Amino acid salts of nicotinic acid riboside as an anti-aging agent

Abstract

To provide a method for treating a disease. [Solution] The present invention is NAD + This relates to the amino acid salt of nicotinic acid riboside of formula I, and its composition, which is useful for treating disorders and diseases associated with the deficiency of: TIFF2026063054000038.tif2048(here, M 1 , R 1 , R 2 , and R 3 (This is as described in the present specification.) Surprisingly, the present invention produces remarkable effects, as described in detail and demonstrated concretely in the present specification. These effects could not have been easily predicted by those skilled in the art from the prior art.

Description

[Technical Field]

[0001] Related applications This application claims priority and benefits of U.S. Provisional Application No. 62 / 675,065, filed on 22 May 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] This invention relates to inorganic salts of nicotinic acid riboside and compositions thereof, which are useful for treating age-related disorders and diseases. [Background technology]

[0003] Aging is the result of a complex interplay of biological, physical, and biochemical processes that cause cellular and organ dysfunction, which manifests as various diseases and other outcomes. For example, a woman's fertility is significantly affected by aging. The USA Centers for Disease Control and Prevention (CDC) reports that the rate of pregnancies and births associated with assisted reproductive technology (ART) gradually decreased among women in their mid-30s and beyond, from approximately 25% of ART cycles resulting in singleton births to 14% by age 40. 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, and the CDC reports that women over 44 have a very low chance of success. The rates of live births and singleton live births decreased to about 1% in this group. A woman's age is generally considered the most important factor influencing the chances of live birth when her own eggs (oocytes) are used.

[0004] It is understood that the qualitative deterioration of oocytes due to aging is a fundamental factor in the decline of fertility. In older women, for example, oocytes are more susceptible to abnormal chromosome division, and it has been reported that they exhibit reduced mitochondrial quality, lower ATP production, increased oxidative stress, and decreased 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).

[0005] For all the reasons mentioned above, oocytes represent an excellent target tissue for evaluating therapeutic modes that are expected to have an impact on the aging process and, furthermore, offer the potential to address age-related infertility.

[0006] One possible treatment for aging is NAD + Includes medications that enhance the level of treatment. NAD + NAD is an essential component of cellular processes necessary to support various metabolic functions. + Its classical role is that of a coenzyme that catalyzes cellular redox reactions in many fundamental metabolic processes such as glycolysis, fatty acid beta-oxidation, or the tricarboxylic acid cycle, and is reduced to NADH. In order to perform these roles, NAD+ plays an important role as a substrate for NAD-consuming enzymes such as poly-ADP-ribose polymerase (PARP), sirtuin, and CD38 / 157 ectoenzymes. These NAD + -consuming enzymes are known to mediate many basic cellular processes. +

[0007] NAD + has five major precursors and intermediates for synthesis: tryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD + can be synthesized de novo by converting the amino acid tryptophan to nicotinic acid mononucleotide (NaMN) through multiple enzymatic steps. NaMN is converted to nicotinic acid dinucleotide (NaAD + ) by NMN / NaMN adenylyltransferase (NMNAT), and then amidated to NAD + by NAD + synthetase.

[0008] In mammals, the major pathway of NAD + biosynthesis is the salvage pathway from nicotinamide. Nicotinamide is converted to NMN, an important NAD+ intermediate, by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway. Then NMNAT converts NMN to NAD + . NAMPT plays an important role in controlling cellular NAD+ levels. On the other hand, nicotinic acid is converted to NaMN by nicotinic acid phosphoribosyltransferase (NPT). NR needs to be converted to NMN by nicotinamide ribose kinases that phosphorylate NR16, namely, NMRK1 and NMRK2 (also known as NRK1 and NRK2). Maintenance of proper NAD + biosynthesis is crucial for cell survival and function. Deterioration from normal NAD + homeostasis is the NAD + / NADH pool as well as NAD for important cellular functions + It also substantially affects the activity of dependent enzymes. Currently, NAD + There is a growing consensus that levels decline at the cellular, tissue / organ, and biological levels during the aging process. + The activity of the consuming enzyme is related to this NAD + This decline is affected and contributes to a wide range of age-related issues.

[0009] Nicotinamide adenine dinucleotide is an essential enzyme cofactor for the function of several enzymes involved in reduction-oxidation reactions and energy metabolism. (Katrina L. Bogan & Charles Brenner, Nicotinic Acid, Nicotinamide and Nicotinamide Riboside: A Molecular Evaluation of NAD) + Precursor Vitamins in Nutritions, 28, Annual Review of Nutrition 115 (2008). N.A.D. + It functions as an electron carrier in the energy metabolism of amino acids, fatty acids, and carbohydrates (Bogan & Brenner, 2008). NAD + It is important as a substrate for redox reactions and for signal transduction by PARP (polyadenoside diphosphate ribose polymerase) and sirtuins (SIRT1-SIRT7) in the regulation of DNA repair, energy metabolism, cell survival, and circadian rhythms (Bronkowski, MS & Sinclair, D., Nat. Rev. Mole. Cell. Bio., 17, 679-690, 2016). NAD + Increased concentrations slow aging in yeast, flies, and mice (Mouchiroud et al. Cell 154, 464-471, 2014). Also, recently, NAD +It has also been demonstrated that it directly regulates protein-protein interactions, and that this regulation may have a direct impact on aging, as well as protection from cancer and radiation exposure (Li et al., Science 355, 1312-1317, 2017). Therefore, NM NADs such as N and NR + Interventions using intermediates are available NAD + There is growing evidence supporting the idea that restoring these systems can strengthen them and mitigate age-related physiological decline.

[0010] NAD + NAD can be de novo synthesized from the amino acid tryptophan, but this process does not occur in all tissues, and most cells obtain NAD from other intracellular intermediates that become available primarily through dietary sources. + It is necessary to rely on salvage pathways (described above) for regeneration (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 nicotinic acid and nicotinamide can also be administered to enhance the bioavailability of NAD in cells. However, clinically relevant levels of nicotinic acid are associated with undesirable flushing at therapeutic doses (MacKay, D., Hathcock, J. & Guarneri, E., Nutr. Rev. 70, 357-366 (2012)), and nicotinamide does not reliably activate sirtuins despite increased NAD levels (it may even inhibit them) (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 nicotinic acid or nicotinamide is unlikely to be widely adopted to maintain health and function in the context of aging.

[0011] In contrast to nicotinic acid and nicotinamide, NADs such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) + The administration of metabolites is NAD + It appears to increase levels of NAD and improves several physiological functions in animal models (Yoshino, J. et al., Cell Metab. 14, 528-536 (2011); Mills, KFet et al., Cell Metab. 24, 795-806 (2016); and Frederick, DWet et al., Cell Metab. 24, 269-282 (2016)). At least one of these metabolites is well-tolerated in humans and has been reported to lead to elevated NAD levels and improved physiological functions, but further research is needed to confirm the findings of this exploratory study (Christopher R. Martens, et al., Nat. Commun. 9, 1286, (2018)). Furthermore, recent studies have shown that a single dose of NR increases blood cell NAD in healthy humans. + It has been shown that this metabolite stimulates metabolism in a dose-dependent manner (Trammell, SA et al., Nat. Commun. 7, 12948 (2016)), indicating its limitations. However, many known NAD+ metabolites are unstable in various physiological environments and therefore do not constitute viable pharmaceutical agents for administration to patients who require such metabolites to increase NAD+ levels.

[0012] NAD in important cells and physiological pathways + Considering the central role it plays, NAD in disease states or during the aging process + Developing novel stabilizers with improved properties that can raise levels is necessary to improve the human condition. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Nelson SM,Telfer EE,Anderson RA.The aging ovary and uterus:new biological insights.Hum Reprod Update.2013;19:67-83. [Overview of the Initiative] [Means for solving the problem]

[0014] In this specification, surprisingly, cellular NAD + Amino acid salts of NaR that increase levels are provided.

[0015] A first aspect of this application relates to salts of formula (I): as well as their enantiomers, stereoisomers, and tautomers. [ka] (In the ceremony M 1 It is a zwitterionic amino acid; R 1 , R 2 and R 3 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, and C(O)R a , -C(O)OR a -C(O)NR a R b , or -[CH2-CH2-O] k -R a And, or R 1 and R 2 or R 2 and R 3 These, together with the atoms to which they are bonded, form 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 It forms a five-membered heterocyclic ring optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; R a and R b Independently, in each instance, is H or C1-C6 alkyl, and the alkyl is (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 Optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; k is an integer between 1 and 8. Regarding.

[0016] Another aspect of this disclosure relates to a pharmaceutical composition comprising a salt of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

[0017] Another aspect of this application relates to a method for treating or preventing age-related disorders, comprising administering an effective amount of a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, to a subject in need thereof.

[0018] Another aspect of this application relates to a method for treating or preventing infertility, comprising administering an effective amount of a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, to a subject in need thereof.

[0019] Another aspect of this application relates to a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, for use in a method for treating age-related disorders.

[0020] Another aspect of this application relates to a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, for use in a method for treating infertility.

[0021] Another aspect of this application relates to the use of a salt of formula (I), or its enantiomer, stereoisomer, or tautomer, in the manufacture of a drug for treating age-related disorders.

[0022] 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 treating infertility.

[0023] Another aspect of the present disclosure provides a method of improving the quality and maturation of oocytes, comprising administering a therapeutically effective amount of a salt of formula I to a subject in need thereof.

[0024] 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 age-related disorders.

[0025] In another aspect, the present invention includes the ex vivo treatment of oocytes with a salt of formula (I) prior to implantation into a subject for the treatment of age-related infertility.

[0026] In another aspect, the present invention includes the ex vivo treatment of blastocysts with a salt of formula (I) prior to implantation into a subject for the treatment of age-related infertility.

[0027] In another aspect, the present invention includes the ex vivo treatment of oocytes with a salt of formula (I) prior to implantation into a subject for the treatment of infertility.

[0028] In another aspect, the present invention includes the ex vivo treatment of blastocysts with a salt of formula (I) prior to implantation into a subject for the treatment of infertility.

[0029] In another aspect, the salt of formula (I) is provided as a component in a solution for use in ex vivo cell treatment for use in the treatment of age-related disorders. In some embodiments, the age-related disorder is age-related infertility. In other aspects, the salt of formula (I) is provided as a component in a solution for use in ex vivo cell treatment for use in the treatment of infertility.

[0030] 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 a metal-alkali hydroxide under suitable conditions effective for producing a salt of formula I.

[0031] The disclosure also relates to a method for accelerating recovery from a disease or disorder. The method comprises administering an effective amount of a salt of formula (I) to a subject in need in combination with a prescribed treatment for the disease.

[0032] 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 medium. [Modes for carrying out the invention]

[0033] This application relates to salts and compositions capable of treating or preventing age-related disorders. This application relates to a method for treating, preventing or improving age-related diseases or disorders, characterized by administering a therapeutically effective amount of a salt of formula (I), or its enantiomer, stereoisomer, or tautomer, to a patient in need thereof. The method of this application may be used in the treatment of a variety of diseases and disorders by preventing or improving the processes of aging and cellular regeneration, including but not limited to infertility and cellular deterioration.

[0034] Salt of formula (I) is potent and effective at clinically achievable doses, and has various potential The drug is stable in its dosage form, has acceptable solubility and pH, is crystalline, has a low tendency to absorb water, and is easy to handle, all of which are consistent with the development, manufacture, and use of the drug. Furthermore, the salt disclosed herein is cellular NAD + It provides increased levels, increased stability, and increased biological activity at a more physiologically acceptable pH.

[0035] A first aspect of this disclosure relates to the salt of formula I. [ka] (In the formula, M 1 , R 1 , R 2 , and R 3 (as described herein).

[0036] The articles “a” and “an” are used in this disclosure to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements.

[0037] Unless otherwise indicated, the terms “and / or” are used in this disclosure to mean either “and” or “or.”

[0038] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group could be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group could have substituents other than hydrogen. For example, it could bond 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 may contain other functional groups, but does not necessarily have any further functional groups. Preferred substituents used for any substitution of the listed groups include, but are not limited to, halogens, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1~C6)alkyl, (C1~C6)alkyl, C1~C6 alkoxy, (C1~C6)haloalkyl, C1~C6 haloalkoxy, -O-(C2~C6)alkenyl, -O-(C2~C6)alkynyl, (C2~C6)alkenyl, (C2~C6)alkynyl, -OH, -OP(O)(O These include H)2, -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. Substituents may optionally be substituted themselves. "Optionally substituted" also means substituted or unsubstituted when used herein, the meanings of which are set out below.

[0039] As used herein, the term “substituted” means that a particular group or moiety has one or more suitable substituents that can be attached to that particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to one atom of the aryl group by bonding or by fusing with the aryl group to share two or more common atoms.

[0040] As used herein, the term “unsubstituted” means that a particular group does not have substituents.

[0041] Unless otherwise specifically defined, the term “aryl” refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If two aromatic rings (e.g., bicyclic) are present, the aromatic rings of the aryl group may be joined at one point (e.g., biphenyl) or condensed (e.g., naphthyl). The aryl group may optionally be substituted with one or more substituents, e.g., one to five substituents, at any bonding site. Exemplary substituents include -H, -halogen, -O-(C1~C6)alkyl, (C1~C6)alkyl, -O-(C2~C6)alkenyl, -O-(C2~C6)alkynyl, (C2~C6)alkenyl, (C2~C6)alkynyl, -OH, -OP(O)(OH)2, -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, -S(O)2-(C1~C6)alkyl, -S(O)NH(C1~C6)alkyl, and S(O)N((C1~C6)alkyl)2. Substituents may optionally be substituted themselves. Furthermore, when containing two fused rings, the aryl groups as defined herein may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoanurenyl.

[0042] Unless otherwise specified, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, or S. Aromatic radicals are optionally and independently substituted with one or more substituents as described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, i Midazo[1,2-b]pyrazolyl, flo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, Indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanil, quinolinil, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,3-b]pyrazinyl, quinazo Linyl, 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]pyridinyl, tetrahydropyrrolo[1,2-a]pyridinyl, 3,4-dihydro-2H-1□ 2-Pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoisoxazolyl, flo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridinyl, [1,2 This includes, but is not limited to, 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]imidazole-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 their derivatives. Furthermore, when containing two fused rings, the aryl groups as defined herein may have an unsaturated or partially saturated ring fused with 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.

[0043] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0044] Alkyl refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0045] "Alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms with a terminal "O" in its chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0046] "Alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkenyl" group contains at least one double bond in its chain. The double bond of the alkenyl group can be non-conjugated or conjugated to other unsaturated groups. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. The alkenyl group may be unsubstituted or substituted. Alkenyl, as defined herein, can be branched or straight-chain.

[0047] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in its chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. The alkynyl group may be unsubstituted or substituted.

[0048] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups can become alkylene by removing a second hydrogen atom from the alkyl. As defined herein, alkylene can also be C1-C6 alkylene. Alkylene can further be C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0049] "Cycloalkyl" refers to a group of 3 to 18 carbon atoms (for example, -C3 to -C3). 10 This refers to monocyclic or polycyclic saturated carbon rings (e.g., condensed, bridged, or spirocycles) containing ). Examples of cloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0050] "Heterocyclyl" or "heterocycloalkyl" means a monocyclic or polycyclic ring (e.g., condensed, bridged, or spiro-ring) containing carbon and heteroatoms obtained from oxygen, nitrogen, or sulfur, in which there are no delocalized π electrons (aromatic) shared between the ring carbons or heteroatoms. Heterocycloalkyls can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered rings. The heterocycloalkyl ring structure may be substituted by one or more substituents. Substituents may optionally be substituted by themselves. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. According to this application, a 3-10 membered heterocyclyl refers to a saturated or partially saturated non-aromatic ring structure containing 3-10 atoms, wherein at least one heteroatom selected from the group N, O, or S is present.

[0051] The term "hydroxyalkyl" refers to the alkyl group defined above, in which 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)-.

[0052] The term "haloalkyl," as used herein, 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, and trichloromethyl.

[0053] The term "haloalkoxy," as used herein, 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, and trichloromethoxy.

[0054] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0055] The term "amine" as used herein refers to primary (R-NH2, R≠H) and secondary (R a -NH, R b ≠H) and Grade 3 (R a -N, R≠H) refers to amines. A substituted amine is intended to mean an amine in which at least one hydrogen atom is replaced by a substituent.

[0056] As used herein, the term "amino" means a substituent containing at least one nitrogen atom. In particular, NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide, carbamide, urea and sulfamide substituents are included in the term "amino".

[0057] As used herein, the term "oxo" refers to the "=O" group.

[0058] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. This structural difference can be in composition (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the salt of formula (I) may have one or more chiral carbon atoms and may arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0059] This disclosure also includes a pharmaceutical composition comprising an effective amount of the disclosed salt and a pharmaceutically acceptable carrier. Typical "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansilic acid, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estrulate, esylate, fumarate, finalate, gluceptate, gluconate, glutamate, glycolyl arsanylate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, and magnesium. This includes nesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-meten-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiozide, and valerate.

[0060] "Patient" or "subject" means a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0061] “Effective dose” means, when used in connection with salts and / or pharmaceutical compositions, an amount effective in treating or preventing the disease described herein.

[0062] When used in this disclosure, the term “carrier” includes carriers, excipients, and diluents, and means a substance, composition, or vehicle or encapsulating material such as a liquid or solid filler, diluent, excipient, or solvent that is involved in the transport or delivery of a pharmaceutical agent from one organ or part of the body to another.

[0063] With respect to the subject, the term "treatment" refers to the improvement of at least one symptom of the disorder in the subject. Treatment includes the cure, improvement, or at least partial improvement of the disorder.

[0064] Unless otherwise indicated, the term “disability” is used in this disclosure to mean the terms disease, condition, or illness, and is interchangeable with those terms.

[0065] When used in this disclosure, the terms “administer,” “dosing,” or “administer” refer to either directly administering the disclosed salt or composition to a subject, or administering a prodrug derivative or analogue or composition of the salt that can form an equivalent amount of the active compound in the subject body.

[0066] Salt of this application This application relates to age-related disorders, which are useful in treating diseases and disorders associated with aging and cell regeneration. This relates to salts or their enantiomers, stereoisomers, or tautomers that can be used to treat or prevent illness.

[0067] In some embodiments of the present invention, Ra Independently, in each occurrence, is H or a C1-C6 alkyl group. In other embodiments, R a In other embodiments, R a is a C1-C6 alkyl group. In other embodiments, R a These include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, and (C0-C3 alkylene)C6-C 14 It is a C1-C6 alkyl group substituted with one or more substituents selected from aryl groups or (C0-C3 alkylene) heteroaryl groups. In other embodiments, R a is a C1-C6 alkyl group substituted with one or more substituents selected from C1-C6 alkyl groups. In other embodiments, R a is a C1-C6 alkyl group substituted with one or more C2-C6 alkenyl groups. In other embodiments, R a is a C1-C6 alkyl group substituted with one or more C2-C6 alkynyl groups. In other embodiments, R a is a C1-C6 alkyl substituted with one or more m(C0-C3 alkylene)C3-C8 cycloalkyl groups. In other embodiments, R a is a C1-C6 alkyl group substituted with one or more (C0-C3 alkylene) heterocycloalkyl groups. In other embodiments, R a This is one or more (C0-C3 alkylenes) C6-C 14 It is an aryl-substituted C1-C6 alkyl group. In other embodiments, R a is a C1-C6 alkyl substituted with one or more (C0-C3 alkylene) heteroaryls. In other embodiments, R a is methyl. In other embodiments, R a These include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, and (C0-C3 alkylene)C6-C 14It is methyl substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl.

[0068] In a further embodiment, R 1 is 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 is C1-C6 alkyl. In another embodiment, R 1 is C1-C6 haloalkyl. In another embodiment, R 1 is (C0-C3 alkylene)C(O)C1-C6 alkyl. In another embodiment, R 1 is -C(O)OR a . In another embodiment, R 1 is -[CH2-CH2-O] k -R a . In another embodiment, R 1 is C(O)C1-C6 alkyl.

[0069] In one embodiment, R 2 is 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 is C1-C6 alkyl. In another embodiment, R 2 is C1-C6 haloalkyl. In another embodiment, R 2 is (C0-C3 alkylene)C(O)C1-C6 alkyl. In another embodiment, R2 is -C(O)OR a In another embodiment, R 2 is -[CH2-CH2-O] k -R a In another embodiment, R 2 These are C(O)C1~C6 alkyl groups.

[0070] In one embodiment, R 3 These 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 3 In another embodiment, R 3 is a C1-C6 alkyl group. In another embodiment, R 3 is a C1-C6 haloalkyl group. In another embodiment, R 3 is (C0-C3 alkylene)C(O)C1-C6 alkyl. In another embodiment, R 3 is -C(O)OR a In another embodiment, R 3 is -[CH2-CH2-O] k -R a in Yes. In another embodiment, R 3 These are C(O)C1~C6 alkyl groups.

[0071] In a further embodiment of the salt of formula I, R 1 and R 2 These, together with the atoms to which they are bonded, can form a five-membered heterocyclic ring. In a further embodiment of the salt of formula I, R 1 and R 2 These, together with the atoms to which they are bonded, can form a six-membered heterocyclic ring. In further embodiments of the salt of formula I, R 1 and R 2These, together with the atoms to which they are bonded, form 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 A five-membered heterocyclic ring may be formed by substituting one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups. In further embodiments of the salt of formula I, R 1 and R 2 These, together with the atoms to which they are bonded, form 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 It can form a six-membered heterocyclic ring substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups.

[0072] In a further embodiment of the salt of formula I, R 2 and R 3 These, together with the atoms to which they are bonded, can form a five-membered heterocyclic ring. In a further embodiment of the salt of formula I, R 2 and R 3 These, together with the atoms to which they are bonded, can form a six-membered heterocyclic ring. In further embodiments of the salt of formula I, R 2 and R 3 These, together with the atoms to which they are bonded, form 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 A five-membered heterocyclic ring may be formed by substituting one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups. In further embodiments of the salt of formula I, R 2 and R 3These, together with the atoms to which they are bonded, form 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 It can form a six-membered heterocyclic ring substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups.

[0073] In another embodiment of the salt of formula I, M 1 is a zwitterionic amino acid. In another embodiment, M 1 This is a zwitterionic amino acid of formula II: [ka] That is the case.

[0074] In one embodiment of the salt of formula I, R 5 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 It is an aryl or (C0-C3 alkylene) heteroaryl. In another embodiment, R 5 In another embodiment, R 5 is a C1-C6 alkyl group. In another embodiment, R 5 In another embodiment, R 5 C2~C6 Al It is Kinil. In another embodiment, R 5 is (C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R 5 is a (C0-C3 alkylene) heterocycloalkyl. In another embodiment, R 5 (C0~C3 alkylene) C6~C 14 It is an arrow. In another embodiment, R 5 is a (C0-C3 alkylene) heteroaryl. In another embodiment, R5 H, one or more (C0-C3 alkylenes) SR c These are C1-C4 alkyl groups substituted with [a specific compound].

[0075] In another embodiment, R 5 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C1-C6 alkyl group substituted with one or more substituents selected from the following. In another embodiment, R 5 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C2-C6 alkenyl substituted with one or more substituents selected from. In another embodiment, R 5 This is 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 Alkilen) 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 )NRc 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C2-C6 alkynyl substituted with one or more substituents selected from. In another embodiment, R 5 This is 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 Alkilen) 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 Urec , or (C0~C3 alkylene)BO p R c R d It is a (C0-C3 alkylene)C3-C8 cycloalkyl substituted with one or more substituents selected from. In another embodiment, R 5 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a (C0-C3 alkylene) heterocycloalkyl substituted with one or more substituents selected from. In another embodiment, R 5 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d (C0-C3 alkylene) C6-C substituted with one or more substituents selected from 14 It is an arrow. In another embodiment, R 5 This is 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 Alkilen) 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)NRc 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a (C0-C3 alkylene) heteroaryl substituted with one or more substituents selected from the following.

[0076] In one embodiment of the salt of formula I, R 4 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 It is an aryl or (C0-C3 alkylene) heteroaryl. In another embodiment, R 4 In another embodiment, R 4 is a C1-C6 alkyl group. In another embodiment, R 4 In another embodiment, R 4 In another embodiment, R 4 is (C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R 4 is a (C0-C3 alkylene) heterocycloalkyl. In another embodiment, R 4 (C0~C3 alkylene) C6~C 14 It is an arrow. In another embodiment, R 4 It is a (C0-C3 alkylene) heteroaryl compound.

[0077] In another embodiment, R 4 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C1-C6 alkyl group substituted with one or more substituents selected from the following. In another embodiment, R 4 This is 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 Alkilen) SR c (C0~C3 Alkylene) C(O)SRc (C0~C3 alkylenes) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C2-C6 alkenyl substituted with one or more substituents selected from. In another embodiment, R 4 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a C2-C6 alkynyl substituted with one or more substituents selected from. In another embodiment, R 4 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R dIt is a (C0-C3 alkylene)C3-C8 cycloalkyl substituted with one or more substituents selected from. In another embodiment, R 4 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a (C0-C3 alkylene) heterocycloalkyl substituted with one or more substituents selected from. In another embodiment, R 4 This is 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 Alkilen) SRc (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 Ure c , or (C0~C3 alkylene)BO p R c R d (C0-C3 alkylene) C6-C substituted with one or more substituents selected from 14 It is an arrow. In another embodiment, R 4 This is 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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is a (C0-C3 alkylene) heteroaryl substituted with one or more substituents selected from the following.

[0078] In another embodiment, R 6 is H or C1-C6 alkyl. In another embodiment, R 6 In another embodiment, R 6 is a C1-C6 alkyl group. In another embodiment, R 6 This is cyano, halo, (C0~C3 alkylene) NR c R d , or (C0~C3 alkylene) OR c It is a C1-C6 alkyl group substituted with one or more substituents selected from the following. In another embodiment, R 5 H is H.

[0079] In another embodiment, R 5 and R 6 These, together with the atoms to which they are bonded, can form a five-membered ring. In another embodiment, R 5 and R 6 These, together with the atoms they are bonded to, form cyano, halo, and (C0-C3 alkylene) NR compounds. c R d , or (C0~C3 alkylene) OR c A five-membered ring can be formed by substituting one or more substituents selected from. In another embodiment, R 5 and R 6These, together with the atoms to which they are bonded, can form a six-membered ring. In another embodiment, R 5 and R 6 These, together with the atoms they are bonded to, form cyano, halo, and (C0-C3 alkylene) NR compounds. c R d , or (C0~C3 alkylene) OR c It can form a six-membered ring substituted with one or more substituents selected from the following.

[0080] In further embodiments, R d In each embodiment, R is independently H or C1-C6 alkyl. d In another embodiment, R d is a C1-C6 alkyl group. In another embodiment, R d (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 It is a C1-C6 alkyl group substituted with one or more substituents selected from aryl groups or (C0-C3 alkylene) heteroaryl groups.

[0081] In further embodiments, R c In each embodiment, R is independently H or C1-C6 alkyl. c In another embodiment, R c is a C1-C6 alkyl group. In another embodiment, R c (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 It is a C1-C6 alkyl group substituted with one or more substituents selected from aryl groups or (C0-C3 alkylene) heteroaryl groups.

[0082] In another embodiment, k is 1, 2, 3, 4, 5, 6, 7, or 8 in each occurrence. 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.

[0083] In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2.

[0084] 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.

[0085] 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.

[0086] In some embodiments of the salt of formula I, the salt has the structure of formula Ia: [ka] It has.

[0087] In some embodiments of the salt of formula I, the salt has the structure of formula Ib: [ka] It has.

[0088] In some embodiments of the salt of formula I, the salt has the structure of formula Ic: [ka] It has.

[0089] In some embodiments of the salt of formula I, the salt has the structure of formula Id: [ka] It has.

[0090] In some embodiments of the salt of formula I, the salt has the structure of formula Ie: [ka] It has.

[0091] In some embodiments of the salt of formula I, the salt has the structure of formula If: [ka] It has.

[0092] In some embodiments of the salt of formula I, the salt has the structure of formula Ig: [ka] It has.

[0093] In some embodiments of the salt of formula I, the salt has the structure of formula Ih: [ka] It has.

[0094] In some embodiments of the salt of formula I, the salt has the structure of formula Ii: [ka] It has.

[0095] In some embodiments of the salt of formula I, the salt has the structure of formula Ij: [ka] It has.

[0096] In some embodiments of the salt of formula I, the salt has the structure of formula Ik: [ka] It has.

[0097] In some embodiments of the salt of formula I, the salt has the structure of formula Il: [ka] It has.

[0098] In some embodiments of the salt of formula I, the salt has the structure of formula Im: [ka] It has.

[0099] In some embodiments of the salt of formula I, the salt has the structure of formula In: [ka] It has.

[0100] In some embodiments of the salt of formula I, the salt has the structure of formula Io: [ka] It has.

[0101] In some embodiments of the salt of formula I, the salt has the structure of formula Ir: [ka] It has.

[0102] In another embodiment, preferred salts include, but are not limited to: (S)-2-ammonio-3-phenylpropanoate compound (1:1)(I-001) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; (2S,3S)-2-ammonio-3-methylpentanoate compound (1:1) (I-002) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; (S)-2-ammonio-3-(1H-indole-3-yl)propanoate compound (1:1) (I-003) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S )-6-amino-2-ammoniahexanoate (1:1) (I-004); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate(S)-5-amino-2-ammonio-5-oxopentanoate(1:1)(I-005); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-methylpentanoate(1:1)(I-006); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-carboxybutanoate(1:1)(I-007); (S)-2-Ammonia-3-methylbutanoate-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1)(I-008); (S)-2-Ammonia-5-Guanidinopentanoate-1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(Hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1)(I-009); and 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-3-(1H-imidazole-4-yl)propanoate (1:1)(I-010) It includes.

[0103] Method for preparing salt The salts of this application can be produced by various methods, including standard chemistry. A preferred synthesis route is shown in the scheme provided below.

[0104] Salts of formula (I) can be prepared by methods known in the art of organic synthesis, as partially shown by the following synthetic scheme. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed, according to general principles or chemistry. Protecting groups are operated according to standard methods of organic synthesis (TW Greene and PGMWuts, “Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of salt synthesis using methods readily apparent to those skilled in the art. The selection process, and the reaction conditions and sequence of their execution, shall be consistent with those for the preparation of the salt of formula (I).

[0105] Those skilled in the art will recognize whether a stereocenter exists in the salt of formula (I). Therefore, this application includes both possible stereoisomers (unless otherwise specified by synthesis), including not only the racemic salt but also the individual enantiomers and / or diastereomers. Where the compound or salt is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by the resolution of the final product or any convenient intermediate. The resolution of the final product, intermediate, or starting material may be influenced by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by ELEliel, S.H. Wilen, and LNMander (Wiley-Interscience, 1994).

[0106] The salts and compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0107] The salts of this application can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the salts of this application can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or types thereof as understood to those skilled in the art. These methods include, but are not limited to, those described below. The salts of this application can be synthesized by following the steps outlined in General Scheme 1, which include different sequences for assembling various intermediates. Starting materials are commercially available or prepared by known procedures or as illustrated in reported literature. Scheme 1 [ka]

[0108] The mixture of enantiomers, diastereomers, and cis / trans isomers obtained from the above process can be separated into their single components by chiral salt techniques, normal-phase, reverse-phase, or chiral column chromatography, depending on the separation characteristics.

[0109] In the descriptions and formulas shown above, the base R in the scheme is R as defined above, unless otherwise indicated. 3 It should be understood that this represents [the following]. Furthermore, for synthetic purposes, the salts of general scheme 1 are merely representative examples with selected radicals to illustrate the general synthetic methodology of the salt of formula (I) as defined herein.

[0110] Furthermore, it should be understood that the salts disclosed herein have a neutral charge, and that the structure of formula I is merely representative of a genus that may be balanced with counterions to allow the salt to exhibit a neutral charge, if necessary. Such counterions may include, but are not limited to, bromine, chlorine, and triflate. In one embodiment, the salts of the present invention may be produced in situ without requiring isolation from solution. In some embodiments, the salts disclosed herein may be separate 1:1 or 1:2 salts. In some embodiments, the salts described herein may also exist in other ratios, e.g., 1:1.5, 1:5, or 1:10.

[0111] How to use the disclosed salt Another aspect of this disclosure relates to methods for treating or preventing diseases or disorders associated with aging, cellular deterioration, and / or cellular regeneration. Non-limiting examples of such diseases and disorders include infertility, age-related infertility, age-related loss of ocular function, decreased bone density, obesity, and insulin insensitivity. In one embodiment, a salt of formula (I) is useful for treating age-related infertility. In another embodiment of a salt of formula (I), it is useful for treating infertility.

[0112] Another aspect of this application relates to a method for treating or preventing diseases or disorders associated with aging, cellular deterioration, and / or cellular regeneration. In one embodiment, the salts of the Disclosure are useful in treating infertility. In another embodiment,

[0113] The present invention also relates to the use of salts of formula I, as well as its enantiomers, stereoisomers, and tautomers, for the manufacture of agents for treating aging, cell regeneration, cell deterioration, or infertility.

[0114] A further aspect of this disclosure relates to a method for improving the quality and maturation of oocytes or blastocysts. The method comprises contacting oocytes or blastocysts with an IVF medium containing a salt of formula (I) for an effective period of time.

[0115] In another embodiment, the disclosure provides a culture medium containing a salt of formula (I). The salt of formula (I) exhibits surprising and unexpected long-term stability in solution and is therefore useful in a culture medium for exposing oocytes, oocytes and / or blastocysts for the period necessary to enhance NAD+ production prior to implantation in subjects suffering from infertility or age-related infertility. In some embodiments, a culture medium containing a salt of formula (I) is provided. In some embodiments, the culture medium contains various reagents and factors necessary for oocytes, oocytes or blastocysts, depending on the stage of maturation and development in which the oocytes, oocytes or blastocysts are present. For example, the culture medium may contain reagents or factors useful for IVF culture mediums, as listed in Table 1 below: [Table 1]

[0116] Furthermore, a cell culture medium for in vitro fertilization is also provided, comprising one or more salts of formula (I) and a culture medium.

[0117] In one embodiment, the culture medium is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, 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.

[0118] In one embodiment, the energy substrate is glucose, pirubate, lactate, pirubate, or any combination thereof.

[0119] In one embodiment, the amino acids are essential amino acids. In one embodiment, the essential amino acids are arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof.

[0120] In one embodiment, the amino acid is a non-essential amino acid.

[0121] In one embodiment, the non-essential amino acid is alanine, asparagine, aspartic acid, glutamic acid, proline, serine, or any combination thereof.

[0122] In one embodiment, the chelating agent is clathrochelate, 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, trinitrile acetic acid, pentetic acid (DTPA), phosphonate, phytokerati, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof.

[0123] In one embodiment, the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridin, or any combination thereof.

[0124] In one embodiment, the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof.

[0125] In one embodiment, the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.

[0126] In one embodiment, the vitamins are ascorbic acid, biotin, menadione sodium bisulfite, mitomycin C, pyridoxamine dihydrochloride, retinyl acetate, (-)-riboflavin, (+)-L-sodium ascorbate, (+)-α-tocopherol, and vitamin B 12 These include thiamine hydrochloride, i-inositol, pyridoxal hydrochloride, nicotinamide, folic acid, calcium D-pantothenate, choline chloride, or any combination thereof.

[0127] In one embodiment, the growth factors are adrenomedullin, angiopoietin, 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 stimulant, macrophage-stimulating protein, myostatin, neurotrophin, T cell growth factor, thrombopoietin, transforming growth factor, tumor necrosis factor-alpha, vascular endothelial growth factor, or any combination thereof.

[0128] In one embodiment, the cell culture medium further comprises oocytes, zygotes, blastocysts, or any combination thereof.

[0129] Also provided are kits for IVF media containing various drugs and factors necessary for the maturation of oocytes or blastocysts, including one or more salts of formula (I). These drugs and cofactors can be dissolved in solution to produce IVF media immediately before use to expose oocytes or blastocysts pre-implantation to patients requiring treatment for infertility or age-related infertility.

[0130] The present invention also relates to the use of salts of formula I, as well as its enantiomers, stereoisomers, and tautomers, for the manufacture of agents for treating aging, cell regeneration, cell deterioration, or infertility. In a given embodiment, the infertility to be treated is age-related infertility.

[0131] Another aspect of the present invention is a pharmaceutical composition comprising a salt of formula I and a pharmaceutically acceptable carrier.

[0132] Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier containing a salt of formula I and one or more additional therapeutic agents in a therapeutically effective amount.

[0133] In some embodiments, administration of a pharmaceutical composition comprising a salt of formula (I) or the salt of the present invention and a pharmaceutically acceptable carrier induces changes in the cell cycle and cell survival.

[0134] In some embodiments, administration of a pharmaceutical composition comprising a salt of formula (I) or the salt of the present invention and a pharmaceutically acceptable carrier induces a prophylactic change in age-related disorders or diseases.

[0135] The salts disclosed in the present invention may be administered in amounts effective for treating or preventing age-related disorders and / or preventing the onset of disorders or diseases in a subject.

[0136] The administration of the disclosed salts may be achieved through any mode of administration for the therapeutic agent. These modes include systemic or partial administration, such as oral, nasal, parenteral, transdermal, subcutaneous, transvaginal, buccal, rectal, or topical administration.

[0137] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, or suspensions, sometimes in unit doses, consistent with conventional pharmaceutical practices. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms of use are well known to those skilled in the art of pharmaceuticals.

[0138] The effective dosage of the disclosed salt, when used for the indicated effect, ranges from about 0.5 mg to about 5000 mg of the disclosed salt, depending on the need 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 salt, or a range from one amount to another in this dosage list. In one embodiment, the composition is in the form of a perforated tablet.

[0139] Dosage regimens utilizing the disclosed salts are selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the specific disclosed salt used. A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective dose of the drug necessary to prevent, counteract, or halt the progression of the condition. Cut.

[0140] Exemplary pharmaceutical compositions include the salts and pharmaceutically acceptable carriers of the present invention, for example: a) Diluents, for example, purified water, triglyceride oils, for example, hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) Lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, acetic acid c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g., acacia, tragacanth, or sodium alginate, wax and / or polyvinylpyrrolidone, if desired, d) Disintegrants, e.g., 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, e.g., Tween Tablets and gelatin capsules containing 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS, or other acceptable emulsifiers, and / or agents that enhance the absorption of salts, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0141] Most amino acids can have buffering properties as salts, and their multiple pKa values ​​are more compatible with biological fluids, resulting in a wider range of stable pH values ​​that are more suitable for IV administration. Naturally occurring amino acids, NMN, and NaMN are endogenous substances. Therefore, mixtures of such substances are less likely to be toxic to mammals. Some of the products may have improved solubility and solid morphological stability. In one embodiment, the salt may have improved water solubility. In one embodiment, the salt may have improved solid morphological stability. In one embodiment, the salt may have improved chemical stability. [Examples]

[0142] This disclosure is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that no limitation is intended to the scope of this disclosure. It should be further understood that various means to various other embodiments, modifications and equivalents may be taken, which themselves may be suggested to those skilled in the art, without departing from the spirit of this disclosure and / or the appended claims.

[0143] The following salts disclosed herein were prepared using general synthetic methodologies that include, but are 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, and isopropanol were also used. The following abbreviations are used in the following examples and elsewhere in this specification: Acetic acid (ACOH) anh. anhydrous Atm (atm) atmospheric pressure aq. Water-based br broad Boc tert-butyloxycarbonyl Brine (saturated aqueous sodium chloride) n-BuLi n-butyllithium n-BuOH (n-butanol) Calc'd (Calculated) CDCl3 (deuterated chloroform) CDI (Carbonyldiimidazole) Chloroform-d Deuterated chloroform d doublet dd doublet doublet dt Triplet doublet D2O Deuterized water (deuterium oxide) DCE Dichloroethane DCM Dichloromethane DIAD Diisopropyl Azodicarboxylate DIPEA N,N-diisopropylethylamine DMAc N,N-dimethylacetamide DMAP N,N-dimethylpyridine-4-amine DME 1,2-Dimethoxyethane DMEDA N,N'-dimethylethylenediamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) DMSO-d6 Deuterated Dimethyl Sulfoxide EDA (Ethylenediamine) EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol ESI Electrospray Ionization g grams h hours (multiple hours possible) H Hydrogen 1 H NMR nuclear magnetic resonance (proton nucleus) HATU [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 3-[bis(dimethylamino)methylene]-3H-benzotriazole-1-oxidehexafluorophosphate HOBt hydroxybenzotriazole HPLC (High-Pressure (or High-Performance) Liquid Chromatography) Hz (Hertz) J coupling constant KHCO3 Potassium Bicarbonate KHMDS Potassium Hexamethyl Disilazide KOAc Potassium Acetate LCMS (Liquid Chromatography Mass Spectrometry) LHMDS Lithium Hexamethyl Disilazide [#] M molar concentration m multiplet [M+H] + Molecular ions plus hydrogen [M-tBu+H] + Molecular ion minus tert-butyl plus hydrogen mCPBA (Meth-chloroperoxybenzoic acid) Me2NH dimethylamine Me4NBr Tetramethylammonium bromide MeCN acetonitrile MeNH2 methylamine MeOH methanol Methanol-D4 Deuterated methanol 2-MeTHF 2-methyltetrahydrofuran mg milligrams MHz (megahertz) min mmol millimol mL (milliliter) MS mass spectrometry MS ES Mass Spectrometry Electrospray Ms2O Methanesulfonic acid anhydride MTBE methyl tert-butyl ether MW microwave m / z mass-to-charge ratio μL (microliter) N2 Nitrogen NaHCO3 (sodium bicarbonate) NaMN nicotinic acid mononucleotide NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PEPPSI-iPr [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride PdCl2(Amphos) Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) Pd(OAc)2 Palladium(II) acetate PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(MeCN)2-bis(acetonitrile)dichloropalladium(II) PdCl2(PPh3)2-bis(triphenylphosphine palladium(II) dichloride) Pd(P(Cy)3)2Cl2 dichlorobis(tricyclohexylphosphine)palladium(II) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) Pd(t-Bu3P)2bis(tri-tert-butylphosphine)palladium(0) pH (hydrogen ion concentration) PMB 4-methoxybenzyl PMBCl 4-Methoxybenzyl Chloride ppm parts per million prep preparative py pyridine q quartet qd quadruplet of doublets quant. quantitative quin. quintet quind (doublet quintet) RBF round-bottom flask Rt retention time rt room temperature s singlet sat. saturation sat.aq. saturated aqueous SEMCl 2-(trimethylsilyl)ethoxymethylchloride t triplet t-BuLi tert-butyllithium td Triplet of doublets TMS (trimethylsilyl) TMSCl (Trimethylsilyl Chloride) tt Triplet doublet T3P Polyphosphonic anhydride TBAB Tetrabutylammonium bromide TEA (Triethylamine) TFA (Trifluoroacetic Acid) TFAA Trifluoroacetic anhydride THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) TPPO (Triphenylphosphine Oxide) XantPhos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Example 1.1 Synthesis of (S)-2-ammonio-3-phenylpropanoate compound (1:1) having ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate [ka] A 50 mL 1N RBF flask equipped with a water condenser was mixed with NaR (0.100 g, 0.392 mmol, 1 equivalent) and 10 mL of distilled deionized water to form a solution (including a faint suspension). This solution was cooled using an ice / water bath. L-phenylalanine (0.0647 g, 392 mmol, 1.0 equivalent) was then added to the solution all at once. After this addition, the pH became approximately 4.9-5.2, and all the solids were incorporated into the solution. The flask was then removed, and the colorless solution was frozen using liquid nitrogen. While it was drying, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product becomes a colorless solid. Yield: 160.6 mg (98%) Melting point: 130-133°C (corrected, decomposition), gas release at 145°C Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.47 (s,1H ), 9.18 (d, 1H), 8.96 (d, 1H), 8.21 (dd, 1H) , 7.48-7.32 (m, 5H), 6.25 (d, 1H),4.51 (m, 2H), 4.38 (t, 1H), 4.10-4.00 ( 2 x dd,2H),3. 92 (dd, 1H), 3.31 (dd, 1H),3.15 (dd, 1H) ppm

[0144] Example 2.1 Synthesis of a (2S,3S)-2-ammonio-3-methylpentanoate compound (1:1) having ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate [ka] A 50 mL 1N RBF (Rich-Board Fiber) container equipped with a water condenser was mixed with NaR (0.100 g, 0.392 mmol, 1 equivalent) and 20 mL of distilled deionized water to form a solution (including a slight suspension). This solution was cooled using an ice / water bath. Then, L-isoleucine (0.080 g, 392 mmol, 1.0 equivalent) was added to the solution all at once. After this addition, the pH became approximately 4.6-4.9, and all solids were incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product became a colorless solid. Yield: 147.1 mg (97%) Melting point: 144-148°C (corrected, decomposition) Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.48 (s,1H ), 9.18 (d, 1H), 8.98 (d, 1H), 8.21 (dd, 1H) , 6.24 (d, 1H), 4.48-4.55 (m, 2H),4.38 (t, 1H), 4.07 (dd, 1H), 3.93 (dd, 1H), 3.69(d,1 H), 2.00 (m, 1H), 1.55-1.45(m, 1H), 1.35-1.24 (m, 1H), 1.04 (d, 3H), 0.95 (t,3H)ppm

[0145] Example 3.1 Synthesis of (S)-2-ammonio-3-(1H-indole-3-yl)propanoate compound (1:1) having ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate [ka] A 50 mL 1N RBF (Raw Bone Fluid) equipped with a water condenser was mixed with NaR (0.100 g, 0.392 mmol, 1 equivalent) and 30 mL of distilled deionized water to form a solution (including a slight suspension). This solution was cooled using an ice / water bath. Then, L-tryptophan (0.080 g, 392 mmol, 1.0 equivalent) was added to the solution all at once. After this addition, the pH was approximately 4.9-5.2, and all solids were incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Upon drying, the product became a yellow solid. Yield: 171.8 mg (96%) Melting point: 117-126°C (corrected, decomposition), gas release at 133°C Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.42 (s,1H ), 9.12 (d, 1H), 8.93 (d, 1H), 8.15 (dd, 1H) , 7.72 (d, 1H), 7.53 (d, 1H), 7.30(s + t, 2H), 7.20 (t, 1H), 6.28 (d, 1H), 4.481(m,2H), 4.38 (t, 1H), 4.10-4.00( m, 2H), 3.92 (dd, 1H), 3.51 (dd, 1H), 3.32 (dd,1H) ppm

[0146] Example 4.1 Synthesis of ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-6-amino-2-ammoniohexanoate (1:1) [ka] A 250 mL 1N RBF (Rich Broken Fiber) container equipped with a water condenser was mixed with NaR (0.200 g, 0.784 mmol, 1 equivalent) and 40 mL of distilled deionized water to form a solution (including a faint suspension). This solution was cooled using an ice / water bath. Then, L-lysine (0.115 g, 0.744 mmol, 0.95 equivalents) was added to the solution all at once. After this addition, the pH became 9.63, and all solids were incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer, which gradually removed the water. Upon drying, the product became a brown-colored solid. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.43 (s,1H ), 9.13 (d, 1H), 8.92 (d, 1H), 8.17 (dd, 1H) , 6.21 (d, 1H), 4.48 (m, 2H), 4.33(t, 1H), 4 .02 (dd, 1H), 3.88 (dd, 1H), 3.46 (t, 1H), 2.98 (d, 2H), 1.8-1.6(m,4H),1.5-1.3 (m, 2H ) ppm

[0147] Example 5.1 Synthesis of ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate(S)-5-amino-2-ammonio-5-oxopentanoate (1:1) [ka] A solution (including a slight suspension) was formed by adding NaR (0.200 g, 0.784 mmol, 1 equivalent) and 15 ml of distilled deionized water to 100 mL of 1N RBF equipped with a water condenser and mixing. This solution was cooled using an ice / water bath. Then, L-glutamine (0.109 g, 0.744 mmol, 0.95 equivalents) was added to the solution all at once. After this addition, the pH became 4.95 and all the solids were incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer, which gradually removed the water. Upon drying, the product became a brown-colored solid. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.45 (s,1H ), 9.13 (d, 1H), 8.92 (d, 1H), 8.17 (dd, 1H) , 6.20 (d, 1H), 4.50-4.43 (m, 2H),4.33 (t, 1H), 4.03 (dd, 1H), 3.89 (dd, 1H), 3.75(t,1 H), 2.50-2.37 (ddd, 2H),2.15-2.07 (m, 2H) ppm

[0148] Example 6.1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-methylpentanoate (1:1) [ka] A solution (including a slight suspension) was formed by adding NaR (0.200 g, 0.784 mmol, 1 equivalent) and 15 ml of distilled deionized water to 100 mL of 1N RBF equipped with a water condenser and mixing. This solution was cooled using an ice / water bath. Then, L-leucine (0.098 g, 0.744 mmol, 0.95 equivalents) was added to the solution all at once. After this addition, the pH became 5.61 and all solids were incorporated into the solution. Next, the flask was removed and the colorless solution was frozen using liquid nitrogen. While it was drying, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product becomes colorless. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.43 (s,1H ), 9.12 (d, 1H), 8.92 (d, 1H), 8.17 (dd, 1H) , 6.21 (d, 1H), 4.50-4.43 (m, 2H),4.34 (t, 1H), 4.03 (dd, 1H), 3.89 (dd, 1H), 3.71(app t, 1H), 1.8-1.6 (m, 3H),0.98-0.9 (2xd, 6H)ppm

[0149] Example 7.1 Synthesis of ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-carboxybutanoate (1:1) [ka] A solution (including a slight suspension) was formed by adding NaR (0.200 g, 0.784 mmol, 1 equivalent) and 15 ml of distilled deionized water to 100 mL of 1N RBF equipped with a water condenser and mixing. This solution was cooled using an ice / water bath. Then, L-glutamic acid (0.110 g, 0.744 mmol, 0.95 equivalents) was added to this solution all at once. After this addition, the pH became 3.52, and all solids were incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product became colorless. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.45 (appm , 1H), 9.15 (app m, 1H), 8.94 (app m, 1H), 8.18 (app m, 1H), 6.21 (app m, 1H),4.50-4.43( m, 2H), 4.34 (m, 1H), 4.05 ( m, 1H), 3.89 (m,1H), 3.78 (app m, 1H),2.55 (m, 2H),2.25-2. 15 (m, 2H) ppm

[0150] Example 8. Synthesis of (S)-2-ammonia-3-methylbutanoate-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1) [ka] A 100 mL 1N RBF with a water condenser is mixed with NaR (0.200 g, 0.784 g). A solution (including a slight suspension) was prepared by adding L-valine ( mmol, 1 equivalent) and 15 ml of distilled deionized water and mixing. This solution was cooled using an ice / water bath. Then, L-valine (0.087 g, 0.744 mmol, 0.95 equivalents) was added to the solution all at once. After this addition, the pH became 5.67, and all the solid was incorporated into the solution. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product became colorless. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.43 (s,1H ), 9.13 (d, 1H), 8.92 (dt, 1H), 8.17 (dd, 1H ), 6.21 (d, 1H), 4.50-4.43 (m, 2H),4.34 (t, 1H), 4.03 (dd, 1H), 3.89 (dd, 1H),3.59(d, 1H), 2.30-2.20 (m, 1H), 1.03,0.97(2 xd, 6H ) ppm

[0151] Example 9. Synthesis of (S)-2-Ammonia-5-Guanidinopentanoate-1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(Hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1) [ka] 100 mL of 3N RBF was mixed with NaR (0.25 g, 0.979 mmol, 1 equivalent) and 25 mL of distilled deionized water to form a solution (a faint suspension is also acceptable). This solution was cooled using an ice / water bath. Then, L-arginine (0.152 g, 0.979 mmol, 1.0 equivalent) was added to this solution all at once. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Upon drying, the product became a yellow solid. Yield: Quantitative Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.42 (s,1H ), 9.12 (d, 1H), 8.93 (d, 1H), 8.15 (dd, 1H) , 6.28 (d, 1H), 4.481 (m, 2H), 4.38(t, 1H), 4.10-3.9 (dq, 2H), 3.3 (m, 1H), 3.18 (dd, 1H). 1.5-1.8 (m, 4H) ppm

[0152] Example 10.1 Synthesis of ((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-3-(1H-imidazole-4-yl)propanoate (1:1) [ka] 100 mL of 3N RBF was mixed with NaR (0.25 g, 0.979 mmol, 1 equivalent) and 25 mL of distilled deionized water to form a solution (including a faint suspension). This solution was cooled using an ice / water bath. Then, L-histidine (0.152 g, 0.979 mmol, 1.0 equivalent) was added to this solution all at once. Next, the flask was removed, and the colorless solution was frozen using liquid nitrogen. While the flask was freezing, it was connected to a freeze-dryer. This gradually removed the water. Once dried, the product became a colorless solid. Yield: Quantitative. Analysis data. 1 H-NMR (400 MHz, D2O) δ = 9.42 (s,1H ), 9.12 (d, 1H), 8.93 (d, 1H), 8.15 (dd, 1H) , 7.72 (d, 1H), 7.05 (s, 1H), 6.28(d, 1H), 4 .481 (m, 2H), 4.38 (t, 1H), 4.10-3.9 (dt, 2H), 4.0 (q, 4H), 3.18 (dd,2H) ppm.

[0153] Example 11. NAD cell assay NAD levels were assayed based on the NAD circulation method of Zhu and Rand, PLoS One (2012), incorporated herein by reference. COV434 cells were maintained in a 6-well plate and treated with the indicated compound at a concentration of 200 μM for 4 hours. The medium was removed, the plate was washed with cold PBS, and the cells were leveled in NAD extraction buffer containing 10 mM nicotinamide, 50 mM Tris HCl, and 0.1% Triton X-100. The cells were homogenized by sonication for 5 seconds, and the samples were centrifuged at 7,000 g at 4°C for 5 minutes. Aliquots were taken for subsequent protein assays, and the samples were then filtered through a 10 kDa Amicon filter at 14,000 g at 4°C for 30 minutes to remove proteins from the samples. Each sample was technically triplicated by adding 25 μL of sample to 100 μL of ADH circulating mix (0.2 mg / ml alcohol dehydrogenase, 2% ethanol, 100 mM Tris-HCl pH 8.5). The samples were circulated at room temperature for 10 minutes, followed by the addition of 50 μL of MTT / PMS solution (0.1 mM phenazine methosulfate, 0.8 mM 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide, 100 mM Tris-HCl pH 8.5). The plates were then incubated for 15 minutes, and absorbance was measured at 570 nM. NAD concentrations were extrapolated from the standard curve and normalized to the protein concentrations determined by the BCA protein assay.

[0154] The results of the assay described above are shown in Table 2 (below). The adjusted multipliers are obtained by a direct molar-to-molar comparison between the salt being compared and its parental counterpart. That is, the compound derived from the NaR parent molecule simply has the same NAD activity level as measured against NaR based on the same amount (moles) of salt tested in cells. For example, the multiplier of compound I-002 is based on the NAD activity observed in a direct comparison with the same molar amount and NaR parent in cells. Similarly, the multiplier of I-003 is based on a direct comparison with NaR. [Table 2]

[0155] Equal portions Those skilled in the art will recognize or confirm, without using anything beyond conventional experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are intended to be covered by the following claims.

[0156] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Salt of formula (I): [ka] or its enantiomer, stereoisomer, or tautomer. (In the formula, M 1 It is a zwitterionic amino acid; R 1 , R 2 , and R 3 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, and C(O)R a -C(O)OR a -C(O)NR a R b , or -[CH2-CH2-O] k -R a And, or R 1 and R 2 , or R 2 and R 3 These, together with the atoms to which they are bonded, form 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 It forms a five-membered heterocyclic ring optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; R a and R b Independently, in each presence, is H or C1-C6 alkyl, and the alkyl is (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 Optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; k is an integer between 1 and 8. (Section 2) R a The salt described in item 1 above, wherein H is present. (Section 3) R a The salt described in item 1 above, wherein the salt is methyl. (Section 4) M 1 This is the zwitterionic amino acid of formula (II): [ka] (In the ceremony R 4 and R 5 Independently, in each presence, H or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14The alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is cyano, halo, SeH, or (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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is optionally substituted with one or more substituents selected from; R 6 is H or C1-C6 alkyl, and the alkyl is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0~C3 alkylene) OR c It is optionally substituted with one or more substituents selected from or R 5 and R6 These, together with the atoms they are bonded to, form cyano, halo, and (C0-C3 alkylene) NR compounds. c R d , or (C0~C3 alkylene) OR c Forms a 5-6 membered ring optionally substituted with one or more substituents selected from; R c , and R d Independently, in each presence, is H or C1-C6 alkyl, and the alkyl is (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 Optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; (m, n, and p are independently 0, 1, or 2 in each existence.) The salt described in any one of the above items 1 to 3. (Section 5) R 4 The salt is H, as described in any one of items 1 to 4 above. (Section 6) R 6 The salt is H, as described in any one of items 1 to 5 above. (Section 7) R 5 The salt is H, as described in any one of items 1 to 6 above. (Section 8) R 5 C1-C4 alkyl, (C0-C3 alkylene) C6-C 14 Aryl, or (C0-C3 alkylene) heteroaryl, or one or more (C0-C3 alkylene) SR c A salt according to any one of items 1 to 6 above, wherein the C1 to C4 alkyl group is substituted with [the specified C1-C4 alkyl group]. (Section 9) R 5 The salt is a C1-C4 alkyl group, as described in item 8 above. (Section 10) M 1 teeth, [ka] The salt described in item 1 or 9 above. (Section 11) R 1 The salt is H, as described in any one of items 1 to 10 above. (Section 12) R 1 The salt is a C(O)C1-C3 alkyl salt as described in any one of items 1 to 10 above. (Section 13) R 1 The salt is a C1-C3 alkyl group, as described in any one of items 1 to 10 above. (Section 14) R 2 The salt is H, as described in any one of items 1 to 13 above. (Section 15) R 2 The salt is a C(O)C1-C3 alkyl group, as described in any one of items 1 to 13 above. (Section 16) R 2 The salt is a C1-C3 alkyl group, as described in any one of items 1 to 13 above. (Section 17) (S)-2-ammonio-3-phenylpropanoate compound (1:1)(I-001) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; (2S,3S)-2-ammonio-3-methylpentanoate compound (1:1) (I-002) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; (S)-2-ammonio-3-(1H-indole-3-yl)propanoate compound (1:1) (I-003) having 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate; 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-6-amino-2-ammoniohexanoate(1:1)(I-004); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate(S)-5-amino-2-ammonio-5-oxopentanoate(1:1)(I-005); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-methylpentanoate(1:1)(I-006); 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-4-carboxybutanoate(1:1)(I-007); (S)-2-Ammonia-3-methylbutanoate-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1)(I-008); (S)-2-Ammonia-5-Guanidinopentanoate-1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(Hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate (1:1)(I-009); and 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridine-1-ium-3-carboxylate-(S)-2-ammonio-3-(1H-imidazole-4-yl)propanoate (1:1)(I-010) A salt selected from the group consisting of the above items, as described in item 1. (Section 18) A pharmaceutical composition comprising a salt described in any one of items 1 to 17 above and a pharmaceutically acceptable carrier. (Section 19) A method for treating or preventing age-related infertility, comprising administering an effective amount of a salt described in any one of items 1 to 17 or a composition described in item 18 to a subject in need thereof. (Section 20) A method for treating or preventing infertility, comprising administering an effective amount of a salt described in any one of items 1 to 17 or a composition described in item 18 to a subject in need thereof. (Section 21) A method for improving the quality and maturation of oocytes or blastocysts, comprising contacting the oocytes or blastocysts with an effective amount of the salt described in any one of items 1 to 17 or the composition described in item 18, prior to implantation in a subject requiring treatment for age-related infertility. (Section 22) A method for improving the quality and maturation of oocytes or blastocysts, comprising contacting the oocytes or blastocysts with an effective amount of the salt described in any one of items 1 to 17 or the composition described in item 18, prior to implantation in a subject requiring treatment for age-related infertility. (Section 23) The method according to item 21 or 22, wherein the oocyte or blastocyst is cultured in IVF medium containing the salt. (Section 24) Uses described in any one of items 1 to 17 above in the manufacture of drugs for the treatment of age-related disorders. (Section 25) Use as described in any one of items 1 to 17 above in the manufacture of drugs for treating infertility. (Section 26) Use as described in any one of items 1 to 17 above in the manufacture of a drug for treating age-related infertility. (Section 27) Salt of formula I: [ka] (In the formula: M 1 It is a zwitterionic amino acid; R 1 , R 2 and R 3 These 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 And, or R 1 , R 2 and R 3 These, together with the atoms to which they are bonded, form 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 It forms a five-membered heterocyclic ring optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; R a and R b Independently, in each presence, is H or C1-C6 alkyl, and the alkyl is (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 Optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; k is an integer between 1 and 8. A process for the preparation of a compound of formula II. [ka] (In the ceremony R 4 and R 5Independently, in each presence, H or 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 The alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is cyano, halo, SeH, or (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 Alkilen) 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 Ure c , or (C0~C3 alkylene)BO p R c R d It is optionally substituted with one or more substituents selected from; R 6is H or C1-C6 alkyl, and the alkyl is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0~C3 alkylene) OR c It is optionally substituted with one or more substituents selected from the following: or R 4 and R 6 These, together with the atoms they are bonded to, form cyano, halo, and (C0-C3 alkylene) NR compounds. c R d , or (C0~C3 alkylene) OR c Forms a 5-6 membered ring optionally substituted with one or more substituents selected from; R c , and R d Independently, in each presence, is H or C1-C6 alkyl, and the alkyl is (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 Optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene) heteroaryl groups; (m, n, and p are independently 0, 1, or 2 in each existence.) The process comprises contacting with a metal-alkali hydroxide under conditions effective for producing a product salt of formula I. (Section 28) The process according to item 27, wherein the metal-alkali hydroxide is added dropwise to a solution of the compound of formula II. (Section 29) A cell culture medium for in vitro fertilization: A compound selected from any one of items 1 to 17 above; and Culture medium The cell culture medium comprising the above. (Section 30) The cell culture medium according to item 29 above, wherein the culture medium is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, serum, a vitamin, a growth factor, or any combination thereof. (Section 31) The cell culture medium according to item 30, wherein the inorganic salt is calcium chloride, magnesium chloride, magnesium sulfate, potassium chloride, sodium bicarbonate, sodium chloride, monosodium phosphate, disodium phosphate, or any combination thereof. (Section 32) The cell culture medium according to item 30, wherein the energy substrate is glucose, pirubate, lactate, pirubate, or any combination thereof. (Section 33) The cell culture medium described in item 30 above, wherein the amino acid is an essential amino acid. (Section 34) The cell culture medium according to item 33 above, wherein the essential amino acid is arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof. (Section 35) The cell culture medium described in item 30 above, wherein the amino acid is a non-essential amino acid. (Section 36) The cell culture medium according to item 35, wherein the non-essential amino acid is alanine, asparagine, aspartic acid, glutamic acid, proline, serine, or any combination thereof. (Section 37) The chelating agents mentioned above are clathrochelate, acetylacetone, aminopolycarboxylic acid, ATMP, BAPTA, BDTH2, citric acid, cryptand, deferasirox, 2,3-dihydrobenzoic acid, 2,3-dimercapto-1-propanesulfonic acid, and dimercapto The cell culture medium described in item 30 above, which is succinic acid, DOTA, DTPMP, EDDHA, EDDS, EDTMP, etidronic acid, fura-2, gluconic acid, homocitric acid, iminodiacetic acid, Indo-1, trinitrile acetate, pentetate (DTPA), phosphonate, phytokeratin, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof. (Section 38) The cell culture medium according to item 30, wherein the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridin, or any combination thereof. (Section 39) The cell culture medium according to item 30 above, wherein the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof. (Section 40) The cell culture medium according to item 32 above, wherein the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof. (Section 41) The aforementioned vitamins are ascorbic acid, biotin, menadione sodium bisulfite, mitomycin C, pyridoxamine dihydrochloride, retinyl acetate, (-)-riboflavin, (+)-L-sodium ascorbate, (+)-α-tocopherol, and vitamin B 12 The cell culture medium described in item 30 above, which is thiamine hydrochloride, i-inositol, pyridoxal hydrochloride, nicotinamide, folic acid, calcium D-pantothenate, choline chloride, or any combination thereof. (Section 42) The cell culture medium according to item 30 above, wherein the growth factors are adrenomedullin, angiopoietin, 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 stimulant, macrophage-stimulating protein, myostatin, neurotrophin, T cell growth factor, thrombopoietin, transforming growth factor, tumor necrosis factor-alpha, vascular endothelial growth factor, or any combination thereof. (Section 43) The cell culture medium according to item 29, further comprising oocytes, zygotes, blastocysts, or any combination thereof.

Claims

[Claim 1] A disease related to aging.

Images