336.0(M+H) + ; 1 H NMR (400 MHz, D 2 O) δ 9.45 (s, 1H), 9.28 (d, J = 6.2 Hz, 1H), 9.03 (br d, J = 8.1 Hz, 1H), 8.30 - 8.19 (m, 1H), 6.18 (d, J = 5.3 Hz, 1H), 4.62 - 4.57 (m, 1H), 4.51 (t, J = 5.1 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.29 - 4.10 (m, 2H).

[0328] Incorporation by Reference All U.S. patents and U.S. and PCT patent application publications referred to herein are incorporated herein by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including definitions herein, will control.

[0329] Equivalent While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. A compound having a structure represented by formula (VI), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, Q does not exist, or 【Chemistry 2】 or H, R １ is HPO ４ , H ２ P.O. ４ , —OH, —Oacyl, or —OC(O)R ４ and R ２ and R ３ are independently —OH, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R ４ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; X is O, NH, NR ７ , or S, L is a bond, C １～２０ alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or -R １１ -S-S-R １１ -, and said C １～２０ Alkyl is optionally a group selected from the group consisting of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and wherein said aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and each R ｂ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Y is -C(O)N. ２ 、-C(O)OH、-R ５ 、-P(R ７ ) ３ 、-NH ２ 、-NHR ５ 、 【Transformation 3】 -SH or -OH, R ５ is -C(O)R ４ , 【Chemistry 4】 and R ７ is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R ８ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ９ and R １０ are independently —H, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R １１ is C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Z is H or C １～２０ alkyl, or Z and R １ are optionally joined together as a bond to form a macrocycle; provided that X is O, NH, or NR ７ and L is C １～２０ When Y is alkyl, aryl, heteroaryl, or alkoxy, Y is —C(O)NH ２ , -C(O)OH, -R ５ , -NH ２ , -NHR ５ , —SH, or —OH].

2. Formula VIa: 【Transformation 5】 [In the formula, R ２０ is H, P(O) ２ OH, P(O)(OH) ２ , or acyl, R ２１ and R ２２ are each independently H or acyl; R ２３ is H, alkyl, cycloalkyl, aralkyl, or aryl; R ２４ is H or alkyl, X ２０ is O,N(R ２４ ), or S, G is an anion.

2. The compound of claim 1 having the structure:

3. 3. The compound of claim 2, wherein R20 is H, P(O)(OH)2, or acyl.

4. R ２３ is H or alkyl.

5. R ２３ The compound of claim 2, wherein is alkylaminoalkyl, or alkylamidoalkyl.

6. R ２３ is substituted with triarylphosphonium, vinyl, amide, ester, halo, or alkyl. 【Request Item 7】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 wherein G is a pharmaceutically acceptable anion.

2. The compound of claim 1 selected from the group consisting of:

8. Formula VIb: 【Chemistry 12】 [In the formula, R ３０ is alkyl, aryl, heteroaryl, or cycloalkyl; X ３０ is O,N(R ３４ ), or S, R ３４ is H or alkyl.

2. The compound of claim 1 having the structure:

9. X ３０ is NH or O.

10. R ３０ is substituted with triarylphosphonium, alkyl, hydroxyl, amido, amino, alkoxy, alkenyl, or ester. 【Request Item 11】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 wherein G is a pharmaceutically acceptable anion.

2. The compound of claim 1 selected from the group consisting of:

12. A nicotinate / nicotinamide riboside compound or derivative of formula (V), or a salt, hydrate, or solvate thereof: 【Chemistry 17】 [In the formula, Q does not exist, or [Chemistry 18] or H, R １ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ２ and R ３ are independently —OH, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R ４ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; X is O, NH, NR ７ , or S, L is a bond, C １～２０ alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or -R １１ -S-S-R １１ -, and said C １～２０ Alkyl is optionally a group selected from the group consisting of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and wherein said aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and each R ｂ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Y is -C(O)N. ２ 、-C(O)OH、-R ５ 、-P(R ７ ) ３ 、-NH ２ 、-NHR ５ 、 【Chemistry 19】 -SH or -OH, R ５ is -C(O)R ４ , 【Chemistry 20】 and R ７ In each occurrence, a substituted or unsubstituted C １～６ independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R ８ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ９ and R １０ are independently —H, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R １１ is C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; G is an anion, Z is H or C １～２０ alkyl, or Z and R １ are optionally joined together as a bond to form a macrocycle; provided that X is O, NH, or NR ７ and L is C １～２０ When Y is alkyl, aryl, heteroaryl, or alkoxy, Y is —C(O)NH ２ , -C(O)OH, -R ５ , -NH ２ , -NHR ５ , —SH, or —OH]. 【Request Item 13】 【Chemistry 21】 【Chemistry 22】 and combinations thereof.

14. A compound or derivative of formula (IV), or a salt, hydrate, or solvate thereof: 【Chemistry 23】 [In the formula, R １ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ２ and R ３ are independently —OH, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R ４ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～２０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; R ５ , R ６ , R ７ , R ８ are independently lone pairs, H, C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl and the C ３～１０ Cycloalkyl is optionally selected from -alkyl, -O-alkyl, -N(R ９ ) ２ is replaced by R ９ is -H or C １～１０ is alkyl, G is an anion.

15. A nicotinate / nicotinamide riboside compound or derivative of formula (V), or a salt, hydrate, or solvate thereof: 【Chemistry 24】 [In the formula, Q does not exist, or 【Chemistry 25】 or H, R １ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ２ and R ３ are independently —OH, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R ４ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; X is O, NH, NR ７ , or S, L is a bond, C １～２０ alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or -R １１ -S-S-R １１ -, and said C １～２０ Alkyl is optionally a group selected from the group consisting of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and wherein said aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and each R ｂ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Y is -C(O)N. ２ 、-C(O)OH、-R ５ 、-P(R ７ ) ３ 、-NH ２ 、-NHR ５ 、 【Chemistry 26】 -SH or -OH, R ５ is -C(O)R ４ , 【Chemistry 27】 and R ７ In each occurrence, a substituted or unsubstituted C １～６ independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R ８ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ９ and R １０ are independently —H, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R １１ is C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Z is H or C １～２０ alkyl, or Z and R １ are optionally joined together as a bond to form a macrocycle; provided that X is O, NH, or NR ７ and L is C １～２０ When Y is alkyl, aryl, heteroaryl, or alkoxy, Y is —C(O)NH ２ , -C(O)OH, -R ５ , -NH ２ , -NHR ５ , —SH, or —OH].

16. A compound or derivative of formula (IV), or a salt, hydrate, or solvate thereof: 【Chemistry 28】 [In the formula, R １ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４ and R ２ and R ３ are independently —OH, —C(O)R ４ , -C(O)OR ４ , —C(O)NHR ４ , or halogen, R ４ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～２０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; R ５ , R ６ , R ７ , R ８ are independently lone pairs, H, C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl and the C ３～１０ Cycloalkyl is optionally selected from -alkyl, -O-alkyl, -N(R ９ ) ２ is replaced by R ９ is -H or C １～１０ alkyl].

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient.

18. A method for producing the compound of claim 1, comprising the steps of: Providing a nicotinate / nicotinamide riboside compound or derivative of formula (II), or a salt, hydrate, or solvate thereof: 【Chemistry 29】 [In the formula, R １’ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４’ and R ２’ and R ３’ are independently —OH, —C(O)R ４’ 、 -C(O)OR ４ ', -C(O)NHR ４’ 、 or a halogen, R ４’ is -H, C １～２０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; and contacting the compound or derivative of formula (II), or a salt, hydrate, or solvate thereof, with a coupling agent and a compound of formula (III): 【Transformation 30】 [In the formula, X ’ is O, NH, NR ７’ , or S, L' is a bond, C １～２０ Alkyl, aryl, heteroaryl, aryl alkylaryl, aryl alkyl, alkoxy, -R １１’ -S-S-R １１’ -, and said C １～２０ Alkyl is optionally a group selected from the group consisting of an amino acid side chain, -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and wherein said aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy are optionally substituted with one or more groups selected from -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ｂ , -CO ２ R ｂ , —O—C(O)R ｂ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NO ２ , -CN, and -SO ２ R ｂ and each R ｂ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Y' is C １～２０ Alkyl, perfluoroalkyl, —C(O)NH ２ , -C(O)OH, -R ５’ , -C(R ６’ ) ３ , -P(R ７’ ) ３ , -NH ２ , -NHR ５ ', 【Chemistry 31】 -SH, -OH, R ５’ is -C(O)R ４’’ , 【Chemistry 32】 and R ６’ In each occurrence, C １～６ Alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, -H, -halogen, -OH, and -NH ２ are individually selected from the group consisting of: R ７’ In each occurrence, a substituted or unsubstituted C １～６ independently selected from the group consisting of alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R ８’ is HPO ４ , H ２ P.O. ４ , —OH, or —OC(O)R ４’’ and R ９’ and R １０’ are independently —OH, —C(O)R ４’’ , -C(O)OR ４’’ , —C(O)NHR ４’’ , or halogen, R １１’ is C １～１０ Alkyl, C ３～１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, １～１０ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from the group consisting of -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; R ４’’ is optionally selected from -OH, halogen, -alkyl, -O-alkyl, -N-alkyl, -alkenyl, -alkynyl, -O-aryl, -O-heteroaryl, -N-aryl, -N-heteroaryl, -aryl, -C(O)R ａ , -CO ２ R ａ , —O—C(O)R ａ , -NHC(O)R ａ , -NR ａ C(O)R ａ , -NO ２ , -CN, and -SO ２ R ａ C substituted with one or more groups selected from １～２０ alkyl, and each R ａ are independently Ar, C １～６ Alkyl, or CH ２ Ar, wherein Ar is aryl or heteroaryl; Z' is H or C １～２０ is alkyl, G is an anion. The method comprising:

19. 17. A composition for treating a skin condition in a subject in need thereof, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

20. 20. The composition of claim 19, wherein the skin condition is selected from the group consisting of contact dermatitis, irritant contact dermatitis, allergic contact dermatitis, atopic dermatitis, actinic keratosis, dyskeratosis, eczema, epidermolysis bullosa disease, exfoliative dermatitis, seborrheic dermatitis, erythema multiforme, erythema nodosum, damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer, and the effects of natural aging.

21. A method for preparing Compound 1, the method comprising the steps of Scheme I: 【Transformation 33】 wherein: R ５０ is alkyl, G １ is an anion, G ２ is a cation.

22. A method for preparing Compound 1, said method comprising the steps of Scheme II: 【Transformation 34】 wherein: R ５０ is alkyl or aralkyl, G ３ is an anion.

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