Quaternary ammonium salts of nicotinic acid and nicotinamide mononucleotides and ribosides as anti-aging agents.

Abstract

The present invention relates to NAD + and nicotinic acid and nicotinamide amino acid salts and compositions thereof of formula I, useful for treating disorders and diseases associated with a deficiency of In the formula, A, L, M 1 , M 2 , R 1 , R 2 , and R 3 is as described herein. [Selection diagram] None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 713,046, filed August 1, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to quaternary salts of nicotinic acid mononucleotide and nicotinamide mononucleotide and compositions thereof useful in the treatment of disorders and diseases associated with aging. [Background technology]

[0003] Aging is the result of complex interactions involving biological, physical, and biochemical processes that cause cellular and organ dysfunction that manifests in a variety of diseases and other outcomes. For example, female fertility is particularly sensitive to the effects of aging. For example, the USA Centers for Disease Control reports that among women in their mid-30s and beyond, the rate of assisted reproductive technology (ART)-associated pregnancies and births has steadily declined from approximately 25% of ART cycles resulting in singleton births to 14% by age 40 (Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2011 Assisted Reproductive Technology National Summary Report. Atlanta (GA): US Dept of Health and Human Services; 2013). This trend increases significantly above age 40, with the CDC reporting that women over 44 years of age have a very low probability of success. In this group, the rate of births and singleton births has declined to about 1%. In general, a woman's age is considered to be the most important factor affecting her chances of having a child when using her own eggs (oocytes).

[0004] The deterioration of oocyte quality due to aging is understood to be the underlying cause of decreased fertility. For example, in older women, it has been reported that oocytes are more susceptible to abnormal chromosome division, exhibit reduced mitochondrial quality, decreased ATP production, increased oxidative stress, and decreased antioxidant levels (Nelson SM, Telfer EE, Anderson RA. The ageing 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 aforementioned reasons, oocytes represent an excellent target tissue for the evaluation of therapeutic modalities expected to affect the aging process and further offer the prospect of addressing age-related infertility.

[0006] One such potential therapeutic modality for treating aging is NAD + Includes drugs that increase therapeutic levels of NAD. + NAD is an essential component of cellular processes required to support a variety of metabolic functions. + The typical role of is as a coenzyme that catalyzes cellular redox reactions and is reduced to NADH in many fundamental metabolic processes, such as glycolysis, fatty acid β-oxidation, or the tricarboxylic acid cycle. In addition to these roles, NAD +It is involved in the regulation of NAD by poly-ADP-ribose polymerase (PARP), sirtuins, and CD38 / 157 ectoenzymes. + It plays an important role as a substrate for NAD consuming enzymes. + Consumable enzymes are known to mediate many fundamental cellular processes.

[0007] NAD + There are five main precursors and intermediates for the synthesis of NAD: tryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). + Nicotinic acid 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 NAD + NAD by synthetic enzyme + The compound is amidated to the desired product.

[0008] In mammals, NAD + The major pathway of biosynthesis is the salvage pathway from nicotinamide, which is converted to essential NAD by the rate-limiting enzyme in this pathway, nicotinamide phosphoribosyltransferase (NAMPT). + NMN is then converted to the intermediate NMN by NAD + NAMPT converts cellular NAD + It plays an important role in regulating the levels of NAD. Meanwhile, nicotinic acid is converted to NaMN by nicotinic acid phosphoribosyltransferase (NPT). NR needs to be converted to NMN by nicotinamide ribose kinases, NMRK1 and NMRK2 (also known as NRK1 and NRK2), which phosphorylate NR. Adequate NAD + Maintenance of NAD biosynthesis is essential for cell survival and function. + Deviation from homeostasis reduces the amount of NAD required for redox reactions.+ / NADH pool as well as NAD for important cellular functions + The activity of dependent enzymes is also substantially affected.

[0009] Currently, NAD + There is growing consensus that NAD levels are decreased at the cellular, tissue / organ, and organismal levels. + The activity of the consuming enzyme is + These conditions are subject to decline and contribute to a wide range of age-related pathophysiology.

[0010] Nicotinamide adenine dinucleotide is an enzyme cofactor essential 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. + NAD functions as an electron carrier in the energy metabolism of amino acids, fatty acids, and carbohydrates (Bogan & Brenner, Annu. Rev. Nutr. 2008, 28, 115-130). + NAD is important for redox reactions in DNA repair, energy metabolism, cell survival, and regulation of cardiovascular rhythms, and as a substrate for signaling by PARP (polyadenoside diphosphate ribose polymerase) and sirtuins (SIRT1-SIRT7), all of which have been shown to be important in the aging process (Bronkowski, MS & Sinclair, D., Nat. Rev. Mole. Cell. Bio., 17, 679-690, (2016)). + Increasing concentrations slow aging in yeast, fish, and mice (Mouchiroud et al. Cell 154, 464-471, (2014)). NAD+ However, it has also been recently demonstrated that NMN and NR directly regulate protein-protein interactions, which may protect against cancer and radiation exposure as well as directly affect aging (Li et al., Science 355, 1312-1317, 2017). Thus, increasing evidence supports the role of NADs such as NMN and NR in the regulation of aging. + Interventions that use intermediates can increase the amount of available NAD + These findings support the idea that restoring ATP can strengthen the system and attenuate the physiological decline associated with aging.

[0011] NAD + NAD can be synthesized de novo from the amino acid tryptophan, but this process does not occur in all tissues, and most cells derive NAD from other intracellular intermediates available primarily through dietary sources. + In order to increase NAD cellular bioavailability, other NAD precursors such as nicotinic acid and nicotinamide can also be administered. 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)). Also, nicotinamide does not reliably activate (and may even inhibit) sirtuins even though it increases NAD concentrations (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)). Thus, administration of nicotinic acid or nicotinamide is unlikely to be widely adopted to maintain health and function with aging.

[0012] In contrast to nicotinic acid and nicotinamide, NADs such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) + Administration of metabolites increases NAD + It appears that NR increases the levels of NAD and improves multiple physiological functions in animal models (Yoshino, J. et al., Cell Metab. 14, 528-536 (2011), Mills, KF et al., Cell Metab. 24, 795-806 (2016), and Frederick, DW et al., Cell Metab. 24, 269-282 (2016)). Although further studies are needed to confirm the findings of this exploratory study, it has been reported that at least one of these metabolites is well tolerated in humans and leads to increased NAD levels and improved physiological functions (Christopher R. Martens, et al., Nat. Commun. 9, 1286, (2018)). Furthermore, a recent study showed that a single dose of NR significantly increased blood cell NAD in healthy humans. + showed that it stimulated the metabolism of β-lactamase in a dose-dependent manner (Trammell, SA et al., Nat. Commun. 7, 12948 (2016)), indicating the limitation of this metabolite. However, the known NAD + Many of the metabolites are unstable in various physiological environments and therefore may affect the NAD levels in the patient. + Such metabolites are not suitable as viable pharmaceutical agents for administration to patients requiring increased levels. NAD + Given that NAD plays a key role in important cellular and physiological pathways, it is important to understand how NAD plays a key role in disease states and / or during the aging process. + The development of new stabilizers with improved properties that can increase levels is necessary to ameliorate human pathologies. [Prior art documents] [Non-patent literature]

[0013]

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[0014] A first aspect of the present application relates to a salt of formula (I): [ka] and its enantiomers, stereoisomers, and tautomers, During the ceremony, A is NR a R b Or O - and L is a bond or [ka] and M 1 and M 2 are independently absent or a quaternary cation, with the proviso that M 1 or M 2 at least one of is a quaternary cation; R 1 and R 2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, -C(O)OR a , -C(O)NR a R b , -[CH2-CH2-O] k -R a , -C(O)[CH2-CH2-O] k -R a , -[CH2-CH2-CH2-O] k -Ra , or -C(O)[CH2-CH2-CH2-O] k -R a and or R 1 and R 2 together with the atom to which they are attached, represent 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 forming a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene)heteroaryl; R 3 is a negative charge, H, or C1-C6 alkyl; R a and R b is independently at each occurrence H or C1-C6 alkyl, where alkyl is selected from the group consisting of (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; k is an integer from 1 to 8; however, a) When L is a bond, M 1 does not exist, b) A is NR a R b If M 2 does not exist.

[0015] Another aspect of the disclosure relates to a pharmaceutical composition comprising a salt of Formula I, or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable carrier.

[0016] Another aspect of the present application relates to a method for treating or preventing an age-related disorder, comprising administering to a subject in need thereof an effective amount of a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof.

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

[0018] Another aspect of the present application relates to a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, for use in a method for treating an age-related disorder.

[0019] Another aspect of the present application relates to a salt of Formula (I), or an enantiomer, stereoisomer, or tautomer thereof, for use in a method for treating infertility.

[0020] 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 an age-related disorder.

[0021] 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.

[0022] Another aspect of the present disclosure relates to a method of improving oocyte quality and maturation, comprising administering a therapeutically effective amount of a salt of Formula I to a subject in need thereof.

[0023] Another aspect of the disclosure relates to the use of a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating an age-related disorder.

[0024] In another aspect, the invention involves treating oocytes with a salt of formula (I) ex vivo prior to implantation into a subject for the treatment of age-related infertility.

[0025] In another embodiment, the invention involves treating blastocysts with a salt of formula (I) ex vivo prior to implantation into a subject for the treatment of age-related infertility.

[0026] In another aspect, the invention involves treating oocytes with a salt of formula (I) ex vivo prior to implantation into a subject for the treatment of infertility.

[0027] In another embodiment, the invention involves treating blastocysts with a salt of formula (I) ex vivo prior to implantation into a subject for the treatment of infertility.

[0028] In another aspect, the salt of formula (I) is provided as a component in a solution for use in treating cells ex vivo for use in treating age-related disorders.In some embodiments, the age-related disorder is age-related infertility.In another aspect, the salt of formula (I) is provided as a component in a solution for use in treating cells ex vivo for use in treating infertility.

[0029] 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 to produce the salt of formula I.

[0030] The present disclosure also relates to a method of accelerating recovery from a disease or disorder, comprising administering to a subject in need thereof an effective amount of a salt of formula (I) in combination with a given treatment for the disease.

[0031] In another aspect, the disclosure relates to a cell culture medium for in vitro fertilization comprising one or more salts of formula (I) and culture agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] This application relates to salts and compositions that can treat or prevent age-related disorders. This application features a method of treating, preventing, or ameliorating an age-related disease or disorder by administering a therapeutically effective amount of a salt of formula (I), or an enantiomer, stereoisomer, or tautomer thereof, to a patient in need thereof. The method of this application can be used to treat a variety of diseases and disorders by preventing or ameliorating the processes of aging and cell repair, including, but not limited to, infertility, cell deterioration.

[0033] The salts of formula (I) are potent, effective at clinically achievable doses, stable in a variety of potential dosage forms, have acceptable solubility, acceptable pH, are crystalline, have reduced tendency to absorb water, and exhibit ease of handling, all of which are consistent with pharmaceutical development, manufacture, and use. In addition, the salts disclosed herein promote increased cellular NAD + The present invention provides improved glycerol levels, increased stability, and increased biological activity at a more physiologically acceptable pH.

[0034] A first aspect of the disclosure relates to a salt of formula I: [ka] In the formula, A, L, M 1 , M 2 , R 1 , R 2 , and R 3 is as described herein.

[0035] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0036] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0037] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bound to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be bound at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CHCN, -O(C1-C6)alkyl, (C1-C6)alkyl, C1-C6alkoxy, (C1-C6)haloalkyl, C1-C6haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)( OH), -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH, -NH((C1-C6)alkyl), -N((C1-C6)alkyl), -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). The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substitution or non-substitution, the meaning of which is described below.

[0038] As used herein, the term "substituted" means that the specified group or moiety has one or more suitable substituents, and these substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0039] As used herein, the term "unsubstituted" means that the specified group bears no substituents.

[0040] Unless expressly defined otherwise, 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. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., one to five substituents. Exemplary substituents include, but are not limited to, -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. The substituents themselves may be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein can have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0041] Unless expressly defined otherwise, "heteroaryl" refers to 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 refers to a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, or S. The aromatic radicals are optionally substituted, independently, 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, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, Imidazo[1,2-b]pyrazolyl, furo[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 , indolinyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinolinyl, Zolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4, 3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings, the aryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0042] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0043] "Alkyl" refers to a straight or branched chain 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.

[0044] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0045] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond within the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as defined herein, can be straight or branched chain.

[0046] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond within the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0047] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can also be a C1-C6 alkylene. Alkylene can further be a 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-, and the like.

[0048] "Cycloalkyl" means a monocyclic or polycyclic saturated carbon ring (e.g., a fused ring, a bridged ring, or a spiro ring) containing 3 to 18 carbon atoms (e.g., C3 - C 10 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norbornenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0049] "Heterocyclyl" or "heterocycloalkyl" means a monocyclic or polycyclic ring (e.g., a fused ring, a bridged ring, or a spiro ring) containing carbon and a heteroatom selected from oxygen, nitrogen, or sulfur, and having no delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. Heterocycloalkyl can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, 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 the present application, a 3- to 10-membered heterocyclyl refers to a saturated or partially saturated non-aromatic ring structure containing 3 to 10 atoms, wherein at least one heteroatom selected from N, O, or S is present.

[0050] The term "hydroxyalkyl" means an alkyl group as defined above, wherein the alkyl group is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0051] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0052] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0053] The term "cyano" as used herein refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, ie, C≡N.

[0054] The term "amine" as used herein refers to primary (R-NH2, R≠H), secondary (R2-NH, R2≠H), and tertiary (R3-N, R≠H) amines. A substituted amine is intended to mean an amine in which at least one of the hydrogen atoms has been replaced by a substituent.

[0055] The term "amino" as used herein refers to a substituent containing at least one nitrogen atom. Specifically, NH, -NH(alkyl) or alkylamino, -N(alkyl) or dialkylamino, amido, carbamido, urea, and sulfamido substituents are included in the term "amino".

[0056] The term "oxo" as used herein refers to a "=O" group.

[0057] "Quaternary cation" refers to a quaternary ammonium or phosphonium ion having four substituents, which may be the same or different, on its nitrogen or phosphorus atom. Specific examples of such quaternary cations include trimethylglycine, carnitine, choline, etc.

[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. The structural difference can be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the salts of formula (I) can have one or more asymmetric carbon atoms and can occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0059] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed salts and a pharma- ceutically acceptable carrier. Exemplary "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, methylcellulose ... Water soluble and insoluble salts include sodium, 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-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate salts.

[0060] A "patient" or "subject" is a mammal, e.g., a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0061] An "effective amount" when used in connection with a salt or pharmaceutical composition is an amount effective to treat or prevent a disease in a subject as described herein.

[0062] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a drug from one organ or part of the body of a subject to another organ or part of the body.

[0063] The term "treating" with respect to a subject refers to improving at least one symptom of a disorder in a subject. Treatment includes curing, ameliorating, or at least partially ameliorating a disorder.

[0064] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0065] The terms "administer," "administering," or "administration" as used in this disclosure refer to either administering a disclosed salt or composition directly to a subject, or administering to a subject a prodrug derivative or analog of the salt or composition, which can form an equivalent amount of the active salt in the subject's body.

[0066] Salts of the present application The present application relates to salts or enantiomers, stereoisomers, or tautomers thereof that are useful in the treatment of diseases and disorders associated with aging and cell repair, and that can treat or prevent age-related disorders.

[0067] In one embodiment of the salt of formula I, A is O - In another embodiment, A is NR a R b It is.

[0068] In one embodiment of the salt of formula I, L is a bond. In another embodiment, L is [ka] It is.

[0069] In some embodiments of the present invention, R a is independently at each occurrence H, or C1-C6 alkyl. a is H. In other embodiments, R a is C1-C6 alkyl. In another embodiment, R a is 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 aryl, or C1-C6 alkyl substituted with one or more substituents selected from (C0-C3 alkylene)heteroaryl. a is C1-C6 alkyl substituted with one or more substituents selected from C1-C6 alkyl. a is C1-C6 alkyl substituted with one or C2-C6 alkenyl. a is C1-C6 alkyl substituted with one or more C2-C6 alkynyl. In another embodiment, R a is C1-C6 alkyl substituted with one or more m(C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R a is C1-C6 alkyl substituted with one or more (C0-C3 alkylene)heterocycloalkyl. In other embodiments, R a is one or more (C0-C3 alkylene)C6-C 14 In another embodiment, R a is C1-C6 alkyl substituted with one or more (C0-C3 alkylene)heteroaryl. a is methyl. In other embodiments, R a is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14aryl, or methyl substituted with one or more substituents selected from (C0-C3 alkylene)heteroaryl.

[0070] In some embodiments of the present invention, R b is independently at each occurrence H, or C1-C6 alkyl. b is H. In other embodiments, R b is C1-C6 alkyl. In another embodiment, R b is 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 aryl, or C1-C6 alkyl substituted with one or more substituents selected from (C0-C3 alkylene)heteroaryl. b is C1-C6 alkyl substituted with one or more substituents selected from C1-C6 alkyl. b is C1-C6 alkyl substituted with one or C2-C6 alkenyl. b is C1-C6 alkyl substituted with one or more C2-C6 alkynyl. In another embodiment, R b is C1-C6 alkyl substituted with one or more m(C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R b is C1-C6 alkyl substituted with one or more (C0-C3 alkylene)heterocycloalkyl. In other embodiments, R b is one or more (C0-C3 alkylene)C6-C 14 In another embodiment, R b is C1-C6 alkyl substituted with one or more (C0-C3 alkylene)heteroaryl. b is methyl. In other embodiments, R bis 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 aryl, or methyl substituted with one or more substituents selected from (C0-C3 alkylene)heteroaryl.

[0071] In yet another embodiment, R 3 is a negative charge, H, or C1-C6 alkyl. 3 represents a negative charge. 3 is H. In another embodiment, R 3 is C1-C6 alkyl.

[0072] In a further embodiment, R 1 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, -C(O)OR a , -C(O)NR a R b , -[CH2-CH2-O] k -R a , -C(O)[CH2-CH2-O] k -R a , -[CH2-CH2-CH2-O] k -R a , or -C(O)[CH2-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 -Ra In another embodiment, R 1 is C(O)C1-C6 alkyl. In another embodiment, R 1 is -C(O)C1-C6 haloalkyl. In another embodiment, R 1 is -C(O)[CH2-CH2-O] k -R a In another embodiment, R 1 is -[CH2-CH2-CH2-O] k -R a In another embodiment, R 1 is -C(O)[CH2-CH2-CH2-O] k -R a It is.

[0073] In one embodiment, R 2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, -C(O)OR a , -C(O)NR a R b , -[CH2-CH2-O] k -R a , -C(O)[CH2-CH2-O] k -R a , -[CH2-CH2-CH2-O] k -R a , or -C(O)[CH2-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, R 2 is -C(O)OR a In another embodiment, R 2 is -[CH2-CH2-O] k -R a In another embodiment, R2 is C(O)C1-C6 alkyl. In another embodiment, R 2 is -C(O)C1-C6 haloalkyl. In another embodiment, R 2 is -C(O)[CH2-CH2-O] k -R a In another embodiment, R 2 is -[CH2-CH2-CH2-O] k -R a In another embodiment, R 2 is -C(O)[CH2-CH2-CH2-O] k -R a It is.

[0074] In a further embodiment of the salt of formula I, R 1 and R 2 may be taken together with the atoms to which they are attached to form a 5-membered heterocyclic ring. In a further embodiment of the salt of formula I, R 1 and R 2 may be taken together with the atoms to which they are attached to form a six-membered heterocyclic ring. In a further embodiment of the salt of formula I, R 1 and R 2 together with the atom to which they are attached, represent C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 In a further embodiment of the salt of formula I, R 1 and R 2 together with the atom to which they are attached, represent 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 may form a 6-membered heterocycle substituted with one or more substituents selected from aryl and (C0-C3 alkylene)heteroaryl.

[0075] In one embodiment of the salt of formula I, M 1 In one embodiment of the salt of formula I, M 1 is a quaternary cation. In another embodiment, M 1 is represented by formula II, formula III, or formula IV: [ka] In another embodiment, M 1 is a quaternary cation of formula II. In another embodiment, M 1 is a quaternary cation of formula III. In another embodiment, M 1 is a quaternary cation of formula IV.

[0076] In one embodiment of the salt of formula I, M 2 In one embodiment of the salt of formula I, M 2 is a quaternary cation. In another embodiment, M 2 is represented by formula II, formula III, or formula IV: [ka] In another embodiment, M 2 is a quaternary cation of formula II. In another embodiment, M 2 is a quaternary cation of formula III. In another embodiment, M 2 is a quaternary cation of formula IV.

[0077] In one embodiment of the salt of formula I, M 1 does not exist, and M 2 is a quaternary cation. In another embodiment, M 1 does not exist, and M 2 is represented by formula II, formula III, or formula IV: [ka] is a quaternary cation.

[0078] In one embodiment of the salt of formula I, M 2 does not exist, and M 1is a quaternary cation. In another embodiment, M 2 does not exist, and M 1 is represented by formula II, formula III, or formula IV: [ka] is a quaternary cation.

[0079] In one embodiment of the salt of formula I, M 1 and M 2 Each is a quaternary cation. In another embodiment, M 1 and M 2 each independently represents Formula II, Formula III, or Formula IV: [ka] is a quaternary cation.

[0080] In one embodiment of the salt of formula I, M 1 is represented by formula IIa: [ka] where r is 0 or 1.

[0081] In one embodiment of the salt of formula I, M 2 is represented by formula IIa: [ka] where r is 0 or 1.

[0082] In one embodiment of the salt of formula I, M 1 teeth, [ka] In another embodiment, M 1 teeth, [ka] In another embodiment, M 1 teeth, [ka] In another embodiment, M 1 teeth, [ka] It is.

[0083] In one embodiment of the salt of formula I, M 1 and M 2 teeth, [ka] In another embodiment, M 1 and M 2 teeth, [ka] In another embodiment, M 1 and M 2 teeth, [ka] In another embodiment, M 1 and M 2 teeth, [ka] It is.

[0084] In one embodiment of the salt of formula I, R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 aryl, or (C0-C3 alkylene)heteroaryl. In another embodiment, R 4 is H. In another embodiment, R 4 is C1-C6 alkyl. In another embodiment, R 4 is C2-C6 alkenyl. In another embodiment, R 4is C2-C6 alkynyl. In another embodiment, R 4 is (C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R 4 is (C0-C3 alkylene)heterocycloalkyl. In another embodiment, R 4 is (C0-C3 alkylene)C6-C 14 In another embodiment, R 4 is (C0-C3 alkylene)heteroaryl. In another embodiment, R 4 is one or more (C0-C3 alkylene)SR c is a C1-C4 alkyl substituted with

[0085] In another embodiment, R 4 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c, or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is 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)ORc , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d, (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 4 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c, or (C0-C3 alkylene)BO p R c R d In another embodiment, R is a (C0-C3 alkylene)heterocycloalkyl substituted with one or more substituents selected from 4 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d (C0-C3 alkylene)C6-C 14 In another embodiment, R 4 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)Rc , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d is a (C0-C3 alkylene)heteroaryl substituted with one or more substituents selected from the following:

[0086] In one embodiment of the salt of formula I, R 5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 aryl, or (C0-C3 alkylene)heteroaryl. In another embodiment, R 5 is H. In another embodiment, R 5 is C1-C6 alkyl. In another embodiment, R 5 is C2-C6 alkenyl. In another embodiment, R 5 is C2-C6 alkynyl. In another embodiment, R5 is (C0-C3 alkylene)C3-C8 cycloalkyl. In another embodiment, R 5 is (C0-C3 alkylene)heterocycloalkyl. In another embodiment, R 5 is (C0-C3 alkylene)C6-C 14 In another embodiment, R 5 is (C0-C3 alkylene)heteroaryl.

[0087] In another embodiment, R 5 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R5 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c, (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)On R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d In another embodiment, R 5 is cyano, halo, SeH, (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (C0-C3 alkylene)OC(O)R c , (C0-C3 alkylene)C(O)OR c , (C0-C3 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R dIn another embodiment, R is a (C0-C3 alkylene)heterocycloalkyl substituted with one or more substituents selected from 5 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c R d , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d (C0-C3 alkylene)C6-C 14 In another embodiment, R 5 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 alkylene)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 OR c , or (C0-C3 alkylene)BO p R c R d is a (C0-C3 alkylene)heteroaryl substituted with one or more substituents selected from the following:

[0088] In another embodiment, R 6 is H or C1-C6 alkyl. In another embodiment, R 6 is H. In another embodiment, R 6 is C1-C6 alkyl. In another embodiment, R 6 is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c is a C1-C6 alkyl substituted with one or more substituents selected from the following:

[0089] In another embodiment, R 7 is H or C1-C6 alkyl. In another embodiment, R 7 is H. In another embodiment, R 7is C1-C6 alkyl. In another embodiment, R 7 is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c is a C1-C6 alkyl substituted with one or more substituents selected from the following:

[0090] In another embodiment, R 8 is H or C1-C6 alkyl. In another embodiment, R 8 is H. In another embodiment, R 8 is C1-C6 alkyl. In another embodiment, R 8 is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c is a C1-C6 alkyl substituted with one or more substituents selected from the following:

[0091] In yet another embodiment, R 4 and R 6 may be taken together with the atoms to which they are attached to form a five-membered ring. 4 and R 6 together with the atoms to which they are attached, form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c In another embodiment, R 4 and R 6 may be taken together with the atoms to which they are attached to form a six-membered ring. 4 and R 6 together with the atoms to which they are attached, form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c may form a six-membered ring substituted with one or more substituents selected from:

[0092] In yet another embodiment, R 7 and R 8 may be taken together with the atoms to which they are attached to form a five-membered ring. 7 and R 8 together with the atoms to which they are attached, form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c In another embodiment, R 7 and R 8 may be taken together with the atoms to which they are attached to form a six-membered ring. 7 and R 8 together with the atoms to which they are attached, form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c may form a six-membered ring substituted with one or more substituents selected from:

[0093] In a further embodiment, R d is independently at each occurrence H or C1-C6 alkyl. d is H. In another embodiment, R d is C1-C6 alkyl. In another embodiment, R d is C1-C6 alkyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 and one or more substituents selected from aryl, (C0-C3 alkylene)heteroaryl.

[0094] In a further embodiment, R c is independently at each occurrence H or C1-C6 alkyl. c is H. In another embodiment, R c is C1-C6 alkyl. In another embodiment, R cis C1-C6 alkyl, (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14 and one or more substituents selected from aryl, (C0-C3 alkylene)heteroaryl.

[0095] In another embodiment, k at each occurrence is 1, 2, 3, 4, 5, 6, 7, or 8. In another embodiment, k is 1. In another embodiment, k is 2. In another embodiment, k is 3. In another embodiment, k is 4. In another embodiment, k is 5. In another embodiment, k is 6. In another embodiment, k is 7. In another embodiment, k is 8.

[0096] In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2.

[0097] 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.

[0098] 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.

[0099] In one embodiment, q is 0, 1, 2, 3, 4, or 5. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5.

[0100] In one embodiment, r is 0 or 1. In another embodiment, r is 0. In another embodiment, r is 1.

[0101] In some embodiments, the salt of Formula I has the formula (Ia): [ka] It has the structure:

[0102] In some embodiments, the salt of Formula I is represented by Formula Ib: [ka] It has the structure:

[0103] In some embodiments, the salt of Formula I has formula Ic: [ka] It has the structure:

[0104] In some embodiments, the salt of Formula I has the formula Id: [ka] It has the structure:

[0105] In some embodiments, the salt of Formula I has formula Ie: [ka] It has the structure:

[0106] In some embodiments, the salt of Formula I has the formula If: [ka] It has the structure:

[0107] In some embodiments, the salt of formula I has formula Ig: [ka] It has the structure:

[0108] In some embodiments, the salt of formula I has formula Ik: [ka] It has the structure:

[0109] In some embodiments, the salt of Formula I has the formula Il: [ka] It has the structure:

[0110] In some embodiments, the salt of formula I has the formula Im: [ka] It has the structure:

[0111] In some embodiments, the salt of formula I has the formula In: [ka] It has the structure:

[0112] In some embodiments, the salt of formula I has formula Io: [ka] It has the structure:

[0113] In some embodiments, the salt of Formula I is represented by formula Ip: [ka] It has the structure:

[0114] In some embodiments, the salt of formula I has formula Iq: [ka] It has the structure:

[0115] In some embodiments, the salt of Formula I has the formula Ir: [ka] It has the structure:

[0116] In some embodiments, the salt of Formula I has the formula Is: [ka] It has the structure:

[0117] In another embodiment, suitable salts include, but are not limited to, [ka] Examples include:

[0118] Method of preparing salt The salts of the present application may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes provided below.

[0119] Salts of formula (I) can be prepared by methods known in the art of organic synthesis, as described in part by the following synthetic schemes. In the schemes described below, it is fully understood that protective groups for sensitive or reactive groups are used as necessary according to general principles or chemistry. Protective groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Huts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the salt synthesis, using methods that are readily apparent to those skilled in the art. The selected processes, as well as the reaction conditions and the order of their execution, shall be consistent with the preparation of salts of formula (I).

[0120] Those skilled in the art will recognize whether a stereocenter exists in the salt of formula (I). Thus, the present application includes both possible stereoisomers (unless specified in the synthesis), including racemic salts as well as individual enantiomers and / or diastereomers. When a compound or salt is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

[0121] The salts and compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes.

[0122] The salts of the present application can be prepared in several ways well known to those skilled in the art of organic synthesis. For example, the salts of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof that will be understood by those skilled in the art. These methods include, but are not limited to, the methods described below. The salts of the present application can be synthesized by following the steps outlined in general schemes 1 and 2, which include different sequences of assembling various intermediates. The starting materials are either commercially available or made by known procedures in the reported literature, or as illustrated. [ka]

[0123] The mixtures of enantiomers, diastereomers, and cis / trans isomers resulting from the above processes can be separated into their single components by chiral salt techniques, or chromatography using normal phase, reverse phase, or chiral columns, depending on the nature of the separation.

[0124] In the explanations and formulae given above, the group R in the scheme is R 4 and R 5 and it should be understood that other variables are as defined above unless otherwise indicated. Additionally, for synthetic purposes, the salts of General Schemes 1 and 2 are merely representative, with radicals selected to illustrate the general synthetic methodology of salts of formula (I) defined herein.

[0125] It should also be understood that the salts disclosed herein have a neutral charge, and the structure of formula I only represents a genus that can be balanced with counterions, if necessary, to allow the salt to present a neutral charge. Such counterions can include, but are not limited to, bromine, chlorine, and triflate. In an embodiment, the salts of the present invention can be generated in situ without the need to be isolated from solution. In some embodiments, the salts disclosed herein can be separate 1:1 or 1:2 salts. In some embodiments, the salts can also be present in other ratios, for example, 1:1.5, 1:5, and 1:10.

[0126] Methods of Using the Disclosed Salts Another aspect of the present disclosure relates to a method for treating or preventing diseases or disorders associated with aging, cell deterioration, and / or cell repair.Non-limiting examples of such diseases and disorders include infertility, age-related infertility, age-related eye function loss, decreased bone density, obesity, and insulin insensitivity.In one embodiment, the salt of formula (I) is useful in treating age-related infertility.In another embodiment, the salt of formula (I) is useful in treating infertility.

[0127] Another aspect of the present disclosure relates to a method for treating or preventing an age-related disease or disorder, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of a salt of Formula I to a subject in need thereof.

[0128] Yet another aspect of the present disclosure relates to a method for improving the quality and maturation of an oocyte or blastocyst, the method comprising contacting the oocyte or blastocyst with an IVF medium comprising a salt of formula (I) for an effective period of time.

[0129] In another aspect, the present disclosure provides a medium containing a salt of formula (I). The salt of formula (I) has shown surprising and unexpected long-term stability in solution, and thus can be used to treat NADPH prior to transplantation into a subject suffering from infertility or age-related infertility. + It is useful in media for exposing eggs, oocytes, and / or blastocysts for the period of time required to enhance production. In some embodiments, media are provided that include a salt of formula (I). In some embodiments, the media includes various reagents and factors required for the eggs, oocytes, or blastocysts depending on which stage of maturation and development the eggs, oocytes, or blastocysts are in. For example, the media can contain any of the agents or factors useful in IVF media listed in Table 1 below. [Table 1]

[0130] Also provided is a cell culture medium for in vitro fertilization comprising one or more salts of formula (I) and culture agents.

[0131] In one embodiment, the culture agent is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof. In one embodiment, the inorganic salt is calcium chloride, magnesium chloride, magnesium sulfate, potassium chloride, sodium bicarbonate, sodium chloride, monosodium phosphate, disodium phosphate, or any combination thereof.

[0132] In one embodiment, the energy substrate is glucose, pyruvate, lactate, pyruvate, or any combination thereof.

[0133] In one embodiment, the amino acid is an essential amino acid, hi one embodiment, the essential amino acid is arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof.

[0134] In one embodiment, the amino acid is a non-essential amino acid.

[0135] In one embodiment, the non-essential amino acid is alanine, asparagine, aspartate, glutamate, proline, serine, or any combination thereof.

[0136] 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, nitrile triacetic acid, pentetic acid (DTPA), phosphonate, phytochelate, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof.

[0137] In one embodiment, the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridine, or any combination thereof.

[0138] In one embodiment, the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof.

[0139] In one embodiment, the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.

[0140] In one embodiment, the vitamins are ascorbic acid, biotin, menadione sodium bisulfite, mitomycin C, pyridoxamine dihydrochloride, retinyl acetate, (-)-riboflavin, (+)-sodium L-ascorbate, (+)-α-tocopherol, vitamin B 12 , thiamine hydrochloride, i-inositol, pyridoxal hydrochloride, nicotinamide, folic acid, calcium D-pantothenate, choline chloride, or any combination thereof.

[0141] In one embodiment, the growth factor is 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, gibberellin growth factor, growth differentiation factor 9, hepatocyte growth factor, insulin, insulin-like growth factor, interleukin, keratinocyte growth factor, migration stimulating factor, macrophage stimulating protein, myostatin, neurotrophin, t cell growth factor, thromboetin, transforming growth factor, tumor necrosis factor-alpha, vascular endothelial growth factor, or any combination thereof.

[0142] In one embodiment, the cell culture medium further comprises an oocyte, a zygote, a blastocyst, or any combination thereof.

[0143] Also provided are kits for IVF media containing various agents and factors necessary for maturation of oocytes or blastocysts comprising one or more salts of formula (I). These agents and cofactors can be dissolved in solution to produce the IVF media immediately prior to use in exposing oocytes or blastocysts prior to implantation in patients in need of treatment for infertility or age-related infertility.

[0144] The present invention also relates to the use of the salt of formula I and its enantiomers, stereoisomers and tautomers for the manufacture of a medicament for treating aging, cell repair, cell deterioration, or infertility. In certain embodiments, the infertility treated is age-related infertility.

[0145] Another aspect of the invention is a pharmaceutical composition comprising a salt of Formula I and a pharma- ceutically acceptable carrier.

[0146] Another aspect of the invention is a pharmaceutical composition comprising a salt of Formula I and a pharma- ceutically acceptable carrier containing a therapeutically effective amount of one or more additional therapeutic agents.

[0147] In some embodiments, administration of a pharmaceutical composition comprising a salt of Formula (I), or a salt of the invention, and a pharma- ceutically acceptable carrier induces changes in the cell cycle or cell viability.

[0148] In some embodiments, administration of a pharmaceutical composition comprising a salt of Formula (I), or a salt of the invention, and a pharma- ceutically acceptable carrier induces a prophylactic alteration of an age-related disorder or disease.

[0149] Administration of the disclosed salts can be accomplished via any mode of administration for therapeutic agents, including oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0150] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, in some cases in unit dosage amounts, consistent with conventional pharmaceutical practice. Similarly, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0151] The pharmaceutical compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed salts by weight or volume.

[0152] In one embodiment, the present invention relates to a method for preparing a pharmaceutical composition of the present invention by mixing at least one pharma- ceutically acceptable salt of the present invention and, optionally, one or more pharma- ceutically acceptable carriers, additives, or excipients.

[0153] In another embodiment, the present invention relates to a method for preparing a pharmaceutical composition of the present invention by mixing at least one pharma- ceutically acceptable salt of the present invention with one or more additional therapeutic agents.

[0154] The effective dosage of the salt of formula (I), when used in the described method, ranges from about 0.5 mg to about 5000 mg of the disclosed salt, as needed to treat a condition. Compositions for in vivo or in vitro use can 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 the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored.

[0155] Dosage regimens utilizing the disclosed salts are selected according to a variety of factors, including the type, race, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed salt being used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0156] Exemplary pharmaceutical compositions include a salt of the invention and a pharma- ceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils) or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine, b) a lubricant, such as silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, c) a glycerin, such as glycerin, tert-butyl ether ... In the case of tablets, also if desired, c) binders, for example magnesium aluminium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or β-lactose, corn sweeteners, etc.), natural and synthetic gums (such as acacia, tragacanth, or sodium alginate, waxes, and / or polyvinylpyrrolidone, etc.), d) disintegrating agents, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colouring agents, flavourings and sweeteners, f) emulsifying or dispersing agents, for example Tween and g) an absorption enhancing agent such as a salt of cyclodextrin, hydroxypropyl-cyclodextrin, PEG 400, and / or PEG 200.

[0157] For preparing pharmaceutical compositions from the salts of formula (I), inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be composed of about 5 to about 95% of the active ingredient. Suitable solid carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, or lactose, are known in the art. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma- ceutically acceptable carriers and methods of preparation of various compositions can be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0158] Liquid form preparations include solutions, suspensions and emulsions. For example, water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0159] Liquids, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed salts are dissolved in or mixed with a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, thereby forming an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0160] Parenteral injectable administration is generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0161] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0162] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions. EXAMPLES

[0163] The present disclosure is further illustrated by the following examples and synthesis schemes, which should not be interpreted as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and are not intended to limit the scope of the present disclosure. It should be further understood that various other embodiments, modifications, and their equivalents that may suggest themselves to those skilled in the art can be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0164] The following salts disclosed herein were prepared using common synthetic methods including, but not limited to, reagents such as valine, leucine, alanine, isoleucine, methionine, phenylalanine, tryptophan, and tyrosine, and suitable solvents such as methanol, ethanol, water, acetic acid, ethylene glycol, isopropanol, etc. Abbreviations used in the examples below and elsewhere in the specification are as follows: AcOH Acetic acid anh. anhydride ATM atmosphere aq. aqueous solution br Wide area Boc tert-Butyloxycarbonyl Saturated sodium chloride solution n-BuLi n-Butyl lithium n-BuOH n-Butanol Calc'd Calculated value CDCl3 Deuterated Chloroform CDI Carbonyldiimidazole Chloroform-d Deuterated chloroform d doublet dd Doublet of Doublets dt Triplet doublet D2O Deuterated water (deuterium oxide) DCE Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMAc N,N-Dimethylacetamide DMAP N,N-Dimethylpyridin-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 EtOAc Ethyl acetate EtOH Ethanol ESI Electrospray Ionization g grams h hour(s) 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-oxide hexafluorophosphate HOBt Hydroxybenzotriazole HPLC High Pressure (or Fast) Liquid Chromatography Hz Hertz J coupling constant KHCO3 Potassium Bicarbonate KHMDS Potassium hexamethyldisilazide KOAc Potassium Acetate LCMS Liquid Chromatography Mass Spectrometry LHMDS Lithium hexamethyldisilazide [#]M Molar concentration m multiplet [M+H] + Molecular ion + hydrogen [M-tBu+H] + Molecular ion - tert-butyl + hydrogen mCPBA meta-chloroperoxybenzoic acid Me2NH Dimethylamine Me4NBr Tetramethylammonium bromide MeCN Acetonitrile MeNH2Methylamine MeOH Methanol Methanol-d4 Deuterated Methanol 2-MeTHF 2-Methyltetrahydrofuran mg milligram MHz Megahertz min mmol mL Milliliters MS mass spectrometry MS ES Mass Spectroscopy Electrospray Ms2O Methanesulfonic 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)imidazol-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)2Palladium(II) Acetate PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(MeCN)2Bis(acetonitrile)dichloropalladium(II) PdCl2(PPh3)2 Bis(triphenylphosphinepalladium(II) dichloride Pd(P(Cy)3)2Cl2 Dichlorobis(tricyclohexylphosphine)palladium(II) Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd(t-Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0) pH Hydrogen potential PMB 4-Methoxybenzyl PMBCl 4-Methoxybenzyl chloride ppm parts per million prep preparative py Pyridine q Quartet qd Quartet of Doublets quant. quantitative quin. Quin tuple quind quintuplet of doublets RBF Round Bottom Flask Rt retention time rt room temperature s singlet sat. saturation sat.aq. saturated aqueous solution SEMCl 2-(trimethylsilyl)ethoxymethyl chloride t triplet t-BuLi tert-butyl lithium td Triplet of Doublets TMS Trimethylsilyl TMSCl Trimethylsilyl chloride tt Triplet of Triplets T3P Polyphosphoric 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(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0165] Example 1. Synthesis of 2-hydroxy-N,N,N-trimethylethanaminium 1-((2R,3R,4S,5R)-5-(((hydrogen phosphonate)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate [ka] A 50 mL 3N RBF fitted with a water condenser, rubber septum and internal thermometer was charged with NAMN (0.200 g, 5.97 mmol, 1 equiv.) and 15 mL of distilled deionized water and mixed to form a solution. This solution was cooled using an ice / water bath to bring the internal temperature below 5 °C. 5.67 mL of 0.1 M choline hydroxide solution was then added slowly dropwise via syringe to ensure the temperature did not increase. The resulting solution was stirred for 10 minutes. After this addition, the pH was 4.2-4.8. The flask was then removed and the solution transferred to a 100 mL 1N RBF. The solution was then frozen using liquid nitrogen while swirling, making sure that the frozen solution coated the entire interior of the RBF. While freezing, the flask was attached to a freeze dryer and allowed to evaporate overnight. Upon drying, the product becomes a yellow solid. Yield: 253mg (97%) Analysis data. 1 H-NMR(400MHz,D2O)δ=9.32(s,1H),9.25(d,1H),8.96(d,1H),8.24(t,1H),6.21(d,1H),4.6 4(p,1H),4.575(t,1H),4.48(m,1H),4.18(dq,1H),4.08(m,2H),3.53(m,2H),3.22(s,9H)ppm

[0166] Example 2. Synthesis of (R)-3-carboxy-2-hydroxy-N,N,N-trimethylpropan-1-aminium 1-((2R,3R,4S,5R)-5-(((hydrogen phosphonate)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate [ka] A 100 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.300 g, 0.894 mmol, 1 equiv.) and 30 mL distilled deionized water and mixed to form a solution. A faint suspension is acceptable. The solution was cooled using an ice / water bath to bring the internal temperature below 10° C. To this solution was then added 8.77 mL of 0.1 M L-carnitine solution (0.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature does not rise. All suspension is in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was approximately 3.2. The flask was then removed and the colorless solution was decanted into a 100 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 0.321.2g (72%) Melting point: 92℃ (deterioration, correction) 146℃ degassing Analysis data. 1 H-NMR(400MHz,D2O)δ=9.36(s,1H),9.26(d,1H),8.98(d,1H),8.26(dd,1H),6.24(d,1H),4.65(m ,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),3.50(m,2H),3.25(s,9H),2.60-2.70(m,2H)ppm

[0167] Example 3. Synthesis of 1-carboxy-N,N,N-trimethylmethaniminium 1-((2R,3R,4S,5R)-5-(((hydrogen phosphonate)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate [ka] A 50 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.100 g, 0.298 mmol, 1 equiv.) and 10 mL distilled deionized water and mixed to form a solution. The solution was cooled using an ice / water bath to bring the internal temperature below 10 °C. To this solution was then added 2.92 mL of a 0.1 M solution of betaine (0.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature did not increase. All suspension was in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was approximately 1.8-2.3. The flask was then removed and the colorless solution was decanted into a 50 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 140.2 mg (quantitative yield) Melting point: 122-133℃ (deterioration, correction) Analysis data. 1 H-NMR(400MHz,D2O)δ=9.45(s,1H),9.30(d,1H),9.05(d,1H),8.28(dd,1H),6.25(d,1H),4.6 6(p,1H),4.57(t,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),4.04(s,2H),3.30(s,9H)ppm

[0168] Example 4. Synthesis of (R)-3-carboxy-2-hydroxy-N,N,N-trimethylpropan-1-aminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate [ka] A 50 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NMN (0.250 g, 0.748 mmol, 1 equiv.) and 25 mL of distilled deionized water and mixed to form a solution. The solution was cooled using an ice / water bath to bring the internal temperature below 10° C. To this solution was then added 7.33 mL of 0.1 M L-carnitine solution (0.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature did not rise. All suspension was in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was about 4.4. The flask was then removed and the colorless solution was decanted into a 100 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 249.4mg (67%) Melting point: 68-99℃ (deterioration, correction) Degassing at 136℃ Analysis data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.31(d,1H),9.02(d,1H),8.33(dd,1H),6.25(d,1H),4.68(p,1H) ),4.60(m,2H),4.48(dd,1H),4.33(dq,1H),4.18(dq,1H),3.45(m,2H),3.25(s,9H),2.48(m,2H)ppm

[0169] Example 5. Synthesis of 1-carboxy-N,N,N-trimethylmethanaminium ((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate [ka] A 50 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NMN (0.100 g, 0.299 mmol, 1 equiv.) and 5 mL of distilled deionized water and mixed to form a solution. A faint suspension is acceptable. The solution was cooled using an ice / water bath to bring the internal temperature below 10 °C. To this solution was then added 2.93 mL of a 0.1 M solution of betaine (0.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature does not increase. All suspension is in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was approximately 3.8-4.2. The flask was then removed and the colorless solution was decanted into a 50 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 129.5mg (97%) Melting point: 105℃ (melting) 129℃ (deterioration, correction) Analysis data. 1 H-NMR(400MHz,D2O)δ=9.50(s,1H),9.31(d,1H),9.02(d,1H),8.33(dd,1H),6.25(d,1H),4.6 8(m,1H),4.60(t,1H),4.47(dd,1H),4.33(dq,1H),4.18(dq,1H),3.92(s,2H),3.28(s,9H)ppm

[0170] Example 6. Synthesis of (R)-3-carboxy-2-hydroxy-N,N,N-trimethylpropan-1-aminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonatooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate [ka] A 100 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.250 g, 0.298 mmol, 1 equiv.) and 25 mL of distilled deionized water and mixed to form a solution. A faint suspension is acceptable. The solution was cooled using an ice / water bath to bring the internal temperature below 10 °C. To this solution was then added 14.76 mL of 0.1 M L-carnitine solution (1.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature does not increase. All suspension is in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was approximately 3.3-3.9. The flask was then removed and the colorless solution was decanted into a 100 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 238.9mg (49% after transplantation) Analysis data. 1 H-NMR(400MHz,D2O)δ=9.35(s,1H),9.25(d,1H),8.95(d,1H),8.25(dd,1H),6.23(d,1H),4.65(m,3H) ),4.55(t,1H),4.48(d7,1H),4.33(dq,1H),4.18(dq,1H),3.48(m,4H),3.24(s,18H),2.56(d,4H)ppm

[0171] Example 7. Synthesis of 1-carboxy-N,N,N-trimethylmethanaminium 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((phosphonatooxy)methyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate [ka] A 50 mL 3N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.100 g, 0.298 mmol, 1 equiv.) and 10 mL distilled deionized water and mixed to form a solution. The solution was cooled using an ice / water bath to bring the internal temperature below 10 °C. To this solution was then added 5.85 mL of a 0.1 M solution of betaine (1.98 equiv.) in distilled deionized water, dropwise, slowly so that the temperature did not increase. All suspension was in solution. The resulting solution was stirred for 10 minutes. After this addition, the pH was approximately 2.8-2.3. The flask was then removed and the colorless solution was decanted into a 50 mL 1N RBF and frozen using liquid nitrogen. While the flask was frozen, it was connected to a freeze dryer. Upon drying, the product is a colorless to faint yellow solid. Yield: 167.0 mg (49.5%) Melting point: 82-102℃ (completely melted) 150℃ (deterioration, correction) Analysis data. 1 H-NMR(400MHz,D2O)δ=9.42(s,1H),9.30(d,1H),9.02(d,1H),8.28(dd,1H),6.24(d,1H),4.65 (m,1H),4.58(t,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),4.01(s,4H),3.28(s,18H)ppm

[0172] Example 10. NAD Cellular Assay NAD levels were assayed based on the NAD cycling method of Zhu and Rand, PLoS One (2012), which is incorporated herein by reference. COV434 cells were maintained in 6-well plates and treated with the indicated compounds at a concentration of 200uM for 4 hours. The medium was removed, the plates were washed in cold PBS, and the cells were scraped in NAD extraction buffer containing 10mM nicotinamide, 50mM Tris HCl, 0.1% Triton X-100. The cells were homogenized by sonication for 5 seconds, and the samples were centrifuged at 7,000g for 5 minutes at 4 degrees. An aliquot was taken for later protein assay, and then the samples were passed through a 10kDa Amicon filter at 14,000g for 30 minutes at 4 degrees to remove protein from the samples. 25 μL of sample was added to 100 μL ADH cycling mixture (0.2 mg / mL alcohol dehydrogenase enzyme, 2% ethanol, 100 mM Tris pH 8.5) and each sample was measured in technical triplicate. Samples were cycled for 10 min at room temperature followed by the addition of 50 μL of MTT / PMS solution (0.1 mM phenazine methosulfate, 0.8 mM 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), 100 mM Tris-HCl pH 8.5). Plates were then incubated for 15 min and absorbance was measured at 570 nM. NAD concentrations were estimated from a standard curve and normalized to protein concentrations determined by the BCA protein assay.

[0173] The results of the above assays are shown in Table 2 (below). The fold increase is obtained through a direct comparison on a mole per mole basis between the compared salts and their parent counterparts. [Table 2]

[0174] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the scope of the following claims. The present invention provides, for example, the following items. (Item 1) Salts of formula (I): [ka] or an enantiomer, stereoisomer, or tautomer thereof, During the ceremony, A is NR a R b Or O - and L is a bond or [ka] and M 1 and M 2 is independently absent or a quaternary cation, with the proviso that M 1 or M 2 at least one of is a quaternary cation; R 1 and R 2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, (C0-C3 alkylene)C(O)C1-C6 alkyl, -C(O)OR a , -C(O)NR a R b , -[CH2-CH2-O] k -R a , -C(O)[CH2-CH2-O] k -R a , -[CH2-CH2-CH2-O] k -R a , or -C(O)[CH2-CH2-CH2-O] k -R a or or R 1and R 2 together with the atom to which they are attached, 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 forming a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from aryl or (C0-C3 alkylene)heteroaryl; R 3 is a negative charge, H, or C1-C6 alkyl; R a and R b is independently at each occurrence H or C1-C6 alkyl, said alkyl being selected from the group consisting of (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; k is an integer from 1 to 8; however, a) When L is a bond, M 1 does not exist, b) A is NR a R b If M 2 does not exist, said salt, or an enantiomer, stereoisomer, or tautomer thereof. (Item 2) A is O - 2. The salt according to item 1, (Item 3) A is NR a R b 2. The salt according to item 1, (Item 4) R a The salt according to item 3, wherein is H. (Item 5) R a The salt according to item 3, wherein is methyl. (Item 6) M 1 and M 2is independently absent or represents a group represented by formula (II), formula (III), or formula (IV): [ka] is a quaternary cation of During the ceremony, E is R 4 , R 5 , G-OR 9 , or (C0-C3 alkylene) OR 11 is a C1-C6 alkyl optionally substituted with one or more substituents selected from R 4 and R 5 independently at each occurrence, 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 aryl, or (C0-C3 alkylene)heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl 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 alkylene)SR c , (C0-C3 alkylene)C(O)SR c , (C0-C3 alkylene)SC(O)R c , (C0-C3 alkylene)C(O)NR c R d , (C0-C3 alkylene)NC(O)NR c R d , (C0-C3 alkylene)C(NR c )NR c R d , (C0-C3 alkylene)NR c C(NR c )NR c Rd , (C0-C3 alkylene)P(O)O n R c R d , (C0-C3 alkylene)S(O) m NR c R d , (C0-C3 alkylene)S(O) m OR c , or (C0-C3 alkylene)BO p R c R d and optionally substituted with one or more substituents selected from R 6 , R 7 , R 8 , and R 10 are independently H or C1-C6 alkyl, wherein the alkyl is cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c or optionally substituted with one or more substituents selected from or R 4 and R 6 together with the atom to which they are attached, they form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c or forming a 5- to 6-membered ring optionally substituted with one or more substituents selected from or R 7 and R 8 together with the atom to which they are attached, they form cyano, halo, (C0-C3 alkylene)NR c R d , or (C0-C3 alkylene) OR c Forming a 5- to 6-membered ring optionally substituted with one or more substituents selected from R c and R d is independently at each occurrence H or C1-C6 alkyl, wherein the alkyl is selected from the group consisting of (C0-C3 alkylene)C3-C8 cycloalkyl, (C0-C3 alkylene)heterocycloalkyl, (C0-C3 alkylene)C6-C 14Optionally substituted with one or more substituents selected from aryl, or (C0-C3 alkylene)heteroaryl; R 9 is a negative charge, H, or C1-C6 alkyl; R 11 is H, C1-C6 alkyl, or C(O)C1-C6 alkyl, wherein the C1-C6 alkyl or C(O)C1-C6 alkyl is (C0-C3 alkylene)NR c R d , (C0-C3 alkylene) OR c , (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; G is CH2 or C(O); m, n, and p are independently 0, 1, or 2 at each occurrence; 6. The salt according to any one of items 1 to 5, wherein q is an integer of 0 to 5. (Item 7) M 1 and M 2 is independently absent or a quaternary ammonium cation of formula (IIa); [ka] 7. The salt according to item 6, wherein r is 0 or 1. (Item 8) R 5 The salt according to item 6 or 7, wherein is H. (Item 9) R 6 The salt according to any one of items 6 to 8, wherein is H. (Item 10) R 4 The salt according to any one of items 6 to 9, wherein is H. (Item 11) R 4 C1-C4 alkyl, (C0-C3 alkylene) C6-C14 aryl, or (C0-C3 alkylene)heteroaryl, or one or more (C0-C3 alkylene)SR c The salt according to any one of items 6 to 9, wherein the substituted C1-C4 alkyl is C1-C4 alkyl substituted with (Item 12) M 1 but, [ka] 12. The salt according to any one of items 1 to 11, (Item 13) M 1 and M 2 but, [ka] 12. The salt according to any one of items 1 to 11, (Item 14) R 1 is H. (Item 15) R 1 is C(O)C1-C3 alkyl. (Item 16) R 1 is C1-C3 alkyl. (Item 17) R 2 17. The salt according to any one of items 1 to 16, wherein is H. (Item 18) R 2 17. The salt according to any one of items 1 to 16, wherein is C(O)C1-C3 alkyl. (Item 19) R 2 is C1-C3 alkyl. (Item 20) R 3 20. The salt according to any one of items 1 to 19, wherein is H or methyl. (Item 21) structure [ka] The salt according to item 1, having the formula: (Item 22) 22. A pharmaceutical composition comprising the salt according to any one of items 1 to 21 and a pharma- ceutically acceptable carrier. (Item 23) A method for treating or preventing age-related infertility, comprising administering an effective amount of the salt according to any one of items 1 to 21 or the composition according to item 22 to a subject in need thereof. (Item 24) A method for treating or preventing infertility, comprising administering an effective amount of the salt according to any one of items 1 to 21 or the composition according to item 22 to a subject in need thereof. (Item 25) A method for improving the quality of an oocyte or a blastocyst, comprising contacting the oocyte or the blastocyst with an effective amount of the salt according to any one of items 1 to 21 or the composition according to item 22 before implantation into a subject in need of treatment for age-related infertility. (Item 26) A method for improving maturation of an oocyte or a blastocyst, the method comprising contacting the oocyte or the blastocyst with an effective amount of the salt according to any one of items 1 to 21 or the composition according to item 22 before implantation into a subject in need of treatment for age-related infertility. (Item 27) 27. The method according to item 25 or 26, wherein the oocytes or blastocysts are cultured in an IVF medium containing the salt. (Item 28) 22. Use of a salt according to any one of items 1 to 21 in the manufacture of a medicament for treating an age-related disorder. (Item 29) 22. Use of a salt according to any one of items 1 to 21 in the manufacture of a medicament for treating infertility. (Item 30) 22. Use of the salt according to any one of items 1 to 21 in the manufacture of a medicament for treating age-related infertility. (Item 31) 1. A cell culture medium for in vitro fertilization comprising: A compound selected from any one of items 1 to 21, and a culture agent. (Item 32) 32. The cell culture medium of item 31, wherein the culture agent is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof. (Item 33) 33. The cell culture medium of item 32, 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. (Item 34) 33. The cell culture medium of item 32, wherein the energy substrate is glucose, pyruvate, lactate, pyruvate, or any combination thereof. (Item 35) 33. The cell culture medium of item 32, wherein the amino acid is an essential amino acid. (Item 36) 36. The cell culture medium of item 35, 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. (Item 37) 33. The cell culture medium of item 32, wherein the amino acid is a non-essential amino acid. (Item 38) 38. The cell culture medium of item 37, wherein the non-essential amino acid is alanine, asparagine, aspartic acid, glutamic acid, proline, serine, or any combination thereof. (Item 39) 33. The cell culture medium of item 32, wherein 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, nitrile triacetic acid, pentetic acid (DTPA), phosphonate, phytochelate, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof. (Item 40) 33. The cell culture medium of item 32, wherein the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridine, or any combination thereof. (Item 41) 33. The cell culture medium of item 32, wherein the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof. (Item 42) 33. The cell culture medium of item 32, wherein the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.

Claims

1. Salts of formula (I): 【Chemistry 1】 or an enantiomer, stereoisomer, or tautomer thereof, During the ceremony, A is NR ａ R ｂ Or O － and L is a bond or 【Chemistry 2】 and M １ and M. ２ is independently absent or a quaternary cation, with the proviso that M １ Or M ２ At least one of the formula (II): 【Chemistry 3】 is a quaternary cation of R １ and R ２ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, —C(O)C １ ~C ６ Haloalkyl, (C ０ ~C ３ alkylene)C(O)C １ ~C ６ Alkyl, -C(O)OR ａ , -C(O)NR ａ R ｂ , -[CH ２ -CH ２ -O] ｋ -R ａ , —C(O)[CH ２ -CH ２ -O] ｋ -R ａ , -[CH ２ -CH ２ -CH ２ -O] ｋ -R ａ , or -C(O)[CH ２ -CH ２ -CH ２ -O] ｋ -R ａ or Or R １ and R ２ together with the atoms to which they are attached, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, (C ０ ~C ３ Alkylene) C ３ ~C ８ Cycloalkyl, (C ０ ~C ３ alkylene)heterocycloalkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl, R ３ is a negative charge, H, or C １ ~C ６ is alkyl, R ａ and R ｂ independently at each occurrence H or C １ ~C ６ alkyl, wherein the alkyl is selected from the group consisting of (C ０ ~C ３ Alkylene) C ３ ~C ８ Cycloalkyl, (C ０ ~C ３ alkylene)heterocycloalkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl; k is an integer from 1 to 8; E is R ４ , R ５ , G-OR ９ , or (C ０ ~C ３ Alkylene) OR １１ C optionally substituted with one or more substituents selected from １ ~C ６ is alkyl, R ４ and R ５ independently, at each occurrence, H or C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, (C ０ ~C ３ Alkylene) C ３ ~C ８ Cycloalkyl, (C ０ ~C ３ alkylene)heterocycloalkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is cyano, halo, SeH, (C ０ ~C ３ Alkylene)NR ｃ R ｄ , (C ０ ~C ３ Alkylene) OR ｃ , (C ０ ~C ３ alkylene)OC(O)R ｃ , (C ０ ~C ３ alkylene)C(O)OR ｃ , (C ０ ~C ３ Alkylene)SR ｃ , (C ０ ~C ３ alkylene)C(O)SR ｃ , (C ０ ~C ３ alkylene)SC(O)R ｃ , (C ０ ~C ３ alkylene)C(O)NR ｃ R ｄ , (C ０ ~C ３ (alkylene)NC(O)NR ｃ R ｄ , (C ０ ~C ３ alkylene)C(NR ｃ ) N.R. ｃ R ｄ , (C ０ ~C ３ Alkylene)NR ｃ C (NR ｃ ) N.R. ｃ R ｄ , (C ０ ~C ３ alkylene)P(O)O ｎ R ｃ R ｄ , (C ０ ~C ３ Alkylene)S(O) ｍ N.R. ｃ R ｄ , (C ０ ~C ３ Alkylene)S(O) ｍ OR ｃ , or (C ０ ~C ３ Alkylene)BO ｐ R ｃ R ｄ and optionally substituted with one or more substituents selected from R ６ , R ７ and R8 are independently H or C １ ~C ６ alkyl, wherein the alkyl is cyano, halo, (C ０ ~C ３ Alkylene)NR ｃ R ｄ , or (C ０ ~C ３ Alkylene) OR ｃ or Or R ４ and R ６ together with the atoms to which they are attached, they form cyano, halo, (C ０ ~C ３ Alkylene)NR ｃ R ｄ , or (C ０ ~C ３ Alkylene) OR ｃ or forming a 5- to 6-membered ring optionally substituted with one or more substituents selected from Or R ７ and R ８ together with the atoms to which they are attached, they form cyano, halo, (C ０ ~C ３ Alkylene)NR ｃ R ｄ , or (C ０ ~C ３ Alkylene) OR ｃ forming a 5- to 6-membered ring optionally substituted with one or more substituents selected from R ｃ and R ｄ independently at each occurrence H or C １ ~C ６ alkyl, wherein the alkyl is: (C ０ ~C ３ Alkylene) C ３ ~C ８ Cycloalkyl, (C ０ ~C ３ alkylene)heterocycloalkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl; R ９ is a negative charge, H, or C １ ~C ６ is alkyl, R １１ But, H, C １ ~C ６ Alkyl, or C(O)C １ ~C ６ alkyl, wherein １ ~C ６ Alkyl, or C(O)C １ ~C ６ The alkyl is (C ０ ~C ３ Alkylene)NR ｃ R ｄ , (C ０ ~C ３ Alkylene) OR ｃ , (C ０ ~C ３ Alkylene) C ３ ~C ８ Cycloalkyl, (C ０ ~C ３ alkylene)heterocycloalkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl; G is CH ２ or C(O), m, n, and p are independently 0, 1, or 2 at each occurrence; q is an integer from 0 to 5; however, a) when L is a bond, M １ does not exist, b) A is NR ａ R ｂ If M ２ does not exist, said salt, or an enantiomer, stereoisomer, or tautomer thereof.

2. A is O － The salt of claim 1 ,

3. A is NR ａ R ｂ The salt of claim 1 ,

4. R ａ The salt of claim 3, wherein is H.

5. R ａ The salt of claim 3, wherein is methyl.

6. M １ and M. ２ is independently absent or a quaternary ammonium cation of formula (IIa); 【Chemistry 4】 The salt of claim 1 , wherein r is 0 or 1.

7. R ５ The salt according to claim 1 or 6, wherein is H.

8. R ６ The salt according to any one of claims 1 to 7, wherein is H.

9. R ４ The salt according to any one of claims 1 to 8, wherein is H.

10. R ４ But, C １ ~C ４ Alkyl, (C ０ ~C ３ Alkylene) C ６ ~C １４ Aryl, or (C ０ ~C ３ alkylene)heteroaryl, or one or more (C ０ ~C ３ Alkylene) SR ｃ C substituted with １ ~C ４ The salt according to any one of claims 1 to 8, which is alkyl.

11. M １ but, 【Chemistry 5】 The salt according to any one of claims 1 to 10,

12. M １ and M. ２ but, 【Chemistry 6】 The salt according to any one of claims 1 to 10,

13. R １ The salt according to any one of claims 1 to 12, wherein is H.

14. R １ But C(O)C １ ~C ３ The salt according to any one of claims 1 to 12, which is alkyl.

15. R １ But, C １ ~C ３ The salt according to any one of claims 1 to 12, which is alkyl.

16. R ２ The salt according to any one of claims 1 to 15, wherein is H.

17. R ２ But C(O)C １ ~C ３ The salt according to any one of claims 1 to 15, which is alkyl.

18. R ２ But, C １ ~C ３ The salt according to any one of claims 1 to 15, which is alkyl.

19. R ３ The salt according to any one of claims 1 to 18, wherein is H or methyl.

20. structure 【Chemistry 7】 The salt of claim 1 having the formula:

21. A pharmaceutical composition comprising the salt of any one of claims 1 to 20 and a pharma- ceutically acceptable carrier.

22. A composition comprising the salt according to any one of claims 1 to 20 or the pharmaceutical composition according to claim 21, for treating or preventing age-related infertility.

23. A composition comprising the salt according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for treating or preventing infertility.

24. 22. A composition comprising a salt according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for use in a method for improving the quality of an oocyte or blastocyst, said method comprising contacting said oocyte or blastocyst with said composition or pharmaceutical composition prior to implantation into a subject in need of treatment for age-related infertility.

25. 22. A composition comprising a salt according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for use in a method for improving maturation of an oocyte or a blastocyst, said method comprising contacting said oocyte or blastocyst with said composition or pharmaceutical composition prior to implantation into a subject in need of treatment for age-related infertility.

26. 26. The composition or pharmaceutical composition of claim 24 or 25, wherein the oocytes or blastocysts are cultured in an IVF medium containing the salt.

27. 21. Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of age-related disorders.

28. 21. Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for treating infertility.

29. Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for treating age-related infertility.

30. 1. A cell culture medium for in vitro fertilization comprising: A salt selected from any one of claims 1 to 20; and a culture agent.

31. 31. The cell culture medium of claim 30, wherein the culture agent is an inorganic salt, an energy substrate, an amino acid, a chelating agent, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof.

32. 32. The cell culture medium of claim 31, 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.

33. 32. The cell culture medium of claim 31, wherein the energy substrate is glucose, pyruvate, lactate, pyruvate, or any combination thereof.

34. 32. The cell culture medium of claim 31 , wherein the amino acid is an essential amino acid.

35. 35. The cell culture medium of claim 34, wherein the essential amino acids are arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof.

36. 32. The cell culture medium of claim 31 , wherein the amino acid is a non-essential amino acid.

37. 37. The cell culture medium of claim 36, wherein the non-essential amino acid is alanine, asparagine, aspartic acid, glutamic acid, proline, serine, or any combination thereof.

38. 32. The cell culture medium of claim 31, wherein 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, nitrile triacetic acid, pentetic acid (DTPA), phosphonate, phytochelate, polyaspartic acid, sodium polyaspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof.

39. 32. The cell culture medium of claim 31, wherein the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridine, or any combination thereof.

40. 32. The cell culture medium of claim 31, wherein the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof.

41. 32. The cell culture medium of claim 31 , wherein the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.

42. A composition comprising the salt according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for treating age-related disorders.

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