Amino acid salts of nicotinic acid mononucleotide and nicotinamide mononucleotide as anti-aging agents

Abstract

The present invention relates to amino acid salts of nicotinic acid mononucleotide and nicotinamide mononucleotide of formula I and compositions thereof, which can be used to treat diseases related to NAD + Deficiency-related conditions and diseases: (I), where A, M 1 、M 2 、R 1 、R 2 and R 3 As described in this article. #imgabs0#

Description

[0001] Related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 671,813, filed May 15, 2018, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to amino acid salts of nicotinic acid mononucleotide and nicotinamide mononucleotide and compositions thereof that can be used to treat conditions and diseases associated with aging. Background Art

[0004] Aging results from a complex interplay of biological, physical, and biochemical processes that lead to cellular and organ dysfunction, manifesting as a variety of diseases and other outcomes. For example, female fertility is highly sensitive to the effects of aging. For example, the US Centers for Disease Control and Prevention reports that the percentage of pregnancies and births associated with assisted reproductive technology (ART) steadily declines from approximately 25% of ART cycles, resulting in singleton live births, in women around age 35 to 14% by age 40 (Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2011 Assisted Reproductive Technology National Summary Report. Atlanta (GA): US Dept. of Health and Human Services; 2013). This trend increases significantly after age 40, with the CDC reporting that the likelihood of success is very low for women over 44. In this age group, the percentage of live births and singleton live births drops to approximately 1%. Age is generally considered the most important factor affecting the chance of a live birth when a woman uses her own eggs (oocytes).

[0005] It should be understood that the deterioration of oocytes due to aging is the fundamental factor in decreased fertility. For example, it is reported that in elderly women, oocytes are prone to chromosome division abnormalities, showing decreased mitochondrial quality, low ATP production, increased oxidative stress and reduced antioxidant levels (Nelson SM, Telfer EE, Anderson RA.The aging ovary and uterus:new biological insights.Hum Reprod Update.2013;19:67-83.;Wilding M.Potential long-term risks associated with maternal aging (the role of the mitochondria).Fertil Steril.2015;103:1397-401;3.Meldrum DR,Casper RF,Diez-Juan A,Simon C,Domar AD,Frydman R.Aging and the environment affect gamete and embryo potential:can we intervene?Fertil Steril.2016;105:548-59).

[0006] For all the aforementioned reasons, oocytes represent an excellent target tissue for evaluating therapeutic modalities expected to have an impact on the aging process and, moreover, offer the prospect of addressing age-related infertility.

[0007] One such potential therapeutic modality for treating aging involves increasing NAD + Therapeutic levels of NAD + It is an important component of cellular processes necessary to support a variety of metabolic functions. + The classic role of NAD is as a coenzyme that catalyzes cellular redox reactions in many basic metabolic processes (such as glycolysis, fatty acid β-oxidation or the tricarboxylic acid cycle) and is reduced to NADH. + Also consumes NAD + It plays a key role as a substrate for enzymes such as poly ADP-ribose polymerase (PARP), sirtuin and CD38 / 157 exoenzymes. These are known to consume NAD + Enzymes mediate many fundamental cellular processes.

[0008] There are five main synthetic NAD +Precursors and intermediates of NAD: tryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). + Nicotinic acid mononucleotide (NaMN) can be synthesized de novo by converting the amino acid tryptophan into nicotinic acid dinucleotide (NaAD) via multiple enzymatic steps. NaMN is converted to nicotinic acid dinucleotide (NaAD) by NMN / NaMN adenosyltransferase (NMNAT). + ), then through NAD + Synthetase amidates to NAD + .

[0009] In mammals, NAD + The main biosynthetic pathway is the salvage pathway of nicotinamide. Nicotinamide is converted into the key NAD+ intermediate NMN by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) in this pathway. Then, NMNAT converts NMN into NAD+. + NAMPT plays a key role in regulating cellular NAD+ levels. On the other hand, niacin is converted to NaMN by nicotinic acid phosphoribosyltransferase (NPT). NR needs to be converted into NMN by nicotinamide ribokinase NMRK1 and NMRK2 (also known as NRK1 and NRK2), which phosphorylate NR 16. Maintaining sufficient NAD + Biosynthesis is essential for cell survival and function. Deviation from normal NAD + Homeostasis not only significantly affects the NAD required for redox reactions + / NADH pool, and affects NAD for key cellular functions + dependent enzyme activity.

[0010] Now, NAD at the cellular, tissue / organ, and organismal levels + It is now common knowledge that NAD levels decline during aging. + The activity of the enzyme is affected by this NAD + The effects of age-related decline can lead to various age-related pathophysiologies. Nicotinamide adenine dinucleotide is an enzyme cofactor that is essential for the function of several enzymes involved in redox reactions and energy metabolism. (Katrina L. Bogan and Charles Brenner, Nicotinic Acid, Nicotinamide and Nicotinamide Riboside: A Molecular Evaluation of NAD + Precursor Vitamins in Nutrition, 28, Annual Review of Nutrition 115 (2008). NAD +NAD acts as an electron carrier in the energy metabolism of amino acids, fatty acids, and carbohydrates (Bogan & Brenner, 2008). + It is crucial for redox reactions and as a substrate for signal transduction of PARP (poly ADP-ribose polymerase) and sirtuin (SIRT1 to SIRT7), in the regulation of DNA repair, energy metabolism, cell survival and circadian rhythm (Bronkowski, MS & Sinclair, D., Nat. Rev. Mole. Cell. Bio., 17, 679-690, 2016). + Concentrations of NAD2 can delay aging in yeast, flies, and mice (Mouchiroud et al. Cell 154, 464-471, 2014). + Directly regulate protein-protein interactions, the regulation of which can protect against cancer and radiation exposure and have a direct impact on aging (Li et al., Science 355, 1312-1317, 2017). Therefore, increasing evidence supports the idea that using NAD + Intervention with intermediates such as NMN and NR can restore available NAD + to strengthen the system and mitigate the physiological decline associated with aging.

[0011] Although NAD + Can be synthesized de novo from the amino acid tryptophan, but this process does not occur in all tissues, requiring most cells to rely on salvage pathways (described above) to regenerate NAD from other intracellular intermediates, which are primarily available from dietary sources. +(Christopher R. Martens, et al., Nat. Commun. 9, 1286, (2018) and Bogan, KL & Brenner, C., Annu. Rev. Nutr. 28, 115-130, (2008)). Other NAD precursors, such as niacin and nicotinamide, can also be administered to enhance the cellular bioavailability of NAD. However, clinically relevant levels of niacin are associated with undesirable flushing at therapeutic doses (MacKay, D., Hathcock, J. & Guarneri, E., Nutr. Rev. 70, 357-366 (2012)), and despite elevated NAD concentrations, nicotinamide does not reliably activate (and may even inhibit) sirtuins (Bitterman, KJ, et al., J. Biol. Chem. 277, 45099-45107 (2002); Guan, X., et al., PLoS One. 9, e107729 (2014); and Trammell, SA et al. Nat. Commun. 7, 12948 (2016)). Therefore, administration of niacin or nicotinamide is unlikely to be widely used to maintain health and function as we age.

[0012] Compared with niacin and nicotinamide, administration of NAD + Metabolites such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) appear to increase NAD + levels and improve a variety of physiological functions (Yoshino, J. et al., Cell Metab. 14, 528-536 (2011); Mills, KF et al., Cell Metab. 24, 795-806 (2016); and Frederick, DW et al., Cell Metab. 24, 269-282 (2016)). At least one of these metabolites is reportedly well tolerated in humans, leading to increased NAD levels and improved physiological functions, although further studies are needed to confirm the findings of this exploratory study (Christopher R. Martens, et al., Nat Commun. 9, 1286, (2018)). In addition, recent studies have shown that a single dose of NR stimulates NAD levels in healthy human blood cells in a dose-dependent manner. + Metabolism (Trammell, SA et al., Nat. Commun. 7, 12948 (2016)), which demonstrates the limitations of this metabolite. However, many known NAD+ metabolites are unstable in various physiological environments and therefore cannot be used as viable drugs to be administered to patients who need such metabolites to increase NAD+ levels in the patient.

[0013] Taking NAD into account + NAD plays a central role in key cellular and physiological pathways and development of novel agents that can increase NAD levels in disease states and / or during aging is crucial. + Levels of new stabilizers with improved properties are necessary to improve human conditions. Summary of the Invention

[0014] Provided herein are NaMN and amino acid salts of NMN that surprisingly increase cellular NAD + level.

[0015] The first aspect of the present application relates to salts of formula (I):

[0016]

[0017] and their enantiomers, stereoisomers and tautomers,

[0018] in

[0019] A is NR a R b , OH or O - ;

[0020] M 1 and M 2 are independently cationic amino acids, cationic amines or inorganic cations, provided that M 1 or M 2 At least one of them is a cationic amino acid;

[0021] R 1 and R 2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C3 alkylene) C(O)C1-C6 alkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b or -[CH2-CH2-O] k -R a ,or

[0022] R 1 and R 2 Together with the atoms to which it is attached, it forms a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C8 cycloalkyl, 14 Aryl or (C0-C3 alkylene) heteroaryl;

[0023] R 3 is a negative charge, H;

[0024] R a and R b is independently H or C1-C6 alkyl at each occurrence, wherein alkyl is optionally substituted with one or more substituents selected from the group consisting of (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 aryl or (C0-C3 alkylene)heteroaryl; and

[0025] k is an integer from 1 to 8;

[0026] The prerequisite is that when A is NR a R b When M 2 Does not exist.

[0027] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a salt of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

[0028] Another aspect of the present application relates to a method for treating or preventing age-related disorders, comprising administering to a subject in need thereof an effective amount of a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof.

[0029] Another aspect of the present application relates to a method for treating or preventing infertility, comprising administering to a subject in need thereof an effective amount of a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof.

[0030] Another aspect of the present application relates to a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof for use in a method for treating an age-related disorder.

[0031] Another aspect of the present application relates to a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof for use in a method for treating infertility.

[0032] Another aspect of the present application relates to the use of a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of an age-related disorder.

[0033] Another aspect of the present application relates to the use of a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of infertility.

[0034] Another aspect of the present disclosure relates to a method of improving oocyte quality and maturation, comprising administering a therapeutically effective amount of a salt of Formula I to a subject in need thereof.

[0035] Another aspect of the present disclosure relates to the use of a salt of formula (I) or an enantiomer, stereoisomer or tautomer thereof in the manufacture of a medicament for treating an age-related disorder.

[0036] In another aspect, the present invention comprises treating an oocyte ex vivo with a salt of formula (I) prior to implantation into a subject for use in treating age-related infertility.

[0037] In another aspect, the present invention comprises treating a blastocyst ex vivo with a salt of formula (I) prior to implantation into a subject for the treatment of age-related infertility.

[0038] In another aspect, the present invention comprises treating an oocyte ex vivo with a salt of formula (I) prior to implantation into a subject for use in treating infertility.

[0039] In another aspect, the present invention comprises treating a blastocyst ex vivo with a salt of formula (I) prior to implantation into a subject for the treatment of infertility.

[0040] In another aspect, a salt of formula (I) is provided as a component in a solution for treating cells in vitro for treating age-related conditions. In some embodiments, the age-related condition is age-related infertility. In other aspects, a salt of formula (I) is provided as a component in a solution for treating cells in vitro for treating infertility.

[0041] Another aspect of the present disclosure relates to a process for preparing a salt of formula (I), comprising contacting a nicotinic acid mononucleotide derivative of formula II with an alkali metal hydroxide under suitable conditions effective to produce the salt of formula I.

[0042] The present disclosure also relates to methods of accelerating recovery from a disease or condition. The methods comprise administering to a subject in need thereof an effective amount of a salt of formula (I) in combination with a prescribed treatment for the disease.

[0043] In another aspect, the present disclosure relates to a cell culture medium for in vitro fertilization, comprising: one or more salts of formula (I) and a culture agent. DETAILED DESCRIPTION

[0044] The present application relates to salts and compositions capable of treating or preventing age-related conditions. The present application is characterized in that a method for treating, preventing or alleviating a disease or condition associated with aging is achieved by administering a therapeutically effective amount of a salt of formula (I) or its enantiomers, stereoisomers or tautomers to a patient in need thereof. The methods of the present application can be used to treat a variety of diseases and conditions by preventing or alleviating the process of aging and cell recovery (including but not limited to infertility, cell degeneration).

[0045] The salts of formula (I) are potent and effective at clinically achievable doses; are stable in a variety of potential dosage forms; have acceptable solubility, acceptable pH, are crystalline, have a reduced tendency to absorb water, and are easy to handle - all of which are consistent with the development, manufacture, and use of pharmaceuticals. In addition, the salts disclosed herein provide increased biological activity to increase cellular NAD + levels, increased stability and a more physiologically acceptable pH.

[0046] The first aspect of the present disclosure relates to a salt of formula I

[0047]

[0048] Among them, A, M 1 、M 2 、R 1 、R 2 and R 3 As described in this article.

[0049] The articles "a / an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0050] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean "and" or "or."

[0051] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for use in the optional substitution of the groups include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, C1-C6alkoxy, (C1-C6)haloalkyl, C1-C6haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH), alkyl), -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, as defined below.

[0052] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group may mean that the cycloalkyl group is attached to an atom of the aryl group by a bond or by being fused with the aryl group and sharing two or more common atoms.

[0053] As used herein, the term "unsubstituted" means that the designated group bears no substituents.

[0054] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, NH2, NH((C-C)alkyl), N((C-C)alkyl)2, -S(O)2-(C-C)alkyl, -S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl)2. The substituents themselves may be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulenyl, and the like.

[0055] Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic aromatic radical or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O or S, the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic radical wherein the heteroatoms are selected from N, O or S. Aromatic radicals are optionally substituted independently with one or more substituents as described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2 ,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indolyl, indolinyl, indolonyl, dihydrobenzothiophene benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl , tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1 -pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2, 4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and derivatives thereof. In addition, when containing two fused rings, the aryl group defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzooxanyl.

[0056] Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.

[0057] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0058] "Alkoxy" refers to a straight or branched saturated hydrocarbon containing 1-12 carbon atoms with a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0059] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group may be unbound or bound to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. An alkenyl group may be unsubstituted or substituted. As defined herein, an alkenyl group may be straight or branched.

[0060] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. "Alkynyl" contains at least one triple bond in the chain. Examples of alkenyl include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0061] The term "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be converted to an alkylene group by removing the second hydrogen atom from the alkyl group. As defined herein, an alkylene group can also be a C1-C6 alkylene group. An alkylene group can further be a C1-C4 alkylene group. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0062] "Cycloalkyl" means a cycloalkyl group containing 3 to 18 carbon atoms (e.g., C3-C 10 ) or a monocyclic or polycyclic saturated carbocyclic ring (e.g., a fused ring, a bridged ring, or a spirocycle). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norboranyl, norborenyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl.

[0063] "Heterocyclyl" or "heterocycloalkyl" means a monocyclic or polycyclic ring (e.g., fused, bridged, or spirocyclic) containing carbon atoms and heteroatoms selected from oxygen, nitrogen, or sulfur, and in which there are no delocalized rings shared between ring carbon atoms or heteroatoms. Electronics (aromaticity). Heterocycloalkyl can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered rings. The heterocycloalkyl ring structure can be substituted by one or more substituents. The substituents themselves can be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetane, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine According to the present application, a 3- to 10-membered heterocyclyl group refers to a saturated or partially saturated non-aromatic ring structure containing between 3 and 10 atoms, wherein at least one heteroatom selected from the group consisting of N, O or S is present.

[0064] The term "hydroxyalkyl" means an alkyl group as defined above, wherein the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0065] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0066] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0067] As used herein, the term "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond (ie, C≡N).

[0068] As used herein, the term "amine" refers to primary amines (R-NH2, R≠H), secondary amines (R2-NH, R2≠H), and tertiary amines (R3-N, R≠H). Substituted amines refer to amines in which at least one hydrogen atom has been replaced by a substituent.

[0069] As used herein, the term "cationic amine" refers to a positively charged primary amine (R-NH3 + , R≠H), secondary amine ((R)2-NH2 + , R2≠H) and tertiary amine ((R)3-NH + , R≠H). Exemplary cationic amines include, but are not limited to, 2-hydroxyeth-1-ammonium, 3-aminopropan-1-ammonium, propane-1,3-diammonium, 1-methoxy-2-methylpropan-2-ammonium, N,N-dimethylpropan-1-ammonium, N,N,N-trimethylpropan-1-ammonium, and tris(2-chloroethyl)ammonium.

[0070] As used herein, the term "amino" refers to a substituent containing at least one nitrogen atom. Specifically, the term "amino" includes -NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide-, urea-, urea and sulfonamide substituents.

[0071] As used herein, the term "oxo" refers to a "=0" group.

[0072] The term "isomer" refers to salts and / or compounds having the same composition and molecular weight, but different physical and / or chemical properties. The structural differences can be in configuration (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the salts of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0073] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed salts and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, ansolic acid salt (4,4-diaminobenzylbenzene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, dextrorotatory camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate lauryl sulfate, ethanesulfonate, fumarate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl arsenic acid salt (glycollylarsanilate), hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, salt

[0014] Examples of the present invention include, but are not limited to, iodide, isothionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / hydrogen phosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethyl iodide, and valerate.

[0074] A "patient" or "subject" is a mammal, eg, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0075] When used in conjunction with a salt or pharmaceutical composition, an "effective amount" is an amount effective to treat or prevent a disease in a subject as described herein.

[0076] As used in this disclosure, the term "carrier" encompasses vehicles, excipients, and diluents and means a material, composition, or vehicle involved in carrying or transporting an agent from one organ or part of a subject's body to another organ or part of the body, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0077] The term "treating" with respect to a subject refers to ameliorating at least one symptom of a condition in the subject. Treatment includes curing, ameliorating, or at least partially alleviating a condition.

[0078] Unless otherwise indicated, the term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, illness, or condition.

[0079] As used in this disclosure, the terms "administer," "administering," or "administration" refer to administering a disclosed salt or composition directly to a subject, or administering to the subject a prodrug derivative or analog of the salt or composition that can form an equivalent amount of the active salt in the subject.

[0080] The salt of this application

[0081] The present application relates to salts or enantiomers, stereoisomers or tautomers thereof that are capable of treating or preventing age-related disorders, and can be used to treat diseases and disorders associated with aging and cell rejuvenation.

[0082] In one embodiment of the salt of Formula I, A is O - In another embodiment, A is OH. In another embodiment, A is NR a R b .

[0083] In some embodiments of the present invention, R a In each occurrence, R is independently H or C1-C6 alkyl. a is H. In other embodiments, R a is C1-C6 alkyl. In other embodiments, R a is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C8 14 In other embodiments, R ais a C1-C6 alkyl group substituted with one or more substituents selected from C1-C6 alkyl. a is a C1-C6 alkyl group substituted with one or more C2-C6 alkenyl groups. a is a C1-C6 alkyl group substituted with one or more C2-C6 alkynyl groups. a is a C1-C6 alkyl group substituted with one or more (C0-C3 alkylene) C3-C8 cycloalkyl groups. a is a C1-C6 alkyl group substituted with one or more (C0-C3 alkylene)heterocycloalkyl groups. a is occupied by one or more (C0-C3 alkylene) C6-C 14 In other embodiments, R a is a C1-C6 alkyl group substituted with one or more (C0-C3 alkylene) heteroaryl groups. a In other embodiments, R a is a methyl group substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C8 14 aryl or (C0-C3 alkylene) heteroaryl.

[0084] In another embodiment, R 3 Is a negative charge or H. In one embodiment, R 3 In another embodiment, R 3 For H.

[0085] In another embodiment, R 1 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C3 alkylene) C(O)C1-C6 alkyl, -C(O)OR a 、-C(O)NR a R b or -[CH2-CH2-O] k -R a In another embodiment, R 1 is H. In another embodiment, R 1 In another embodiment, R 1 In another embodiment, R 1 is (C0-C3 alkylene) C(O)C1-C6 alkyl. In another embodiment, R1 -C(O)OR a In another embodiment, R 1 -[CH2-CH2-O] k -R a In another embodiment, R 1 It is a C(O)C1-C6 alkyl group.

[0086] In one embodiment, R 2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C3 alkylene) C(O)C1-C6 alkyl, -C(O)OR a 、-C(O)NR a R b or -[CH2-CH2-O] k -R a In another embodiment, R 2 is H. In another embodiment, R 2 In another embodiment, R 2 In another embodiment, R 2 is (C0-C3 alkylene) C(O)C1-C6 alkyl. In another embodiment, R 2 -C(O)OR a In another embodiment, R 2 -[CH2-CH2-O] k -R a In another embodiment, R 1 It is a C(O)C1-C6 alkyl group.

[0087] In another embodiment of the salt of Formula I, R 1 and R 2 Together with the atoms to which it is attached, a 5-membered heterocyclic ring may be formed. In another embodiment of the salt of Formula I, R 1 and R 2 Together with the atoms to which it is attached, a 6-membered heterocyclic ring may be formed. In another embodiment of the salt of Formula I, R 1 and R 2 Together with the atoms to which they are attached, they may form a 5-membered heterocyclic ring substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C8 cycloalkyl, 14 In another embodiment of the salt of Formula I, R 1 and R 2Together with the atoms to which they are attached, they may form a 6-membered heterocyclic ring substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C8 cycloalkyl, 14 aryl and (C0-C3 alkylene)heteroaryl.

[0088] In another embodiment of the salt of Formula I, M 1 and M 2 In another embodiment, M 1 is a cationic amino acid of formula II:

[0089]

[0090] In another embodiment of the salt of Formula I, M 2 is a cationic amino acid of formula II:

[0091]

[0092] In yet another embodiment, M 1 In some embodiments, M 1 For but not limited to Li + 、Na + , K + , Rb + 、Cs + 、Be 2+ Mg 2+ , Ca 2+ 、Sr 2+ 、Zn 2+ and Ba 2+ In another embodiment, M 1 For Li + In another embodiment, M 1 for Na + In another embodiment, M 1 K + In another embodiment, M 1 Rb + In another embodiment, M 1 Cs + . M 1 It can also be a divalent cation, such as Ca 2+ 、Be 2+ Mg 2+ , Ca 2+ 、Sr 2+ 、Zn 2+ and Ba 2+In one embodiment, M 1 Ca 2+ .

[0093] In another embodiment, in yet another embodiment, M 2 In some embodiments, M 2 For but not limited to Li + 、Na + , K + , Rb + 、Cs + 、Be 2+ Mg 2+ , Ca 2+ 、Sr 2+ 、Zn 2+ and Ba 2+ In another embodiment, M 2 For Li + In another embodiment, M 2 for Na + In another embodiment, M 2 K + In another embodiment, M 2 Rb + In another embodiment, M 2 Cs + . M 2 It can also be a divalent cation, such as Ca 2+ 、Be 2+ Mg 2+ , Ca 2+ 、Sr 2+ 、Zn 2+ and Ba 2+ In one embodiment, M 2 Ca 2+ .

[0094] In one embodiment of the salt of Formula I, R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C 14 In another embodiment, R 4 is H. In another embodiment, R 4 C 1-6 In another embodiment, R 4 In another embodiment, R 4 In another embodiment, R4 is (C0-C3 alkylene) C3-C8 cycloalkyl. In another embodiment, R 4 In another embodiment, R 4 (C0-C3 alkylene)C6-C 14 In another embodiment, R 4 In another embodiment, R 5 is H, substituted by one or more (C0-C3 alkylene)SR c Substituted C1-C4 alkyl.

[0095] In another embodiment, R 4 is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4is a C2-C6 alkenyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is a C2-C6 alkynyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is (C0-C3 alkylene) C3-C8 cycloalkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene) NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c Rd 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is (C0-C3 alkylene) heterocycloalkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0–C3 alkylene)OR c 、(C0–C3 alkylene)OC(O)R c 、(C0–C3 alkylene)C(O)OR c 、(C0–C3 alkylene)SR c 、(C0–C3 alkylene)C(O)SR c 、(C0–C3 alkylene)SC(O)R c 、(C0–C3 alkylene)C(O)NR c R d 、(C0–C3 alkylene)NC(O)NR c R d 、(C0–C3 alkylene)C(NR c )NR c R d 、(C0–C3 alkylene)NR c C(NR c )NR c R d 、(C0–C3 alkylene)P(O)O n R c R d 、(C0–C3 alkylene)S(O) m NR c R d 、(C0–C3 alkylene)S(O) m OR c or (C0–C3 alkylene)BO p R c R d In another embodiment, R 4 (C0-C3 alkylene)C6-C 14 Aryl: cyano, halide, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is (C0-C3 alkylene) heteroaryl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene) NR c R d 、(C0–C3 alkylene)OR c 、(C0–C3 alkylene)OC(O)R c 、(C0–C3 alkylene)C(O)OR c 、(C0–C3 alkylene)SR c 、(C0–C3 alkylene)C(O)SR c 、(C0–C3 alkylene)SC(O)R c 、(C0–C3 alkylene)C(O)NR c R d 、(C0–C3 alkylene)NC(O)NR c R d 、(C0–C3 alkylene)C(NR c )NR c R d 、(C0–C3 alkylene)NR cC(NR c )NR c R d 、(C0–C3 alkylene)P(O)O n R c R d 、(C0–C3 alkylene)S(O) m NR c R d 、(C0–C3 alkylene)S(O) m OR c or (C0–C3 alkylene)BO p R c R d .

[0096] In one embodiment of the salt of Formula I, R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C 14 In another embodiment, R 5 is H. In another embodiment, R 5 C 1-6 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 is (C0-C3 alkylene) C3-C8 cycloalkyl. In another embodiment, R 5 In another embodiment, R 5 (C0-C3 alkylene)C6-C 14 In another embodiment, R 5 It is a (C0-C3 alkylene) heteroaryl group.

[0097] In another embodiment, R 5 is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is a C2-C6 alkenyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c Rd 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is a C2-C6 alkynyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is (C0-C3 alkylene) C3-C8 cycloalkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene) NR c R d 、(C0-C3 alkylene)ORc 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is (C0-C3 alkylene) heterocycloalkyl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene)NR c R d 、(C0–C3 alkylene)OR c 、(C0–C3 alkylene)OC(O)R c 、(C0–C3 alkylene)C(O)OR c 、(C0–C3 alkylene)SR c 、(C0–C3 alkylene)C(O)SR c 、(C0–C3 alkylene)SC(O)R c 、(C0–C3 alkylene)C(O)NR c R d 、(C0–C3 alkylene)NC(O)NR c R d 、(C0–C3 alkylene)C(NR c )NR cR d 、(C0–C3 alkylene)NR c C(NR c )NR c R d 、(C0–C3 alkylene)P(O)O n R c R d 、(C0–C3 alkylene)S(O) m NR c R d 、(C0–C3 alkylene)S(O) m OR c or (C0–C3 alkylene)BO p R c R d In another embodiment, R 5 (C0-C3 alkylene)C6-C 14 Aryl: cyano, halide, SeH, (C0-C3 alkylene)NR c R d 、(C0-C3 alkylene)OR c 、(C0-C3 alkylene)OC(O)R c 、(C0-C3 alkylene)C(O)OR c 、(C0-C3 alkylene)SR c 、(C0-C3 alkylene)C(O)SR c 、(C0-C3 alkylene)SC(O)R c 、(C0-C3 alkylene)C(O)NR c R d 、(C0-C3 alkylene)NC(O)NR c R d 、(C0-C3 alkylene)C(NR c )NR c R d 、(C0-C3 alkylene)NR c C(NR c )NR c R d 、(C0-C3 alkylene)P(O)O n R c R d 、(C0-C3 alkylene)S(O) m NR c R d 、(C0-C3 alkylene)S(O) m OR c or (C0-C3 alkylene)BO p Rc R d In another embodiment, R 5 is (C0-C3 alkylene) heteroaryl substituted by one or more substituents selected from the group consisting of cyano, halo, SeH, (C0-C3 alkylene) NR c R d 、(C0–C3 alkylene)OR c 、(C0–C3 alkylene)OC(O)R c 、(C0–C3 alkylene)C(O)OR c 、(C0–C3 alkylene)SR c 、(C0–C3 alkylene)C(O)SR c 、(C0–C3 alkylene)SC(O)R c 、(C0–C3 alkylene)C(O)NR c R d 、(C0–C3 alkylene)NC(O)NR c R d 、(C0–C3 alkylene)C(NR c )NR c R d 、(C0–C3 alkylene)NR c C(NR c )NR c R d 、(C0–C3 alkylene)P(O)O n R c R d 、(C0–C3 alkylene)S(O) m NR c R d 、(C0–C3 alkylene)S(O) m OR c or (C0–C3 alkylene)BO p R c R d .

[0098] In another embodiment, R 6 is H or C1-C6 alkyl. In another embodiment, R 6 is H. In another embodiment, R 6 C 1-6 In another embodiment, R 6 is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of cyano, halo, (C0-C3 alkylene)NR c R d or (C0-C3 alkylene)OR c In another embodiment, R5 For H.

[0099] In yet another embodiment, R 4 and R 6 Together with the atoms to which it is attached, a 5-membered ring can be formed. In another embodiment, R 4 and R 6 Together with the atoms to which it is attached, it can form a 5-membered ring substituted with one or more substituents selected from the group consisting of cyano, halo, (C0-C3 alkylene)NR c R d or (C0-C3 alkylene)OR c In another embodiment, R 4 and R 6 Together with the atoms to which it is attached, a 6-membered ring can be formed. In another embodiment, R 4 and R 6 Together with the atoms to which it is attached, it can form a 6-membered ring substituted with one or more substituents selected from the group consisting of cyano, halo, (C0-C3 alkylene)NR c R d or (C0-C3 alkylene)OR c .

[0100] In another embodiment, R d In another embodiment, R d is H. In another embodiment, R d C 1-6 In another embodiment, R d is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of: (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C 14 aryl or (C0-C3 alkylene) heteroaryl.

[0101] In another embodiment, R c In another embodiment, R c is H. In another embodiment, R c In another embodiment, R c is a C1-C6 alkyl substituted by one or more substituents selected from the group consisting of: (C0-C3 alkylene) C3-C8 cycloalkyl, (C0-C3 alkylene) heterocycloalkyl, (C0-C3 alkylene) C6-C 14 aryl or (C0-C3 alkylene) heteroaryl.

[0102] In another embodiment, k, at each occurrence, is 1, 2, 3, 4, 5, 6, 7, or 8. In another embodiment, k is 1. In another embodiment, k is 2. In another embodiment, k is 3. In another embodiment, k is 4. In another embodiment, k is 5. In another embodiment, k is 6. In another embodiment, k is 7. In another embodiment, k is 8.

[0103] In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2.

[0104] In one embodiment, n is 0, 1, or 2. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2.

[0105] In one embodiment, p is 0, 1, or 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2.

[0106] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ia:

[0107] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ib:

[0108] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ic:

[0109]

[0110] In some embodiments of the salt of Formula I, the salt has the structure of Formula Id:

[0111]

[0112] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ie:

[0113]

[0114] In some embodiments of the salt of Formula I, the salt has the structure of Formula If:

[0115]

[0116] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ig:

[0117]

[0118] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ih:

[0119]

[0120] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ii:

[0121]

[0122] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ij:

[0123]

[0124] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ik:

[0125]

[0126] In some embodiments of the salt of Formula I, the salt has the structure of Formula II:

[0127]

[0128] In some embodiments of the salt of Formula I, the salt has the structure of Formula Im:

[0129]

[0130] In some embodiments of the salt of Formula I, the salt has the structure of Formula In:

[0131]

[0132] In some embodiments of the salt of Formula I, the salt has the structure of Formula Io:

[0133]

[0134] In some embodiments of the salt of Formula I, the salt has the structure of Formula Ir:

[0135]

[0136] In another embodiment, suitable salts include, but are not limited to:

[0137] (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-001);

[0138] (S)-1-carboxy-2-methylpropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-002);

[0139] (S)-4-amino-1-carboxy-4-oxobutan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-003);

[0140] Bis((S)-1-carboxy-2-methylpropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-004);

[0141] Bis((S)-4-amino-1-carboxy-4-oxobutan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-005);

[0142] (S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-006);

[0143] (S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-007);

[0144] Bis((S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-008);

[0145] (S)-1-carboxy-4-guanidinobutane-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-009);

[0146] (S)-1,3-Dicarboxypropyl-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-010);

[0147] (S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-011);

[0148] (S)-1-carboxy-4-guanidinobutane-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-012);

[0149] (S)-1,3-Dicarboxypropyl-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-013);

[0150] (S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-014);

[0151] Bis((S)-1-carboxy-4-guanidinobutane-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-015);

[0152] Bis((S)-1,3-dicarboxypropyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridinium-1-ium-3-carboxylate (I-016);

[0153] Bis((S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-017);

[0154] (1S,2R)-1-carboxy-2-hydroxypropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-018);

[0155] (1S,2R)-1-carboxy-2-hydroxypropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-019);

[0156] Bis((1S,2R)-1-carboxy-2-hydroxypropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-020);

[0157] (S)-2-Carboxypyrrolidin-1-ium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-021);

[0158] (S)-2-Carboxypyrrolidin-1-ium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-022);

[0159] Bis((S)-2-carboxypyrrolidin-1-ium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-023);

[0160] (S)-5-amino-5-carboxypentan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-024);

[0161] (S)-5-amino-5-carboxypentan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-025);

[0162] (S)-5-amino-5-carboxypentan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-026);

[0163] (S)-1-carboxy-3-(methylthio)propan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-027);

[0164] (S)-1-carboxy-3-(methylthio)propan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-028);

[0165] Bis((S)-1-carboxy-3-(methylthio)propan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-029);

[0166] Carboxymethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-030);

[0167] Carboxymethylammonium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxidophosphoryloxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-031);

[0168] Bis(carboxymethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-032);

[0169] (S)-1-carboxyethyl-1-ammonium ((2R,3S,4R,5R)-5-(3-carboxypyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-033);

[0170] (S)-1-carboxyethyl-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxyphosphoryl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-034);

[0171] Bis((S)-1-carboxyethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-035);

[0172] (S)-1-carboxy-2-hydroxyeth-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-036);

[0173] (S)-1-carboxy-2-hydroxyeth-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-037);

[0174] Bis((S)-1-carboxy-2-hydroxyeth-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-038);

[0175] (S)-1-carboxy-2-phenyleth-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-039);

[0176] (S)-1-carboxy-2-phenyleth-1-aminium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-040);

[0177] Bis((S)-1-carboxy-2-phenyleth-1-aminium)-((2R,3R,4S,5R)-5-(3-carboxypyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-041);

[0178] (R)-1-carboxy-2-mercaptoethyl-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-042);

[0179] (R)-1-carboxy-2-mercaptoethyl-1-aminium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-043);

[0180] Bis((R)-1-carboxy-2-mercaptoethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-044);

[0181] (S)-3-Amino-1-carboxy-3-oxopropan-1-aminium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-045);

[0182] (S)-3-Amino-1-carboxy-3-oxopropan-1-aminium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-046);

[0183] Bis((S)-3-amino-1-carboxy-3-oxopropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-047);

[0184] (S)-1,2-Dicarboxyethyl-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-048);

[0185] (S)-1,2-dicarboxyethyl-1-ammonium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-049);

[0186] Bis((S)-1,2-dicarboxyethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-050);

[0187] Sodium (S)-1-carboxy-2-(1H-indol-3-yl)ethan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-051);

[0188] Sodium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-052);

[0189] Potassium (S)-1-carboxy-2-(1H-indol-3-yl)ethan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-053);

[0190] Potassium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-054);

[0191] (S)-1-carboxy-2-(1H-indol-3-yl)eth-1-aminium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-055);

[0192] 2-Hydroxyeth-1-aminium (S)-4-amino-1-carboxy-4-oxobutan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-056);

[0193] (S)-1-carboxy-3-methylbutan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-057);

[0194] (S)-1-carboxy-3-methylbutan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-058);

[0195] (S)-1-carboxy-3-methylbutan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-059);

[0196] (1S,2S)-1-carboxy-2-methylbutan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-060);

[0197] (1S,2S)-1-carboxy-2-methylbutan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-061);

[0198] (1S,2S)-1-carboxy-2-methylbutan-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-062);

[0199] (R)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-063);

[0200] (R)-1-Carboxy-2-methylpropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-064).

[0201] (R)-1-Carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-065).

[0202] A process for preparing salts.

[0203] The salts of the present application can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below.

[0204] The salt of formula (I) can be prepared by methods known in the field of organic synthesis, and the method is partially described by the following synthesis scheme. In the scheme described below, it should be fully understood that, according to general principles or chemistry, the protecting group of sensitive or reactive groups is used when necessary. According to the standard method of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999), the protecting group is manipulated. These groups are removed at a convenient stage of the salt synthesis using methods obvious to those skilled in the art. The selection process and reaction conditions and the execution order thereof should be consistent with the preparation of the salt of formula (I).

[0205] Those skilled in the art will recognize whether there is a stereocenter in the salt of formula (I). Therefore, the application includes two possible stereoisomers (unless described in synthesis), and not only includes racemic salts, but also includes independent enantiomers and / or diastereomers. When needing compound or salt as single enantiomer or diastereomer, it can be synthesized by stereospecificity or obtained by splitting final product or any convenient intermediate. The splitting of final product, intermediate or starting material can be realized by any suitable method known in the art. Referring to, for example, " Stereochemistry of Organic Compounds ", E.L. Elel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).

[0206] The salts and compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods.

[0207] The salt of the present application can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the salt of the present application can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof known to those skilled in the art. These methods include, but are not limited to, those described below. The salt of the present application can be synthesized by following the steps outlined in General Schemes 1 and 2, which include assembling different orders of various intermediates. The starting material is commercially available or prepared as shown by methods known in the literature reported.

[0208] Solution 1

[0209]

[0210] Option 2

[0211]

[0212] The mixtures of enantiomers, diastereomers, cis / trans isomers produced by the above process can be separated into their single components by chiral salt techniques, chromatography using normal phase, reverse phase or chiral columns, depending on the nature of the separation.

[0213] It should be understood that in the description and formulae shown above, unless otherwise indicated, the groups R in the schemes represent R 4 and R 5 , and the other variables are as defined above. Additionally, for synthetic purposes, the salts of General Schemes 1 and 2 are representative of selected groups only to illustrate the general synthetic methods for the salts of Formula (I) as defined herein.

[0214] It should also be understood that the salts disclosed herein have a neutral charge, and the structure of Formula I represents only a generic class, which can be balanced with counterions to impart a neutral charge to the salt if desired. Such counterions may include, but are not limited to, bromine, chloride, and triflate. In one embodiment, the salts of the present invention can be generated in situ without separation from the solution. In some embodiments, the salts disclosed herein can be discrete 1:1 or 1:2 salts. In some embodiments, the salts can also be present in other ratios, for example, 1:1.5, 1:5, and 1:10.

[0215] Methods of using the disclosed salts

[0216] Another aspect of the present disclosure relates to a method for treating or preventing a disease or condition associated with aging, cell degeneration and / or cell recovery. Non-limiting examples of such diseases and conditions include infertility, age-related infertility, age-related loss of eye function, decreased bone density, obesity, and insulin insensitivity. In one embodiment, a salt of formula (I) can be used to treat age-related infertility. In another embodiment, a salt of formula (I) can be used to treat fertility.

[0217] Another aspect of the present application relates to a method for treating or preventing a disease or condition associated with aging, cell degeneration and / or cell restoration. In one embodiment, the salts of the present disclosure can be used to treat infertility. In another embodiment.

[0218] The present invention also relates to the use of the salt of formula I and its enantiomers, stereoisomers and tautomers in the manufacture of a medicament for treating aging, cell rejuvenation, cell degeneration or infertility.

[0219] Yet another aspect of the present disclosure relates to a method for improving the quality and maturation of an oocyte or blastocyst. The method comprises contacting the oocyte or blastocyst with an IVF culture medium comprising a salt of formula (I) for an effective period of time.

[0220] In another aspect, the present disclosure provides a culture medium containing a salt of formula (I). The salt of formula (I) shows surprising and unexpectedly extended stability in solution, and therefore can be used to expose ovum, oocyte and / or blastocyst to the culture medium for the time period required for enhancing NAD+ production before implanting a patient with infertility or age-related infertility. In some embodiments, a culture medium comprising a salt of formula (I) is provided. In some embodiments, the culture medium comprises various reagents and factors necessary for ovum, oocyte or blastocyst, depending on the stage of maturation and development in which the ovum, oocyte or blastocyst is located. For example, the culture medium may contain any agent or factor that can be used in IVF culture medium listed in Table 1 below:

[0221] Table 1

[0222]

[0223]

[0224] Also provided is a cell culture medium for in vitro fertilization, comprising: one or more salts of formula (I) and a culture agent.

[0225] In one embodiment, the culture agent is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof. In one embodiment, the inorganic salt is calcium chloride, magnesium chloride, magnesium sulfate, potassium chloride, sodium bicarbonate, sodium chloride, monosodium phosphate, disodium phosphate, or any combination thereof.

[0226] In one embodiment, the energy substrate is glucose, pyruvate, lactate, pyruvate, or any combination thereof.

[0227] In one embodiment, the amino acid is an essential amino acid. In one embodiment, the essential amino acid is arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof.

[0228] In one embodiment, the amino acid is a non-essential amino acid.

[0229] In one embodiment, the non-essential amino acid is alanine, asparagine, aspartic acid, glutamic acid, proline, serine, or any combination thereof.

[0230] In one embodiment, the chelating agent is a caged chelate, acetylacetone, aminopolycarboxylic acid, ATMP, BAPTA, BDTH2, citric acid, cryptand, deferasirox, 2,3-dihydrobenzoic acid, 2,3-dimercapto-1-propanesulfonic acid, dimercaptosuccinic acid, DOTA, DTPMP, EDDHA, EDDS, EDTMP, etidronic acid, fura-2, gluconic acid, homocitric acid, iminodiacetic acid, Indo-1, nitrile triacetic acid, valeric acid (DTPA), phosphonate, plant chelate, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof.

[0231] In one embodiment, the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridine, or any combination thereof.

[0232] In one embodiment, the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof.

[0233] In one embodiment, the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.

[0234] In one embodiment, the vitamins are ascorbic acid, biotin, menadione sodium bisulfite, mitomycin C, pyridoxamine dihydrochloride, retinyl acetate, (-)-riboflavin, (+)-sodium L-ascorbate, (+)-α-tocopherol, vitamin B 12 , thiamine hydrochloride, inositol, pyridoxal hydrochloride, niacinamide, folic acid, calcium D-pantothenate, choline chloride, or any combination thereof.

[0235] In one embodiment, the growth factor is adrenomedullin, angiogenin, bone morphogenetic protein, macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), epidermal growth factor, ephrin, erythropoietin, fibroblast growth factor, growth differentiation factor-9, hepatocyte growth factor, insulin, insulin-like growth factor, interleukin, keratinocyte growth factor, migration stimulating factor, macrophage stimulating protein, myostatin, neurotrophic factor, T-cell growth factor, thrombopoietin, transforming growth factor, tumor necrosis factor-α, vascular endothelial growth factor, or any combination thereof.

[0236] In one embodiment, the cell culture medium further comprises oocytes, zygotes, blastocysts, or any combination thereof

[0237] In addition, a kit for IVF culture medium is provided, wherein the IVF culture medium comprises various agents and factors necessary for maturation of oocytes or blastocysts, including one or more salts of formula (I). These agents and co-factors can be dissolved in a solution for use in producing IVF culture medium shortly before exposure of oocytes or blastocysts prior to implantation in a patient requiring treatment for infertility or age-related infertility.

[0238] The present invention also relates to the use of salts of Formula I and their enantiomers, stereoisomers and tautomers in the manufacture of medicaments for treating aging, cell rejuvenation, cell degeneration or infertility. In certain embodiments, the infertility treated is age-related infertility.

[0239] Another aspect of the present invention is a pharmaceutical composition comprising a salt of formula I and a pharmaceutically acceptable carrier.

[0240] Another aspect of the invention is a pharmaceutical composition comprising a salt of Formula I and a pharmaceutically acceptable carrier comprising a therapeutically effective amount of one or more additional therapeutic agents.

[0241] In some embodiments, administration of a salt of Formula (I) or a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier induces changes in cell cycle or cell viability.

[0242] In some embodiments, administration of a salt of Formula (I) or a pharmaceutical composition comprising a salt of the present invention and a pharmaceutically acceptable carrier induces preventive changes in a condition or disease associated with aging.

[0243] The disclosed salts of the invention can be administered in an amount effective to treat or prevent a condition in a subject and / or to prevent the development of a condition or disease associated with aging in a subject.

[0244] Administration of the disclosed salts can be accomplished via any mode of administration of the therapeutic agent. These modes include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0245] Depending on the intended mode of administration, the disclosed compositions can be in solid, semisolid or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and in accordance with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all use forms well known to those skilled in the art of pharmacy.

[0246] When used for the indicated effects, the effective dosage range of the disclosed salts is from about 0.5 mg to about 5000 mg of the disclosed salt required to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed salts, or a range from one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored.

[0247] The dosage regimen using the disclosed salts is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed salt employed. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0248] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a salt of the invention and a pharmaceutically acceptable carrier such as a) a diluent, for example, purified water, a triglyceride oil such as a hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, stearic acid ... c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, for example, Tween 80, Labrasol, HPMC, DOSS, caproyl909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance salt absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0249] Most amino acids can have the same buffering properties as salts, and their multiple pKa values can produce a wider range of stable pH values that are more compatible with biological fluids and are therefore more suitable for IV administration. Naturally occurring amino acids, NMN, and NaMN are endogenous substances and are therefore less likely to be toxic to mammals as a mixture of NaMN, NMN, and naturally occurring amino acids. Some products can have enhanced solubility and solid form stability. In one embodiment, the salt can have enhanced water solubility. In one embodiment, the salt can have enhanced solid form stability. In one embodiment, the salt can have enhanced chemical stability.

[0250] Example

[0251] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the present disclosure to specific procedures as described herein in scope or spirit. It should be understood that the examples are provided to illustrate certain embodiments, and are not intended to limit the scope of the present disclosure. It should be further understood that, without departing from the spirit of the present disclosure and / or the scope of the appended claims, various other embodiments, modifications, and equivalents that may be conceived by those skilled in the art may be adopted.

[0252] The following salts disclosed herein are prepared using general synthetic methods including, but not limited to, reagents such as valine, leucine, alanine, isoleucine, methionine, phenylalanine, tryptophan, and tyrosine. Suitable solvents such as methanol, ethanol, water, acetic acid, ethylene glycol, isopropanol are also used.

[0253] The abbreviations used in the following examples and elsewhere herein are:

[0254] AcOH acetic acid

[0255] anh. anhydrous

[0256] atm atmosphere

[0257] aq. water-based

[0258] br broad peak

[0259] Boc tert-Butoxycarbonyl

[0260] Brine saturated aqueous sodium chloride

[0261] n-BuLi n-butyllithium

[0262] n-BuOH n-butanol

[0263] Calc'd

[0264] CDCl3 deuterated chloroform

[0265] CDI Carbonyldiimidazole

[0266] Chloroform-d deuterated chloroform

[0267] d Doublet

[0268] dd two doublets

[0269] dt two triplets

[0270] D2O Deuterated water (deuterium oxide)

[0271] DCE dichloroethane

[0272] DCM dichloromethane

[0273] DIAD Diisopropyl azodicarboxylate

[0274] DIPEA N,N-Diisopropylethylamine

[0275] DMAc N,N-dimethylacetamide

[0276] DMAP N,N-dimethylpyridin-4-amine

[0277] DME 1,2-dimethoxyethane

[0278] DMEDA N,N′-dimethylethylenediamine

[0279] DMF N,N-dimethylformamide

[0280] DMSO dimethyl sulfoxide

[0281] DMSO-d6 deuterated dimethyl sulfoxide

[0282] EDA Ethylenediamine

[0283] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0284] Et2O ether

[0285] EtOAc

[0286] EtOH

[0287] ESI electrospray ionization

[0288] g grams

[0289] h hour

[0290] H Hydrogen

[0291] 1H NMR Nuclear Magnetic Resonance (proton nucleus)

[0292] HATU [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0293] HBTU 3-[Bis(dimethylamino)methylene]-3H-benzotriazole-1-oxide hexafluorophosphate

[0294] HOBt Hydroxybenzotriazole

[0295] HPLC High pressure (or high performance) liquid chromatography

[0296] Hz Hertz

[0297] J coupling constant

[0298] KHCO3 potassium bicarbonate

[0299] KHMDS Potassium hexamethyldisilazane

[0300] KOAc potassium acetate

[0301] LCMS liquid chromatography-mass spectrometry

[0302] LHMDS Lithium Hexamethyldisilazane

[0303] [#]M molar concentration

[0304] m multiplet

[0305] [M+H] + Molecular ion hydrogenation

[0306] [M-tBu+H] + Molecular ion minus tert-butyl hydrogenation

[0307] mCPBA meta-chloroperbenzoic acid

[0308] Me2NH dimethylamine

[0309] Me4NBr Tetramethylammonium bromide

[0310] MeCN Acetonitrile

[0311] MeNH2 methylamine

[0312] MeOH methanol

[0313] Methanol-d4 deuterated methanol

[0314] 2-MeTHF 2-Methyltetrahydrofuran

[0315] mg milligrams

[0316] MHz Megahertz

[0317] min

[0318] mmol millimole

[0319] mL milliliters

[0320] MS

[0321] MS ES mass spectrometry electrospray

[0322] Ms2O Methanesulfonic anhydride

[0323] MTBE methyl tert-butyl ether

[0324] MW microwave

[0325] m / z mass-to-charge ratio

[0326] μL microliter

[0327] N2 nitrogen

[0328] NaHCO3 sodium bicarbonate

[0329] NAMN Nicotinic acid mononucleotide

[0330] NIS N-iodosuccinimide

[0331] NMP N-Methyl-2-pyrrolidone

[0332] NMR Nuclear Magnetic Resonance

[0333] PEPPSI-iPr[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride

[0334] PdCl2(Amphos) Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)

[0335] Dichloropalladium(II)

[0336] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0337] Pd(OAc)2 Palladium(II) acetate

[0338] PdCl2(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0339] PdCl2(MeCN)2 Bis(acetonitrile)dichloropalladium(II)

[0340] PdCl2(PPh3)2 Bis(triphenylphosphinepalladium(II) dichloride)

[0341] Pd(P(Cy)3)2Cl2 Dichlorobis(tricyclohexylphosphine)palladium(II)

[0342] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0343] Pd(t-Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0)

[0344] pH

[0345] PMB 4-methoxybenzyl

[0346] PMBCl 4-Methoxybenzyl chloride

[0347] ppm parts per million

[0348] prep

[0349] py pyridine

[0350] q quartet

[0351] qd four doublets

[0352] quant.

[0353] quin. Quintuplet

[0354] quind five double peaks

[0355] RBF round bottom flask

[0356] Rt retention time

[0357] rt room temperature

[0358] s single peak

[0359] sat. saturated

[0360] sat.aq. saturated aqueous solution

[0361] SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride

[0362] t Triplet

[0363] t-BuLi tert-butyl lithium

[0364] td three doublets

[0365] TMS trimethylsilyl

[0366] TMSCl trimethylsilyl chloride

[0367] tt Three Triple Peaks

[0368] T3P polyphosphonic anhydride

[0369] TBAB Tetrabutylammonium bromide

[0370] TEA triethylamine

[0371] TFA trifluoroacetic acid

[0372] TFAA trifluoroacetic anhydride

[0373] THF Tetrahydrofuran

[0374] TLC thin layer chromatography

[0375] TPPO triphenylphosphine oxide

[0376] XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0377] XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0378] Example 1. (S)-1-Carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogen phosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-001)

[0379]

[0380] Into a 50mL 3N RBF equipped with a water condenser and an internal thermometer, inject NaMN (0.200g, 0.597mmol, 1 equivalent) and 15ml of distilled deionized water and mix to form a solution. A weak suspension is also acceptable. This solution is cooled using an ice / water bath to keep the internal temperature below 10°C. Then, to this solution, 5.97ml of a 0.1M L-valine solution in distilled deionized water is slowly added dropwise to prevent the temperature from rising. After this addition, the pH is about 2.8. The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0381] Yield: 45.3 mg (95% purity, 83% yield)

[0382] Melting point: 78℃-83℃ (degradation, corrected), degassing at 135℃

[0383] Analyze the data: 1H-NMR(400MHz,D2O)δ=9.42(s,1H),9.32(d,1H),9.04(d,1H),8.28(dd,1H),6.25(d,1H),4.65(m ,2H),4.58(t,1H),4.48(dd,1H),4.32(dq,1H),4.17(dq,1H),3.70(d,1H),2.34(m,1H),1.05(2x d,6H) ppm

[0384] Example 2. (S)-1-Carboxy-2-methylpropan-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-002)

[0385]

[0386] In a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NMN (0.200 g, 0.598 mmol, 1 equivalent) and 5 mL of distilled deionized water were added and mixed to form a solution, although a slight suspension is acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution, 5.68 mL of a 0.1 mL solution of valine in distilled deionized water was then slowly added dropwise to prevent the temperature from rising. Following this addition, the pH was approximately 3.8-4.0.

[0387] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0388] Yield: 312 mg (quantitative)

[0389] Melting point: 148°C (degraded, corrected), degassing at 150°C

[0390] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.52 (s, 1H), 9.32 (d, 1H), 9.02 (d, 1H), 8.33 (dd, 1H), 6.25 (d, 1H), 4.67 (m, 2H), 4.6 1(t,1H),4.48(dd,1H),4.32(dq,1H),4.17(dq,1H),3.62(d,1H),2.30(m,1H),1.08(d,3H),1.02(d,3H)ppm

[0391] Example 3. (S)-4-Amino-1-carboxy-4-oxobutan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-003)

[0392]

[0393] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.200 g, 0.597 mmol, 1 equivalent) and 15 mL of distilled deionized water were added and mixed to form a solution. A slight suspension is acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 5.67 mL of a 0.1 M L-glutamine solution in distilled deionized water to prevent the temperature from rising. Any suspension went into solution. Following this addition, the pH was approximately 2.3-2.5.

[0394] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0395] Yield: 285 mg (quantitative)

[0396] Melting point: 73.8°C (degraded, corrected), degassing at 131.2°C

[0397] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.42(s,1H),9.30(d,1H),9.03(d,1H),8.28(dd,1H),6.24(d,1H),4.65(m,1H ),4.58(t,1H),4.48(dd,1H),4.32(dq,1H),4.17(dq,1H),3.94(t,1H),2.50(m,2H),2.20(m,2H)ppm

[0398] Example 4. Bis((S)-1-carboxy-2-methylpropan-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-004)

[0399]

[0400] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.200g, 0.597mmol, 1 equivalent) and 15ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. A 0.1M L-valine (1.95 equivalent) solution in 11.6ml of distilled deionized water was then slowly added dropwise to this solution to prevent the temperature from rising. After this addition, the pH was approximately 2.8. The flask was then removed and the colorless solution was frozen using liquid nitrogen. After the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0401] Yield: 303.1 mg (89% yield)

[0402] Melting point: 149.3°C (degraded, corrected), degassing at 150°C

[0403] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.39(s,1H),9.28(d,1H),9.00(d,1H),8.28(dd,1H),6.24(d,1H),4.65(m,1H),4.5 8(t,1H),4.47(dd,1H),4.32(dq,1H),4.18(dq,1H),3.73(d,2H),2.33(m,2H),1.07(d,6H),1.04(d,6H)ppm

[0404] Example 5. Bis((S)-4-amino-1-carboxy-4-oxobutan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-005)

[0405]

[0406] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.200 g, 0.597 mmol, 1 eq) and 15 mL of distilled deionized water were added and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 11.6 mL of a 0.1 M L-glutamine solution in distilled deionized water (1.95 eq) to prevent the temperature from rising and any suspension from going into solution. Following this addition, the pH was approximately 2.8.

[0407] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0408] Yield: 374.4 mg (quantitative)

[0409] Melting point: 93.5°C (degradation, corrected), outgassing at 128°C, significant at 147°C

[0410] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.39(s,1H),9.28(d,1H),9.02(d,1H),8.26(dd,1H),6.24(d,1H),4.65(m,1H ),4.57(t,1H),4.48(dd,1H),4.33(dq,1H),4.18(dq,1H),3.90(t,2H),2.50(m,4H),2.20(m,4H)ppm

[0411] Example 6. (S)-1-Carboxy-2-(1H-imidazol-4-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-006)

[0412]

[0413] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 equivalent) and 15 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.83 mL of a 0.1 M L-histidine solution in distilled deionized water (0.95 equivalents) to prevent the temperature from rising and any suspension from going into solution. After this addition, the pH was approximately 4.9.

[0414] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0415] Yield: 138.4 mg (94% yield)

[0416] Melting point: 120.6°C (degraded, corrected), degassing at 131°C

[0417] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.34(s,1H),9.25(d,1H),8.97(d,1H),8.67(s,1H),8.23(dd,1H),7.41(s,1H),6.2 4(d,1H),4.65(m,1H),4.57(t,1H),4.48(dd,1H),4.33(dq,1H),4.18(dq,1H),4.05(t,1H),3.36(d,2H)ppm

[0418] Example 7. (S)-1-Carboxy-2-(1H-imidazol-4-yl)ethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methylphosphate (I-007)

[0419]

[0420] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were added and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.93 mL of a 0.1 M L-histidine solution in distilled deionized water (0.98 eq) to prevent the temperature from rising. All the suspension went into solution. Following this addition, the pH was approximately 6-6.2.

[0421] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0422] Yield: 153.5 mg (quantitative)

[0423] Melting point: 94.5°C (degraded, corrected), degassing at 124.3°C

[0424] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.56(s,1H),9.33(d,1H),9.01(d,1H),8.33(dd,1H),8.25(s,1H),7.24(s,1H),6 .23(d,1H),4.65(m,2H),4.50(dd,1H),4.28(dd,1H),4.13(dq,1H),4.03(dd,2H),3.20-3.40(m,2H)ppm

[0425] Example 8. Bis((S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-008)

[0426]

[0427] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 15 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 5.81 mL of a 0.1 M L-histidine solution in distilled deionized water (1.95 eq) to prevent the temperature from rising. Any suspension went into solution. Following this addition, the pH was approximately 6-6.2.

[0428] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0429] Yield: 192.7 mg (quantitative)

[0430] Melting point: 111.6°C (degraded, corrected), degassing at 130.3°C

[0431] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.32(s+d,2H),8.96(d,1H),8.32(s,2H),8.24(dd,1H),7.26(s,2H),6.22(d,1H) ,4.63(m,1H),4.58(t,1H),4.47(dd,1H),4.28(dq,1H),4.15(dq,1H),4.03(t,2H),3.45-3.22(m,4H)ppm

[0432] Example 9. (S)-1-Carboxy-4-guanidinobutane-1-ammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-009)

[0433]

[0434] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 15 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.92 mL of a 0.1 M L-arginine solution in distilled deionized water (0.98 eq) to prevent the temperature from rising. Any suspension went into solution. Following this addition, the pH was approximately 4.6-4.9.

[0435] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0436] Yield: 158.3 mg (quantitative yield)

[0437] Melting point: 75°C (degradation, corrected), color change at 111°C, degassing at 131°C

[0438] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.35(s,1H),9.27(d,1H),8.98(d,1H),8.25(dd,1H),6.24(d,1H),4.65(m,1H),4.53(t,1 H),4.46(dd,1H),4.30(dq,1H),4.17(dq,1H),3.80(t,1H),3.26(t,2H),1.96-1.90(m,2H),1.83-1.60(m,2H)ppm

[0439] Example 10. (S)-1,3-Dicarboxypropyl-1-ammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-010)

[0440]

[0441] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 5ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being also acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. 2.92ml of 0.1M L-glutamic acid solution (0.95 equivalent) was then slowly added dropwise to this solution to prevent the temperature from rising while all suspensions entered the solution. After this addition, the pH was approximately 2.8. The flask was then removed and the colorless solution was frozen using liquid nitrogen. After the flask was frozen, it was connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to pale yellow solid.

[0442] Yield: 128.7 mg (90% yield)

[0443] Melting point: 111°C (degraded, corrected), degassing at 117°C

[0444] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.425(s,1H),9.30(d,1H),9.04(d,1H),8.27(dd,1H),6.24(d,1H),4.65(m,1 H),4.58(t,1H),4.47(dd,1H),4.32(dq,1H),4.18(dq,1H),3.95(m,1H),2.62(m,2H),2.22(m,2H)ppm

[0445] Example 11. (S)-1-Carboxy-2-(1H-indol-3-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-011)

[0446]

[0447] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 5ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being also acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. 2.92ml of a 0.1M L-tryptophan solution (0.95 equivalent) was then slowly added dropwise to this solution to prevent the temperature from rising while all suspensions entered the solution. After this addition, the pH was approximately 2.3. The flask was then removed and the colorless solution was frozen using liquid nitrogen. After the flask was frozen, it was connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to pale yellow solid.

[0448] Yield: 160.9 mg (quantitative yield)

[0449] Melting point: about 90 ° C (degradation, corrected), degassing at 144.5 ° C

[0450] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.38(s,1H),9.28(d,1H),9.01(d,1H),8.25(dd,1H),7.74(d,1H),7.55(d,1H),7.34(s,1H),7.30(t,1H ),7.21(t,1H),6.24(d,1H),4.65(m,1H),4.56(t,1H),4.47(dd,1H),4.32(dq,1H),4.20(m,2H),3.54(dd,1H),3.39(dd,1H)ppm

[0451] Example 12. (S)-1-Carboxy-4-guanidinobutane-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-012)

[0452]

[0453] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.93 mL of a 0.1 M L-arginine solution in distilled deionized water (0.98 eq) to prevent the temperature from rising and any suspension from going into solution. Following this addition, the pH was approximately 6.8-7.0.

[0454] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to yellow solid.

[0455] Yield: 155.2 mg (99% yield (quantitative))

[0456] Melting point: 72℃-89℃ (degradation, corrected), degassing at 111℃

[0457] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.61(s,1H),9.35(d,1H),9.02(d,1H),8.33(dd,1H),6.22(d,1H),4.70(t,1H),4.65(m,2H ),4.50(dd,1H),4.22(dq,1H),4.03(dq,1H),3.78(t,1H),3.26(t,2H),1.96-1.830(m,4H),1.80-1.60(m,4H)ppm

[0458] Example 13. (S)-1,3-Dicarboxypropyl-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-013)

[0459]

[0460] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 5.86 mL of 0.05 M L-glutamic acid in distilled deionized water (0.98 eq) to prevent the temperature from rising. All the suspension went into solution. Following this addition, the pH was approximately 2.8-3.3.

[0461] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to yellow solid.

[0462] Yield: 140.1 mg (97%)

[0463] Melting point: about 79℃-109℃ (degradation, corrected), degassing at 122℃

[0464] Analyze the data.1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.32(d,1H),9.02(d,1H),8.33(dd,1H),6.24(d,1H),4.65(m,1H ),4.60(t,2H),4.48(dd,1H),4.32(dq,1H),4.18(dq,1H),3.82(t,1H),2.58(m,2H),2.18(m,2H)ppm

[0465] Example 14. (S)-1-Carboxy-2-(1H-indol-3-yl)ethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methylphosphate (I-014)

[0466]

[0467] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 5.86 mL of 0.05 M L-tryptophan in distilled deionized water (0.98 eq) to prevent the temperature from rising. All the suspension went into solution. Following this addition, the pH was approximately 3.3-3.9.

[0468] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to yellow solid.

[0469] Yield: 168.6 mg (quantitative)

[0470] Melting point: about 80 ° C (degradation, corrected), degassing at 137.2 ° C

[0471] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.48(s,1H),9.30(d,1H),9.01(d,1H),8.30(dd,1H),7.75(d,1H),7.55(d,1H),7.34(s,1H),7.30(t,1H),7.21( t,1H),6.24(d,1H),4.65(m,1H),4.57(t,1H),4.47(dd,1H),4.33(dq,1H),4.18(dq,1H),4.08(dd,1H),3.50(dd,1H),3.32(dd,1H)ppm

[0472] Example 15. Bis((S)-1-carboxy-4-guanidinobutane-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-015)

[0473]

[0474] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 5 mL of distilled deionized water were added and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 5.85 mL of a 0.1 M L-arginine solution in distilled deionized water (1.95 eq) to prevent the temperature from rising. All the suspension went into solution. After this addition, the pH was approximately 7-7.2.

[0475] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0476] Yield: 211.5 mg (quantitative)

[0477] Melting point: 78℃-103℃ (degradation, corrected), degassing at 123℃

[0478] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.50(d,1H),9.25(s,1H),8.95(d,1H),8.28(dd,1H),6.22(d,1H),4.63(t,1H),4.60(m,1H ),4.48(dd,1H),4.20(dq,1H),4.08(dq,1H),3.75(t,2H),3.25(t,4H),1.96-1.830(m,4H),1.80-1.60(m,4H)ppm

[0479] Example 16. Bis((S)-1,3-dicarboxypropyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridinium-1-ium-3-carboxylate (I-016)

[0480]

[0481] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 5 ml of distilled deionized water were injected and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 11.62 ml of 0.05 M L-glutamic acid in distilled deionized water (1.95 eq) to prevent the temperature from rising. All the suspension went into solution. After this addition, the pH was approximately 2.3-2.8.

[0482] The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This slowly removed the water. Once dry, the product appeared as a colorless solid.

[0483] Yield: 182.7 mg (97%)

[0484] Melting point: 82℃-111.5℃ (degradation, corrected), degassing at 138.9℃

[0485] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.41(d,1H),9.29(s,1H),9.01(d,1H),8.28(dd,1H),6.23(d,1H),4.68(m,1 H),4.57(t,1H),4.46(m,1H),4.33(dq,1H),4.18(dq,1H),3.92(t,2H),2.62(m,4H),2.21(m,4H)ppm

[0486] Example 17. Bis((S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-017)

[0487]

[0488] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 5 ml of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 11.62 ml of 0.05 M L-tryptophan (1.95 eq) in distilled deionized water to prevent the temperature from rising and all the suspension from going into solution. After this addition, the pH was approximately 2.8.

[0489] The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This slowly removed the water. Once dry, the product appeared as a colorless solid.

[0490] Yield: 225.4 mg (quantitative)

[0491] Melting point: about 80 ° C (degradation, corrected), degassing at 145.9 ° C

[0492] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.36(s,1H),9.28(d,1H),8.98(d,1H),8.25(dd,1H),7.74(d,2H),7.55(d,2H),7.34(2,1H),7.30(t,1H ),7.21(t,2H),6.24(d,1H),4.65(m,1H),4.56(t,1H),4.47(dd,1H),4.32(dq,1H),4.20(m,3H),3.53(dd,2H),3.39(dd,2H)ppm

[0493] Example 18. (1S,2R)-1-carboxy-2-hydroxypropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-018)

[0494]

[0495] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 10 mL of distilled deionized water were charged and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.92 mL of a 0.1 M L-threonine solution in distilled deionized water (0.98 eq) to prevent the temperature from rising and any suspension from going into solution. Following this addition, the pH was approximately 2.3.

[0496] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0497] Yield: 147.6 mg (quantitative yield)

[0498] Melting point: 71°C (degradation, corrected), color changes at 100°C, degassing at 111°C

[0499] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.45(s,1H),9.30(d,1H),9.04(d,1H),8.28(dd,1H),6.24(d,1H),4.65( m,1H),4.58(t,1H),4.46(dd,1H),4.40-4.30(m,2H),4.20(dq,1H),3.31(d,1H),1.36(d,3H)ppm

[0500] Example 19. (1S,2R)-1-carboxy-2-hydroxypropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-019)

[0501]

[0502] In a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were added and mixed to form a solution. A slight suspension was also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution, 2.93 mL of a 0.1 mL solution of threonine (0.98 eq) in distilled deionized water was then slowly added dropwise to prevent the temperature from rising. Any suspension was dissolved. After this addition, the pH was approximately 3.9-4.4.

[0503] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to yellow solid.

[0504] Yield: 137.7 mg (quantitative)

[0505] Melting point: 82°C (degradation, corrected), color change at 94°C, degassing at 107°C

[0506] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.50 (s, 1H), 9.32 (d, 1H), 9.02 (d, 1H), 8.33 (dd, 1H), 6.25 (d, 1H), 4.68 (m, 2H ),4.60(t,1H),4.48(dd,1H),4.33(dq,1H),4.30(m,1H),4.18(dq,1H),3.62(d,1H),1.32(d,3H)ppm

[0507] Example 20. Bis((1S,2R)-1-carboxy-2-hydroxypropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-020)

[0508]

[0509] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. 5.85ml of a 0.1M L-threonine solution (1.98 equivalents) in distilled deionized water was then slowly added dropwise to this solution to prevent the temperature from rising while all the suspension entered the solution. After this addition, the pH was approximately 2.3. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0510] Yield: 172.0 mg (quantitative)

[0511] Melting point: 79°C (degradation, corrected), color change at 111°C, degassing at 124°C

[0512] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),9.02(d,1H),8.28(dd,1H),6.24(d,1H),4.65( m,1H),4.58(t,1H),4.46(dd,1H),4.40-4.30(m,3H),4.20(dq,1H),3.31(d,2H),1.36(d,6H)ppm

[0513] Example 21. (S)-2-Carboxypyrrolidin-1-ium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-021)

[0514]

[0515] In a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100 g, 0.298 mmol, 1 eq) and 10 mL of distilled deionized water were added and mixed to form a solution. A slight suspension is acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. 2.92 mL of a 0.1 M L-proline solution in distilled deionized water (0.98 eq) was then slowly added dropwise to this solution to prevent the temperature from rising. Any suspension was dissolved. Following this addition, the pH was approximately 2.3-2.8.

[0516] The flask is then removed and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0517] Yield: 116.9 mg (87%)

[0518] Melting point: 78°C (degradation, corrected), color change at 102°C, degassing at 104°C

[0519] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.45(s,1H),9.32(d,1H),9.05(d,1H),8.30(dd,1H),6.24(d,1H),4.65(m,1H),4.58(t,1H), 4.46(dd,1H),4.32(dq,1H),4.25(dd,1H),4.18(dq,1H),3.50-3.35(m,2H),2.85-2.95(m,1H),2.0-2.20(m,3H)ppm

[0520] Example 22. (S)-2-Carboxypyrrolidin-1-ium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-022)

[0521]

[0522] Into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer, NMN (0.100 g, 0.299 mmol, 1 eq) and 5 mL of distilled deionized water were injected and mixed to form a solution. A slight suspension is also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise 2.93 mL of a 0.1 mL solution of proline (0.98 eq) in distilled deionized water to prevent the temperature from rising and all the suspension from going into solution. After this addition, the pH was approximately 3.3-3.9. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appeared as a colorless solid.

[0523] Yield: 143.4 mg (quantitative)

[0524] Melting point: 75°C (degraded, corrected), degassing at 99°C

[0525] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.50 (s, 1H), 9.32 (d, 1H), 9.02 (d, 1H), 8.33 (dd, 1H), 6.25 (d, 1H), 4.65 (m, 1H), 4.60 (t, 1H),4.48(dd,1H),4.32(dq,1H),4.20-4.10(m,2H),3.50-3.30(m,2H),2.43-2.33(m,1H),2.15-2.0(m,3H)ppm

[0526] Example 23. Bis((S)-2-carboxypyrrolidin-1-ium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-023)

[0527]

[0528] Into a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution. A weak suspension is also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution, 5.85ml of a 0.1M L-proline solution in distilled deionized water (1.98 equivalents) was then slowly added dropwise to prevent the temperature from rising and all the suspension from entering the solution. After this addition, the pH was approximately 2.3. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid.

[0529] Yield: 142.6 mg (quantitative)

[0530] Melting point: 76°C (degradation, corrected), color change at 94°C, degassing at 105°C

[0531] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.42(s,1H),9.30(d,1H),9.03(d,1H),8.28(dd,1H),6.24(d,1H),4.65(m,1H),4.58(t,1H), 4.46(dd,1H),4.32(dq,1H),4.22(dd,2H),4.20(dq,1H),3.50-3.35(m,4H),2.85-2.95(m,2H),2.0-2.20(m,6H)ppm

[0532] Example 24. (S)-5-Amino-5-carboxypentan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-024)

[0533]

[0534] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being also acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. 2.92ml of 0.1M L-lysine solution (0.98 equivalent) was then slowly added dropwise to this solution to prevent the temperature from rising while all suspensions entered the solution. After this addition, the pH was approximately 3.3. The flask was then removed and the colorless solution was frozen using liquid nitrogen. After the flask was frozen, it was connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to pale yellow solid.

[0535] Yield: 136 mg (95%)

[0536] Melting point: 89°C (degraded, corrected), changes color at 100°C, degassing at 115°C

[0537] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.35 (s, 1H), 9.25 (d, 1H), 8.96 (d, 1H), 8.26 (dd, 1H), 6.24 (d, 1H), 4.65 (m, 1H), 4.58 (t, 1H), 4.46(dd,1H),4.32(dq,1H),4.18(dq,1H),3.78(t,1H),3.02(t,2H),1.92(m,2H),1.70-1.80(p,2H),1.50(m,2H)ppm

[0538] Example 25. (S)-5-Amino-5-carboxypentan-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-025)

[0539]

[0540] NMN (0.100 g, 0.299 mmol, 1 equivalent) and 5 ml of distilled deionized water were injected into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer and mixed to form a solution. A weak suspension is also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution, 0.1 ml of a lysine solution (0.98 equivalent) in 2.93 ml of distilled deionized water was then slowly added dropwise to prevent the temperature from rising and all the suspension from entering the solution. After this addition, the pH was approximately 6-6.2. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appeared as a colorless solid.

[0541] Yield: 143 mg (quantitative)

[0542] Melting point: 102℃-111℃ (degradation, corrected), degassing at 111℃

[0543] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.60(s,1H),9.35(d,1H),9.02(d,1H),8.33(dd,1H),6.24(d ,1H),4.55(m,1H),4.25(dq,1H),4.08(dq,1H),3.77(t,1H),3.03(t,2H),1.95(app q,2H),1.70-1.80(p,2H),1.50(m,2H)ppm

[0544] Example 26. Bis((S)-5-amino-5-carboxypentan-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-026)

[0545]

[0546] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution, a weak suspension being also acceptable. This solution was cooled using an ice / water bath so that the internal temperature was below 10°C. 5.85ml of a 0.1M L-lysine solution (1.98 equivalents) was then slowly added dropwise to this solution to prevent the temperature from rising while all suspensions entered the solution. After this addition, the pH was approximately 6.4-6.7. The flask was then removed and the colorless solution was frozen using liquid nitrogen. After the flask was frozen, it was connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to pale yellow solid.

[0547] Yield: 185.3 mg (99%)

[0548] Melting point: 74°C, decolorizes at 92°C (degraded, corrected), degasses at 118°C

[0549] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.45(d,1H),9.28(s,1H),8.96(d,1H),8.28(dd,1H),6.22(d,1H),4.60(m,1H),4.48(d d,1H),4.22(dq,1H),4.10(dq,1H),3.78(t,2H),3.02(t,4H),1.92(m,4H),1.70-1.80(p,4H),1.50(m,4H)ppm

[0550] Example 27. (S)-1-Carboxy-3-(methylthio)propan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-027)

[0551]

[0552] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution, although a weak suspension is acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. A 0.1M L-methionine solution (0.98 equivalent) in 2.92ml of distilled deionized water was then slowly added dropwise to this solution to prevent the temperature from rising while the entire suspension entered the solution. After this addition, the pH was approximately 2.8. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0553] Yield: 143 mg (99% quantitative yield)

[0554] Melting point: 126℃-130℃ (degradation, corrected)

[0555] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.42 (s, 1H), 9.30 (d, 1H), 9.04 (d, 1H), 8.28 (dd, 1H), 6.24 (d, 1H), 4.65 (m, 1H), 4.5 8(t,1H),4.48(dd,1H),4.32(dq,1H),4.19(dq,1H),4.03(t,1H),2.69(t,2H),2.10-2.35(s+m,3H+2H)ppm

[0556] Example 28. (S)-1-Carboxy-3-(methylthio)propan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-028)

[0557]

[0558] NMN (0.100 g, 0.299 mmol, 1 eq) and 5 ml of distilled deionized water were injected into a 50 mL 3N RBF equipped with a water condenser and an internal thermometer and mixed to form a solution. A weak suspension is also acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution was then slowly added dropwise a 0.1 ml solution of methionine (0.98 eq) in 2.93 ml of distilled deionized water to prevent the temperature from rising and all the suspension from entering the solution. After this addition, the pH was approximately 4.4-4.6. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appeared as a colorless solid (hygroscopic).

[0559] Yield: 134.5 mg (89%)

[0560] Melting point: 137°C-148°C (degradation, corrected)

[0561] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.49(s,1H),9.31(d,1H),9.00(d,1H),8.33(dd,1H),6.25(d,1H),4.68(p,1H),4.6 0(t,1H),4.48(dd,1H),4.33(dq,1H),4.18(dq,1H),3.88(t,1H),2.66(t,2H),2.28-2.10(m+s,1H+3H)ppm

[0562] Example 29. Bis((S)-1-carboxy-3-(methylthio)propan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-029)

[0563]

[0564] In a 50mL 3N RBF equipped with a water condenser and an internal thermometer, NaMN (0.100g, 0.298mmol, 1 equivalent) and 10ml of distilled deionized water were injected and mixed to form a solution, although a weak suspension is acceptable. This solution was cooled using an ice / water bath to keep the internal temperature below 10°C. To this solution, 5.85ml of a 0.1M L-methionine solution (1.98 equivalents) in distilled deionized water was then slowly added dropwise to prevent the temperature from rising while the entire suspension entered the solution. After this addition, the pH was approximately 2.8-3.3. The flask was then removed and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to pale yellow solid.

[0565] Yield: 280 mg (75%)

[0566] Melting point: 125°C (degradation, corrected)

[0567] Analyze the data. 1 H-NMR (400MHz, D2O) δ = 9.40 (s, 1H), 9.28 (d, 1H), 9.02 (d, 1H), 8.28 (dd, 1H), 6.24 (d, 1H), 4.65 (m, 1H), 4.5 8(t,1H),4.48(dd,1H),4.32(dq,1H),4.19(dq,1H),3.99(t,2H),2.68(t,4H),2.10-2.35(s+m,6H+4H)ppm

[0568] Example 30. Carboxymethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-030)

[0569]

[0570] NMN (0.5 g, 1.492 mmol, 1.0 equivalent) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.22). 14.92 ml of a 0.1 M glycine solution was then slowly added dropwise to this solution via a pipette to prevent the temperature from rising. After this addition, the pH was 3.9. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0571] Yield: 516.2 mg (85%)

[0572] Melting point: 110°C (degradation), degassing at 117°C.

[0573] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),3.55(d,2H)ppm

[0574] Example 31. Carboxymethylammonium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxyphosphoryl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-031)

[0575]

[0576] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=1.89 of the solution). 14.92ml of 0.1M glycine solution is then slowly added dropwise via a syringe to this solution to prevent the temperature from rising. After this addition, the pH is 2.26. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0577] Yield: 487.9 mg (80%)

[0578] Melting point: 86℃-92℃ (degradation), degassing at 117℃;

[0579] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),3.65(d,2H)ppm.

[0580] Example 32. Bis(carboxymethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-032)

[0581]

[0582] Into 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water, and mix to form solution under nitrogen. This solution is cooled using an ice / water bath (pH of the solution = 1.89). Then, through a pipette, 29.54ml of 0.1M glycine solution is slowly added dropwise to this solution to prevent the temperature from rising. After this addition, the pH is 2.5. The mixture is transferred to a 250mL RBF, and the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0583] Yield: 544.9 mg (75%)

[0584] Melting point: degassing at 118℃.

[0585] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),3.65(d,4H)ppm

[0586] Example 33. (S)-1-Carboxyethyl-1-ammonium ((2R,3S,4R,5R)-5-(3-carboxypyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-033)

[0587]

[0588] NMN (0.5 g, 1.492 mmol, 1.0 equivalent) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.22). 14.92 ml of 0.1 M L-alanine solution was then slowly added dropwise to this solution via a pipette to prevent the temperature from rising. After this addition, the pH was 3.8. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0589] Yield: 501.7 mg (79%)

[0590] Melting point: 116°C (degradation), degassing at 128°C.

[0591] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),1.50(d,3H)ppm.

[0592] Example 34. (S)-1-Carboxyethyl-1-ammonium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxyphosphoryl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-034)

[0593]

[0594] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.22). 14.96ml of 0.1M L-alanine solution is then slowly added dropwise via a pipette to this solution to prevent the temperature from rising. After this addition, the pH is 2.31. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0595] Yield: 471.9 mg (80%)

[0596] Melting point: 82°C (degradation), degassing at 116°C.

[0597] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(q,1H),1.50(d,3H)ppm.

[0598] Example 35. Bis((S)-1-carboxyethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-035)

[0599]

[0600] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=1.88 of the solution). 29.54ml of 0.1M L-alanine solution is then slowly added dropwise via a pipette to this solution to prevent the temperature from rising. After this addition, the pH is 2.5. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0601] Yield: 625.9 mg (82%)

[0602] Melting point: degassing at 122℃.

[0603] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),3.90(q,2H),1.50(d,6H)ppm

[0604] Example 36. (S)-1-Carboxy-2-hydroxyeth-1-ammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-036)

[0605]

[0606] NMN (0.5 g, 1.492 mmol, 1.0 equivalent) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.22). 14.92 ml of 0.1 M L-serine solution was then slowly added dropwise to this solution via a syringe to prevent the temperature from rising. After this addition, the pH was 3.8. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0607] Yield: 546.8 mg (83%)

[0608] Melting point: 71°C (degraded), degassing at 101°C. Analytical data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),3.9(m,2H),4.8(t,1H)ppm.

[0609] Example 37. (S)-1-Carboxy-2-hydroxyeth-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-037)

[0610]

[0611] NaMN (0.5 g, 1.496 mmol, 1.0 equiv) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 1.89). 14.96 ml of 0.1 M L-serine solution was then slowly added dropwise to this solution via pipette to prevent the temperature from rising. After this addition, the pH was 2.24.

[0612] The mixture is transferred to a 250 mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0613] Yield: 530.2 mg (81%)

[0614] Melting point: 67°C (degradation), degassing at 106°C.

[0615] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(m,2H),3.65(t,1H)ppm.

[0616] Example 38. Bis((S)-1-carboxy-2-hydroxyeth-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-038)

[0617]

[0618] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 1.88). 29.54ml of 0.1M L-serine solution is then slowly added dropwise via a pipette to this solution to prevent the temperature from rising. After this addition, the pH is 2.8. The mixture is transferred to a 100mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0619] Yield: 572.1 mg (70%)

[0620] Melting point: 66℃-92℃, degassing at 115℃.

[0621] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),3.95(m,6H)ppm

[0622] Example 39. (S)-1-Carboxy-2-phenyleth-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-039)

[0623]

[0624] NMN (0.5 g, 1.492 mmol, 1.0 equiv) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.43). 14.92 ml of 0.1 M L-phenylalanine solution was then slowly added dropwise to this solution via a pipette to prevent the temperature from rising. After this addition, the pH was 4.0. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0625] Yield: 702.8 mg (96%)

[0626] Melting point: 135°C (degradation), degassing at 139°C.

[0627] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),7.35(m,5H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),3.9(t,1H),3.2(dq,2H)ppm.

[0628] Example 40. (S)-1-Carboxy-2-phenyleth-1-aminium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphino)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-040)

[0629]

[0630] Into a 100mL 3N RBF, NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml of distilled deionized water were injected and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 1.84). 14.96ml of a 0.1M L-phenylalanine solution was then slowly added dropwise via a pipette to this solution to prevent the temperature from rising. After this addition, the pH was 2.13. The mixture was transferred to a 250mL RBF, the flask was then removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0631] Yield: 627.2 mg (86%)

[0632] Melting point: 123°C (degradation), degassing at 136°C.

[0633] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),7.35(m,5H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(t,1H),3.2(dq,2H)ppm.

[0634] Example 41. Bis((S)-1-carboxy-2-phenyleth-1-aminium)-((2R,3R,4S,5R)-5-(3-carboxypyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-041)

[0635]

[0636] Into a 100mL 3N RBF, NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml of distilled deionized water were injected and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 1.84). 29.54ml of a 0.1M L-phenylalanine solution was then slowly added dropwise to this solution via a pipette to prevent the temperature from rising. After this addition, the pH was 2.1. The mixture was transferred to a 250mL RBF, the flask was then removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0637] Yield: 979.1 mg (quantitative)

[0638] Melting point: 127°C (degradation), degassing at 138°C.

[0639] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),7.4(m,10H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),3.35(dq,4H)ppm

[0640] Example 42. (R)-1-Carboxy-2-mercaptoethyl-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-042)

[0641]

[0642] NMN (0.5 g, 1.492 mmol, 1.0 equiv) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.38). 14.92 ml of 0.1 M L-cysteine solution was then slowly added dropwise to this solution via pipette to prevent the temperature from rising. After this addition, the pH was 3.86.

[0643] The mixture is transferred to a 250 mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0644] Yield: 642.9 mg (95%)

[0645] Melting point: degassing at 129℃.

[0646] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),3.9(t,1H),3.1(dq,2H)ppm.

[0647] Example 43. (R)-1-Carboxy-2-mercaptoethyl-1-ammonium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphino)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-043)

[0648]

[0649] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml of distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.03). 14.96ml of 0.1M L-cysteine solution is then slowly added dropwise via a syringe to this solution to prevent the temperature from rising. After this addition, the pH is 2.33. The mixture is transferred to a 100mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove the water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0650] Yield: 581.1 mg (85%)

[0651] Melting point: 77°C (degraded, corrected), 126°C (degassed)

[0652] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(t,1H),3.2(dq,2H)ppm.

[0653] Example 44. Bis((R)-1-carboxy-2-mercaptoethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-044)

[0654]

[0655] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=2.0 of the solution). 29.54ml of 0.1M L-cysteine solution is then slowly added dropwise via a pipette to prevent the temperature from rising. After this addition, the pH is 2.43. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0656] Output: Quantitative

[0657] Melting point: 63°C (degraded), degassed at 137°C. Analytical data: 1H-NMR (400 MHz, D2O) δ = 9.40 (s, 1H), 9.30 (d, 1H), 8.97 (d, 1H), 8.25 (app t, 1H), 6.22 (d, 1H), 4.62 (p, 1H), 4.56 (t, 1H), 4.44 (m, 1H), 4.27 (dq, 1H), 4.15 (dq, 1H), 4.05 (t, 2H), 3.05 (dq, 4H) ppm.

[0658] Example 45. (S)-3-Amino-1-carboxy-3-oxopropan-1-aminium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-045)

[0659]

[0660] NMN (0.5 g, 1.492 mmol, 1.0 equivalent) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.38). 14.92 ml of a 0.1 M L-asparagine solution was then slowly added dropwise to this solution via a syringe to prevent the temperature from rising. After this addition, the pH was 3.86. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0661] Yield: 642.9 mg (95%)

[0662] Melting point: 68°C, degassing at 114°C.

[0663] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.30(d,1H),8.93(d,1H),8.30(app t,1H),6.21(d,1H),4.65(p,1H),4.57(t,1H),4.46(m,1H),4.32(dq,1H),4.15(dq,1H),3.9(q,1H),2.9(dq,2H)ppm.

[0664] Example 46. (S)-3-Amino-1-carboxy-3-oxopropan-1-aminium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphinoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-046)

[0665]

[0666] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=2.0 of the solution). 14.96ml of 0.1M L-asparagine solution is then slowly added dropwise via a pipette to this solution to prevent the temperature from rising. After this addition, the pH is 2.33. The mixture is transferred to a 100mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0667] Yield: 741.6 mg (quantitative)

[0668] Melting point: 110°C (degradation), degassing at 135°C.

[0669] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.10(dq,1H),4.05(q,1H),2.95(dq,2H)ppm.

[0670] Example 47. Bis((S)-3-amino-1-carboxy-3-oxopropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-047)

[0671]

[0672] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=2.0 of the solution). 29.54ml of 0.1M asparagine solution is then slowly added dropwise via a syringe to this solution to prevent the temperature from rising. After this addition, the pH is 2.6. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0673] Yield: 695.1 mg (76%)

[0674] Melting point: 71°C (degradation), degassing at 122°C.

[0675] Analyze the data: 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.10(dq,1H),4.05(q,2H),2.9(dq,4H)ppm.

[0676] Example 48. (S)-1,2-Dicarboxyethyl-1-ammonium-((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-048)

[0677]

[0678] NMN (0.5 g, 1.492 mmol, 1.0 equivalent) and 25 ml of distilled deionized water were injected into a 100 mL 3N RBF and mixed under nitrogen to form a solution. This solution was cooled using an ice / water bath (pH of the solution = 3.39). 14.92 ml of a 0.1 M aspartic acid solution was then slowly added dropwise to this solution via a syringe to prevent the temperature from rising. After this addition, the pH was 2.99. The mixture was transferred to a 250 mL RBF, the flask was removed, and the colorless solution was frozen using liquid nitrogen. Once the flask was frozen, it was connected to a freeze dryer. This will slowly remove the water. Once dried, the product appears as a colorless to pale yellow solid (hygroscopic).

[0679] Output: Quantitative

[0680] Melting point: 72°C (degradation), degassing at 128°C.

[0681] Analytical data. 1H-NMR (400 MHz, D2O) δ = 9.40 (s, 1H), 9.30 (d, 1H), 8.97 (d, 1H), 8.25 (app t, 1H), 6.22 (d, 1H), 4.62 (p, 1H), 4.56 (t, 1H), 4.44 (m, 1H), 4.27 (dq, 1H), 4.15 (dq, 1H), 4.05 (q, 1H), 3.0 (dq, 2H) ppm.

[0682] Example 49. (S)-1,2-Dicarboxyethyl-1-ammonium-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((hydroxyoxophosphino)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-049)

[0683]

[0684] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml of distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.06). 14.96ml of 0.1M L-aspartic acid solution is then slowly added dropwise via a syringe to this solution to prevent the temperature from rising. After this addition, the pH is 2.31. The mixture is transferred to a 100mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0685] Output: Quantitative

[0686] Melting point: 103°C (degradation), degassing at 125°C.

[0687] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(q,1H),3.0(dq,2H)ppm.

[0688] Example 50. Bis((S)-1,2-dicarboxyethyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-050)

[0689]

[0690] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 25ml of distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.06). 29.54ml of 0.1M L-aspartic acid solution is then slowly added dropwise via a syringe to this solution to prevent the temperature from rising. After this addition, the pH is 2.41. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. Once the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0691] Output: Quantitative

[0692] Melting point: 79°C (degradation), degassing at 144°C.

[0693] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.40(s,1H),9.30(d,1H),8.97(d,1H),8.25(app t,1H),6.22(d,1H),4.62(p,1H),4.56(t,1H),4.44(m,1H),4.27(dq,1H),4.15(dq,1H),4.05(q,2H),3.0(dq,4H)ppm.

[0694] Example 51. Sodium (S)-1-carboxy-2-(1H-indol-3-yl)ethan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-051)

[0695]

[0696] In 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water, and mix to form solution under nitrogen.This solution is cooled using an ice / water bath (pH of the solution=2.24).Then, by pipette, slowly dropwise add 14.17ml of 0.1M aqueous sodium hydroxide solution and 28.4ml of 0.05M aqueous L-tryptophan solution to this solution to prevent temperature increase. After this addition, the pH is 4.51.The mixture is transferred to a 250mL RBF, and the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0697] Yield: 830 mg (98%)

[0698] Analyze the data. 1H-NMR(400MHz,D2O)δ=9.22(s,1H),9.16(d,1H),8.86(d,1H),8.14(dd,1H),7.68(d,1H),7.46(d,1H),7.30-7.20(app t,s,2H),7.13(app t,1H),6.13(d,1H),4.58(p,1H),4.49(t,1H),4.41(dd,1H),4.27(dq,1H),4.12(dq,1H),4.01(dd,1H),3.43(dd,1H),3.26(dd,1H)ppm.

[0699] Example 52. Sodium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-052)

[0700]

[0701] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=2.24 of the solution). 14.17ml of 0.1M aqueous sodium hydroxide solution and 14.17ml of 0.1M aqueous L-valine solution are then slowly added dropwise via a pipette to prevent the temperature from rising. After this addition, the pH is 4.53. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0702] Yield: 670 mg (94.8%)

[0703] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.28(s,1H),9.21(d,1H),8.91(app d,1H),8.19(app t,1H),6.18(d,1H),4.58(p,1H),4.52(t,1H),4.42(dd,1H),4.28(dq,1H ),4.13(dq,1H),3.58(d,1H),2.24(m,1H),1.01(d,3H),0.95(d,3H)ppm.

[0704] Example 53. Potassium (S)-1-carboxy-2-(1H-indol-3-yl)ethan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-053)

[0705]

[0706] In 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water, and mix to form solution under nitrogen.This solution is cooled using an ice / water bath (pH of the solution=2.24).Then, by pipette, slowly dropwise add 14.17ml of 0.1M aqueous potassium hydroxide solution and 28.34ml of 0.05M aqueous L-tryptophan solution to this solution to prevent temperature increase. After this addition, the pH is 3.32.The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0707] Yield: 810 mg (94.2%)

[0708] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.25(s,1H),9.16(d,1H),8.88(d,1H),8.15(dd,1H),7.68(d,1H),7.47(d,1H),7.30-7.20(app t,s,2H),7.14(app t,1H),6.14(d,1H),4.58(p,1H),4.48(t,1H),4.39(dd,1H),4.28(dq,1H),4.13(dq,1H),4.05(dd,1H),3.45(dd,1H),3.29(dd,1H)ppm.

[0709] Example 54. Potassium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I) (I-054)

[0710]

[0711] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH=2.24 of the solution). 14.17ml of 0.1M aqueous potassium hydroxide solution and 14.17ml of 0.1M aqueous L-valine solution are then slowly added dropwise via a pipette to prevent the temperature from rising. After this addition, the pH is 3.24. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0712] Yield: 690 mg (94.4%)

[0713] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.30(s,1H),9.21(d,1H),8.91(app d,1H),8.19(app t,1H),6.18(d,1H),4.59(p,1H),4.51(t,1H),4.41(dd,1H),4.28(dq,1H), 4.13(dq,1H),3.62(d,1H),2.30-2.20(m,1H),1.02(d,3H),0.96(d,3H)ppm.

[0714] Example 55. (S)-1-Carboxy-2-(1H-indol-3-yl)ethan-1-aminium (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-055)

[0715]

[0716] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.24). Then, through a pipette, 14.17ml of a 0.1M aqueous L-valine solution and 28.34ml of a 0.05M aqueous L-tryptophan solution are slowly added dropwise to prevent the temperature from rising. After this addition, the pH is 2.49. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0717] Output: Quantitative

[0718] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.32(s,1H),9.23(d,1H),8.95(d,1H),8.21(dd,1H),7.70(d,1H),7.51(d,1H),7.30-7.20(app s,t,2H),7.17(app t,1H),6.18(d,1H),4.61(p,1H),4.52(t,1H),4.42(dd,1H),4.28(dq,1H),4.18-4.10(m,2H),3.68(br m,1H),3.48(dd,1H),3.32(dd,1H)2.33-2.23(m,1H),1.3(d,3H),0.98(d,3H)ppm.

[0719] Example 56. 2-Hydroxyeth-1-aminium (S)-4-amino-1-carboxy-4-oxobutan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-056)

[0720]

[0721] Into a 100mL 3N RBF, inject NaMN (0.5g, 1.496mmol, 1.0 equivalent) and 15ml distilled deionized water and mix under nitrogen to form a solution. This solution is cooled using an ice / water bath (pH of the solution = 2.10). Then, by pipetting, 14.17ml of a 0.1M aqueous ethanolamine solution and 14.17ml of a 0.1M aqueous L-glutamine solution are slowly added dropwise to prevent the temperature from rising. After this addition, the pH is 5.06. The mixture is transferred to a 250mL RBF, the flask is then removed, and the colorless solution is frozen using liquid nitrogen. After the flask is frozen, it is connected to a freeze dryer. This will slowly remove water. Once dry, the product appears as a colorless to light yellow solid (hygroscopic).

[0722] Output: Quantitative

[0723] Analyze the data. 1 H-NMR(400MHz,D2O)δ=9.30(s,1H),9.22(d,1H),8.92(app d,1H),8.21(app t,1H),6.20(d,1H),4.60(p,1H),4.53(t,1H),4.43(dd,1H),4.28(dq,1H),4.13(dq, 1H),3.80(t,2H),6.76(t,1H),3.12(t,2H),2.50-2.30(m,2H),2.15-2.00(m,2H)ppm.

[0724] Example 57. NAD Cellular Assay

[0725] NAD levels were determined based on the NAD cycle method of Zhu and Rand, PLoS One (2012), which is incorporated herein by reference. COV434 cells were maintained in 6-well plates and treated with the indicated compounds at a concentration of 200uM for 4 hours. The culture medium was removed, the plates were washed in cold PBS, and the cells were scraped from NAD extraction buffer containing 10mM nicotinamide, 50mM Tris HCl, 0.1% Triton X-100. The cells were homogenized by ultrasonic treatment for 5 seconds, and the samples were centrifuged at 7,000g for 5 minutes at 4 degrees. Aliquots were taken for subsequent protein determination, and the samples were then passed through a 10kDa amicon filter at 14,000g for 30 minutes at 4 degrees to remove protein from the sample. Each sample was measured in technical triplicate, with 25 μL of sample added to 100 μL of ADH circulation mixture (0.2 mg / ml alcohol dehydrogenase, 2% ethanol, 100 mM Tris pH 8.5). The sample was circulated at room temperature for 10 minutes, followed by the addition of 50 μL of MTT / PMS solution (0.1 mM phenazine methylsulfate, 0.8 mM 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), 100 mM Tris-HCl pH 8.5). The plate was then incubated for 15 minutes, and absorbance was measured at 570 nM. NAD concentration was deduced from the standard curve and normalized to the protein concentration determined by BCA protein assay.

[0726] The results of the above assays are shown in Table 2 (below). Adjusted fold increases were obtained by direct comparison of the comparative salts with their parent counterparts on a mol / mol basis. In other words, salts of the present disclosure derived from the NMN parent molecule will only have their NAD activity levels measured against NMN based on the same amount (moles) of salt tested in cells. Similarly, those derived from NaMN will have their NAD cellular activity measured against NaMN. For example, the fold increase for compound I-002 is based on the NAD activity observed in a direct comparison of the same molar amount of I-002 tested in cells with the NMN parent. Similarly, the fold increase for I-003 is based on a direct comparison with NaMN.

[0727] Table 2

[0728]

[0729]

[0730] Equivalent solutions

[0731] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A salt selected from the group consisting of: (S)-1-carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-001); (S)-1-carboxy-2-methylpropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-002); (S)-4-amino-1-carboxy-4-oxobutan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-003); Bis((S)-1-carboxy-2-methylpropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-004); Bis((S)-4-amino-1-carboxy-4-oxobutan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-005); (S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-006); Bis((S)-1-carboxy-2-(1H-imidazol-4-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-008); (S)-1-carboxy-4-guanidinobutane-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-009); (S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-011); (S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-014); Bis((S)-1-carboxy-4-guanidinobutane-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-015); Bis((S)-1,3-dicarboxypropyl-1-ammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridinium-1-ium-3-carboxylate (I-016); Bis((S)-1-carboxy-2-(1H-indol-3-yl)ethylammonium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-017); Bis((1S,2R)-1-carboxy-2-hydroxypropan-1-aminium)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-020); (S)-2-Carboxypyrrolidin-1-ium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-022); (R)-5-amino-5-carboxypentan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-026); (S)-1-carboxy-3-(methylthio)propan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogenphosphono)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-027); (S)-1-carboxy-3-methylbutan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-058); (S)-1-carboxy-3-methylbutan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-059); (1S,2S)-1-carboxy-2-methylbutan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate (I-062); and (R)-1-Carboxy-2-methylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (I-065).

2. A pharmaceutical composition comprising the salt according to claim 1 and a pharmaceutically acceptable carrier.

3. Use of an effective amount of the salt of claim 1 for the preparation of a medicament for treating or preventing age-related infertility in a subject in need thereof.

4. Use of an effective amount of the salt of claim 1 in the preparation of a medicament for treating or preventing infertility in a subject in need thereof.

5. Use of an effective amount of the salt of claim 1 for the preparation of a medicament for use in a method for improving oocyte or blastocyst quality and maturation prior to implantation in a subject in need of treatment for age-related infertility. The use according to claim 5 , wherein the oocyte or blastocyst is cultured in an IVF medium containing the salt.

7. Use of the salt according to claim 1 in the manufacture of a medicament for treating age-related disorders.

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