Compounds and Compositions for Differential Modulation of Nicotinamide Adenine Dinucleotide

Abstract

The present invention relates to compounds and compositions for differential modulation of nicotinamide adenine dinucleotide (NAD) in various tissues or cell types. Furthermore, the present invention relates to pharmaceutical compositions comprising one or more NAD-modulating compounds as active pharmaceutical ingredients. The present invention also relates to methods of making such compounds and compositions. Methods of using such compounds or compositions include administering such compounds and compositions to promote increased or maintained intracellular levels of nicotinamide adenine dinucleotide (NAD) in healthy cells and tissues, thereby improving the survival of healthy cells and tissues. Also included are methods of increasing or maintaining intracellular levels of NAD in selected cells or tissues while simultaneously reducing NAD levels in unhealthy tissues or cells, thereby reducing the survival of unhealthy cells and tissues.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 886,869, filed Aug. 14, 2019, and U.S. Provisional Patent Application No. 62 / 889,376, filed Aug. 20, 2019, each of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Nicotinamide adenine dinucleotide (NAD) and related naturally occurring compounds are known as essential coenzymes for cellular redox reactions in all living organisms. A number of lines of evidence indicate that NAD is involved in a number of important signaling pathways in mammalian cells, including poly(ADP-ribosyl)ation in DNA repair (Menissier de Murcia et al., EMBO J., (2003) 22, 2255-2263), mono-ADP-ribosylation in immune response and G protein-coupled signaling (Corda et al., EMBO J., (2003) 22, 1953-8), and the synthesis of cyclic ADP-ribose and nicotinate adenine dinucleotide phosphate (NAADP) in intracellular calcium signaling (Lee, Annu. Rev. Pharmacol. Toxicol., (2001) 41, 317-345). NAD and its metabolites have also been shown to play important roles in transcriptional regulation (Lin et al., Curr. Opin. Cell. Biol., (2003) 15, 241-246). In particular, the discovery of Sir2 NAD-dependent deacetylase activity (e.g., Imai et al., Nature, (2000) 403, 795-800; Landry et al., Biochem. Biophys. Res. Commun., (2000) 278, 685-690; Smith et al., Proc. Natl. Acad. Sci. USA, (2000) 97, 6658-6663) has drawn attention to this role of NAD. Nicotinamide phosphoribosyltransferase (NAMPT) plays a role in the salvage pathway of NAD+ synthesis, and the compound FK866 is a small molecule inhibitor of NAMPT (Kang et al., Mol. Cells, 27, 667-671, 2009; Galli et al., J. Med. Chem. 2013, 56, 16, 6279-6296). A variety of other NAMPT inhibitors have been reported (e.g., Industry-Academic Cooperation Foundation, Yonsei University, EP3 431 472 A2).

[0003] Despite progress in understanding the biology of NAD, there remains a need for improved compositions and methods of using such compositions for pharmacological intervention and / or controlled modulation of NAD pathways in living cells and tissues, including modulation of NAD pathways not possible with naturally occurring compounds. SUMMARY OF THE INVENTION

[0004] The present invention relates to compounds and compositions for the modulation of nicotinamide adenine dinucleotide (NAD, also referred to as NAD+ in its oxidized form and NADH in its reduced form). In some embodiments, the invention relates to methods of making such compounds and compositions. In some embodiments, the invention relates to pharmaceutical compositions containing one or more NAD-modulating compounds as the sole pharmaceutical active ingredient or in combination with one or more other pharmaceutical active ingredients. In further embodiments, the invention relates to methods of using such compounds or compositions to treat diseases and / or improve cell and tissue survival by promoting an increase in the intracellular level of nicotinamide adenine dinucleotide (NAD) in cells and tissues. Methods of using such compounds or compositions include administering such compounds and compositions to promote an increase or maintenance of the intracellular level of nicotinamide adenine dinucleotide (NAD) in healthy cells and tissues, and thus improve or protect the survival of healthy cells and tissues. Also included are methods of increasing or maintaining the intracellular level of NAD in selected cells or tissues while reducing the NAD level in unhealthy tissues or cells, and thus reducing the viability of unhealthy cells and tissues. In certain embodiments, the invention relates to methods of using such compounds or compositions to significantly reduce the viability of unhealthy cells and tissues by a differential decrease in the intracellular level of NAD compared to any reduction in the viability of healthy cells and tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0005]

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 2C

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6A

Figure 6B

MODE FOR CARRYING OUT THE INVENTION

[0006] Definitions Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of this disclosure. As used herein, the following terms have the meanings ascribed to them below, unless specifically defined otherwise.

[0007] In this disclosure, terms such as "comprising," "comprises," "including," and "having" can have the meanings ascribed to them in the United States Patent Law, can mean "including," "includes," etc., and "consisting essentially of" or "consisting essentially" can similarly have the meanings ascribed to them in the United States Patent Law. The term is open-ended and allows for the presence of elements other than those listed, as long as the basic or novel features of the listed elements are not changed by the presence of elements other than those listed, except for prior art embodiments.

[0008] The ranges provided herein are to be understood as all subrange notations of values within the range. For example, the range from 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0009] As used herein, the phrase "one (a)" or "one (an)" entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "one (a)" (or "one (an)"), "one or more", and "at least one" can be used interchangeably herein.

[0010] Unless specifically stated otherwise or not apparent from the context, as used herein, the term "about" is understood to be within the normal tolerances in the art, e.g., within 2 standard deviations of the mean. About can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term about.

[0011] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0012] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, and can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0013] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0014] The term "alkoxy" refers to an alkyl group bonded to oxygen, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0015] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0016] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter of which refers to an alkenyl moiety having a substituent that replaces hydrogen on one or more carbons of the alkenyl group. Such substituents can be present on one or more carbons that are or are not included in one or more double bonds. Further, such substituents include, except in cases where use is prohibited due to stability, all those contemplated for alkyl groups as described below. For example, substitution of an alkenyl group with one or more alkyl, carbocyclic, aryl, heterocyclic or heteroaryl groups is contemplated.

[0017] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight-chain or branched alkyl group is also referred to as a "lower alkyl" group.

[0018] Furthermore, the term "alkyl" (or "lower alkyl"), when used throughout this specification, the examples and the claims, is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter of which refers to an alkyl moiety having a substituent that replaces a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that, where appropriate, moieties substituted on the hydrocarbon chain may themselves be substituted. For example, substituents for substituted alkyl include substituted and unsubstituted amino, azide, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0019] The term "C x~y ", when used in combination with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, means a group containing x to y carbons in the chain. For example, "C x~yThe term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing a straight-chain or branched-chain alkyl group having x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents hydrogen when the group is at the terminal position and a bond when it is internal. "C 2~y alkenyl" and "C 2~y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups having a length and possible substitution similar to those of the above-described alkyl, but containing at least one double bond or triple bond, respectively.

[0020] The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

[0021] The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0022] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which refers to an alkynyl moiety having a substituent that replaces hydrogen on one or more carbons of the alkynyl group. Such substituents can be present on one or more carbons that are or are not included in one or more triple bonds. Further, such substituents include, as described above, all those contemplated for alkyl groups, except in cases where use is prohibited due to stability. For example, substitution of an alkynyl group with one or more alkyl groups, carbocyclic groups, aryl groups, heterocyclic groups or heteroaryl groups is contemplated.

[0023] The term "amide", as used herein, refers to the group

[0024]

Chemical formula

[0025] The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines and their salts, such as

[0026]

Chem.

[0027] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group.

[0028] The term "aryl", as used herein, includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, for example the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0029] The term "carbamate" is recognized in the art and the group

[0030]

Chem.

[0031] The terms "carbocyclic" and "carbocyclic ring" as used herein refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocyclic ring includes both aromatic carbocyclic rings and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings containing at least one double bond.

[0032] The term "carbocyclic ring" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of the bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. The carbocyclic ring includes bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with another ring. Each ring of the fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic when the valency permits. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The "carbocyclic ring" may be substituted at any one or more positions capable of holding a hydrogen atom.

[0033] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0034] The term "carbocyclic alkyl" as used herein refers to an alkyl group substituted with a carbocyclic group.

[0035] The term "carbonate" is recognized in the art and refers to the group -OCO2-R 34 wherein R 34 represents a hydrocarbyl group.

[0036] The term "carboxy" as used herein refers to the group represented by the formula -CO2H.

[0037] The term "ester" as used herein refers to the group -C(O)OR 35 wherein R 35 represents a hydrocarbyl group.

[0038] As used herein, the term "ether" refers to a hydrocarbyl group linked to another hydrocarbyl group via oxygen. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether may be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic. Ethers include the "alkoxyalkyl" group which can be represented by the general formula alkyl-O-alkyl.

[0039] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo and iodo.

[0040] As used herein, the terms "hetaralkyl" and "heteroarylalkyl" refer to an alkyl group substituted with a heteroaryl group.

[0041] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, with the two heteroatoms not adjacent.

[0042] As used herein, the terms "heteroaryl" and "heteroaryl" refer to a substituted or unsubstituted aromatic monocyclic structure (preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring), the ring structure of which includes a structure containing at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "heteroaryl" also include polycyclic ring systems having two or more cyclic rings where two or more carbons are common to two adjacent rings, where at least one of the rings is heteroaromatic, and where the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.

[0043] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0044] The terms "heterocyclyl", "heterocyclic", and "heterocyclic ring" refer to a substituted or unsubstituted non-aromatic ring structure (preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring) that contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms in the ring structure. The terms "heterocyclyl" and "heterocyclic ring" also include polycyclic ring systems having two or more cyclic rings where two or more carbons are common to two adjacent rings, where at least one of the rings is heterocyclic, and where the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.

[0045] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0046] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom having no =O or =S substituents, typically having at least one carbon-hydrogen bond and a predominantly carbon backbone, but optionally containing heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (having an =O substituent on the linking carbon) and ethoxy (linked through oxygen rather than carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0047] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0048] As used herein, the term "lower", when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, means a group having 10 or fewer, preferably 6 or fewer, non-hydrogen atoms in the substituent. "Lower alkyl" refers to, for example, an alkyl group containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, whether they appear alone or in combination with other substituents, for example, in the listing of hydroxyalkyl and aralkyl (in which case, when counting the carbon atoms in an alkyl substituent, the atoms in the aryl group are not counted).

[0049] The terms "polysicyclic", "polycyclic", and "polycyclic ring" refer to two or more rings (e.g., cycloalkyl(s), cycloalkenyl(s), cycloalkynyl(s), aryl(s), heteroaryl(s), and / or heterocyclyl(s)) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each of the polycyclic rings may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0050] The term "silyl" refers to a silicon moiety to which three hydrocarbyl moieties are attached.

[0051] The term "substituted" refers to a moiety having a substituent that replaces one or more hydrogens on one or more carbons of a backbone. It is understood that "substituted" or "substituted with" includes the implicit conditions that such substitution follows the valences of the atoms being substituted and the substituent, and that the substitution results in a stable compound that does not spontaneously undergo conversions such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, acceptable substituents may be one or more and may be the same or different. For the purposes of the present invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that substituents may themselves be substituted where appropriate. Unless specifically stated as "unsubstituted", references herein to chemical moieties are understood to include substitution variants. For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0052] The term "sulfate" is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0053] The term "sulfonamide" is recognized in the art and has the general formula

[0054]

Chem.

[0055] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-R 38 wherein R 38 represents hydrocarbyl.

[0056] The term "sulfonate" is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0057] The term "sulfone" is recognized in the art and refers to the group -S(O)2-R 39 wherein R 39 represents hydrocarbyl.

[0058] The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group.

[0059] The term "thioester", as used herein, refers to the group -C(O)SR 40 or -SC(O)R 40 wherein R 10 represents hydrocarbyl.

[0060] The term "thioether", as used herein, is equivalent to an ether in which oxygen is replaced by sulfur.

[0061] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group within a molecule, shields, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Edition, 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Volumes 1 - 8, 1971 - 1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert - butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2 - trimethylsilyl - ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9 - fluorenylmethyloxycarbonyl ("FMOC"), nitro - veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

[0062] In certain embodiments, the compounds of the invention may be racemic compounds. In certain embodiments, the compounds of the invention may be enriched in one enantiomer. For example, the compounds of the invention may have greater than about 30% ee, greater than about 40% ee, greater than about 50% ee, greater than about 60% ee, greater than about 70% ee, greater than about 80% ee, greater than about 90% ee, or even greater than about 95% ee. In certain embodiments, the compounds of the invention may have two or more stereocenters. In certain such embodiments, the compounds of the invention may be enriched in one or more diastereomers. For example, the compounds of the invention may have greater than about 30% de, greater than about 40% de, greater than about 50% de, greater than about 60% de, greater than about 70% de, greater than about 80% de, greater than about 90% de, or even greater than about 95% de.

[0063] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of the compound (e.g., of formula (1)). An enantiomerically enriched mixture may contain, for example, at least about 60 mole percent, or more preferably at least about 75 mole percent, about 90 mole percent, about 95 mole percent, or even about 99 mole percent of one enantiomer. In certain embodiments, an enantiomerically enriched compound is substantially free of the other enantiomer, and substantially free means that the substance constitutes less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% in a composition or mixture of compounds, as compared to the amount of the other enantiomer. For example, if a composition or mixture of compounds contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it is said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0064] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (1)). The diastereomer-rich mixture may contain, for example, at least about 60 mole percent, or more preferably at least about 75 mole percent, about 90 mole percent, about 95 mole percent, or even about 99 mole percent of one diastereomer.

[0065] As used herein, the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds.

[0066] As used herein, the term “purified” refers to the purity of a given compound. For example, a compound is “purified” when the given compound is the major constituent of the composition, i.e., at least about 50% w / w pure. Thus, “purified” encompasses at least about 50% w / w purity, at least about 60% w / w purity, at least about 70% purity, at least about 80% purity, at least about 85% purity, at least about 90% purity, at least about 92% purity, at least about 94% purity, at least about 96% purity, at least about 97% purity, at least about 98% purity, at least about 99% purity, at least about 99.5% purity, and at least about 99.9% purity, where “substantially pure” encompasses at least about 97% purity, at least about 98% purity, at least about 99% purity, at least about 99.5% purity, and at least about 99.9% purity.

[0067] When used in this specification, the term "salt" refers to a compound containing a cation and an anion, which can be formed by protonation of a proton-accepting moiety and / or deprotonation of a proton-donating moiety. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species whose charge is balanced by the presence of a physiological anion, while deprotonation of the proton-donating moiety results in the formation of an anionic species whose charge is balanced by the presence of a physiological cation. The term "salt" includes zwitterions in its broadest sense. In some uses, the term "salt" may be limited to pairs of anions and cations that are not covalently linked.

[0068] The phrase "pharmaceutically acceptable salt" means a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, etc., or (2) base addition salts formed with the conjugate base of any of the inorganic acids listed above, where the conjugate base contains a cationic constituent selected from Na + 、K + 、Mg 2+ 、Ca 2 +、NH g R 4-g + and R is C 1~3Base addition salts wherein R is alkyl and g is a number selected from 0, 1, 2, 3 or 4 are included. All references to pharmaceutically acceptable salts are to be understood as including the solvate addition form (solvate) or crystal form (polymorph) of the same acid addition salt as defined herein.

[0069] The present invention also includes useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and / or co-precipitates.

[0070] The compounds of the present invention can exist as hydrates or solvates, where the compounds of the present invention form crystals containing molecules of a polar solvent, especially water, methanol or ethanol, for example, as structural elements of the crystal lattice of the compound. Molecules of a polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio with the molecules of the compound. In the case of stoichiometric solvates, such as hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- and the like solvates or hydrates are each possible. The present invention includes all such hydrates or solvates.

[0071] Furthermore, the compounds of the present invention can exist in free form, for example, as a free base or a free acid, or as an amphoteric ion, or in the form of a salt. The salt can be any salt, either an organic or inorganic addition salt, especially any pharmaceutically acceptable organic or inorganic addition salt customarily used in pharmacy or, for example, used for isolating or purifying the compounds of the present invention.

[0072] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or the elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys), commercially relevant mammals, e.g., mammals including cows, pigs, horses, sheep, goats, cats and / or dogs, and / or commercially relevant birds, e.g., birds including chickens, ducks, hens, quails and / or turkeys.

[0073] The terms "treatment", "treating", "alleviating" and "remitting" are used interchangeably herein. These terms refer to a procedure for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit means eradication or remission of the underlying disorder being treated. Moreover, a therapeutic benefit is achieved by eradication or remission of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the patient, even though the patient may still be suffering from the underlying disorder. For a prophylactic benefit, the pharmaceutical compound and / or composition can be administered to a patient at risk of developing a particular disease or reporting one or more of the physiological symptoms of a disease, even if the disease has not been diagnosed in the patient.

[0074] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample in a statistical sample, or delays the onset of, or reduces the severity of, one or more symptoms of the disorder or condition compared to an untreated control sample.

[0075] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is recognized in the art and includes administration of one or more of the disclosed compositions to a subject. When administered prior to the clinical signs of an undesirable condition (e.g., a disease or other undesirable physical condition of the subject), the treatment is prophylactic (i.e., protects the subject from the onset of the undesirable condition), while when administered after the signs of an undesirable condition, the treatment is therapeutic (i.e., is intended to reduce, alleviate or stabilize an existing undesirable condition or its side effects).

[0076] The terms "preparation" or "dosage form" are intended to include both solid and liquid formulations of the active compound, and one of ordinary skill in the art will recognize that the active ingredient can be present in different preparations depending on the desired dosage and pharmacokinetic parameters.

[0077] The term "excipient", as used herein, refers to a compound that is used in the preparation of a pharmaceutical composition and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use.

[0078] The term "greater than zero" refers to an amount that is the lower limit of detection by any quantitative means known in the art. Non-limiting examples of methods for quantifying chemical substances include chromatography (liquid LC, high performance liquid HPLC, gas G), electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI). These separation methods are coupled to a mass spectrometer that identifies the compound being measured. Mass spectrometry techniques include triple quadrupole (QQQ), ion trap (IT), triple quadrupole linear ion trap (QTrap), time of flight (TOF), triple quadrupole time of flight (Q-TOF), orbitrap, and Fourier transform ion cyclotron resonance (FT-ICR). See, for example, Roskar, R. et al Analytical Methods for Quantification of Drug Metabolites in Biological Samples 2012, pages 87-91.

[0079] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of a subject within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0080] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.

[0081] In any definition of a variable element in this specification, the listing of the elements in the list includes the definition of that variable element as any single element or combination (or secondary combination) of the listed elements. The listing of embodiments in this specification includes that embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0082] When values and ranges are provided herein, it should always be understood that all values and ranges encompassed by these values and ranges are meant to be included within the scope of the present invention. Further, all values falling within these ranges, as well as the upper or lower limits of a range of values, are contemplated by this application.

[0083] Incorporation by reference All U.S. patents and U.S. and PCT published patent applications, as well as non-patent literature, described in this specification are hereby incorporated by reference to the same extent as if each individual patent and publication were specifically and individually indicated to be incorporated by reference.

[0084] Compound In this specification, Formulas 1 to 2c shown below Formula 1:

[0085]

Chemical formula

[0086] In various embodiments, the compound of formula 1 is of formula 2:

[0087]

Chemical formula

[0088] In various embodiments, the compound of Formula 2 has a structure represented by Formula 2a:

[0089]

Chemical formula

[0090] In various embodiments of Formula 2 and Formula 2a, R3 is H; R4 is selected from carboxylic acid, substituted or unsubstituted C1-C6 carboxylate, and substituted or unsubstituted carboxamide. In various embodiments, X is H; R4 is a carboxymethyl ester group.

[0091] Various embodiments include Compounds 1-5, 11, 12, 14, 15, 18, 19, 21, 23, 24, 26, 27, 29, 32, and 35.

[0092]

Chemical Formula

[0093] In various embodiments, the compound of Formula 2 has a structure represented by Formula 2b:

[0094]

Chemical Formula

[0095] In various embodiments of Formula 2 and Formula 2b, R1 is a methyl group. In various embodiments of Formula 2 and Formula 2b, R2 is a methoxy group.

[0096] Various embodiments include Compounds 6 and 7.

[0097] [Chemical Formula]

[0098] In various embodiments, the compound of Formula 2 has a structure represented by Formula 2c:

[0099] [Chemical Formula] and / or one or more of its salts, wherein R2 is selected from H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, and a substituted or unsubstituted C1-C6 alkynyl group; R3 is selected from H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a carboxylic acid, a substituted or unsubstituted C1-C6 carboxylate, and a substituted or unsubstituted carboxamide; R4 is selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a carboxylic acid, a substituted or unsubstituted C1-C6 carboxylate, and a substituted or unsubstituted carboxamide; Furthermore, at least one of R2 and R3 is not H.

[0100] In various embodiments of Formula 2 and Formula 2c, R2 is halogen. In various embodiments of Formula 2 and Formula 2c, R3 is selected from a carboxylic acid, a substituted or unsubstituted C1-C6 carboxylate, and a substituted or unsubstituted carboxamide.

[0101] Various embodiments include compounds 8, 9, 16, and 20.

[0102]

Chemical Structure

[0103] Various embodiments of Formula 1 include compounds 10, 13, 17, 22, 25, 28, 30, 31, 33, 34, 36, and 37.

[0104]

Chemical Structure

[0105] In various embodiments, the compound of Formula 1 is one or more salts, and the salts are formed with cations selected from H + , Li + , Na + , K + , Mg 2+ , and Ca 2+ , and / or the salts are formed with anions selected from acetate ion, trifluoromethanesulfonate (triflate) ion, halide ion, trifluoroacetate ion, formate ion, H2PO4 - , HPO4 2- , OH - , HSO4 - , SO4 2- , NO3 - , HCO3 - , and CO3 2- , and mixtures thereof. In various embodiments, the compound is an zwitterion.

[0106] The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl salts, dialkyl salts, trialkyl salts or tetra-alkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine salts, benethamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts and zinc salts.

[0107] In certain embodiments, the compound is a salt with an anion selected from acetate ion, triflate ion, halide ion, trifluoroacetate ion or formate ion. In other embodiments, if the disclosed compound comes into contact with a medium, for example, an aqueous medium, the anion can be selected from, for example, OH - , H2PO4 - , HPO4 2- , HSO4 - , SO4 2- , NO3 - , HCO3 - and CO3 2- .

[0108] In some embodiments, the disclosed compound is in the form of a negatively charged phosphate that can form salts with any suitable cation. The cation can vary when the compound is isolated or transferred into a medium having different anionic species. For example, the disclosed compound may be in the form of a phosphate salt that is a pharmaceutically acceptable salt as described herein. In certain embodiments, the cation is Li + , Na+ , K + , Mg 2+ and Ca 2+ may be selected from.

[0109] Synthesis In various embodiments, a method of synthesizing a compound disclosed herein is provided, which comprises reacting an amine-containing precursor with a nicotinic acid riboside precursor under conditions that condense the precursors to produce a compound according to Formulas 1-2c. In certain embodiments, the compounds according to the invention can be prepared by condensing a suitable nicotinamide or related precursor with 1,2,3,5-tetraacetyl-β-D-ribofuranose. See, for example, Scheme 1.

[0110] In various embodiments, the synthesis can be carried out as a one-pot preparation of a crude triol with purification of the product by precipitation. In various embodiments, the synthesis can be carried out as a one-pot preparation of a crude triol and purification of the product by chromatography.

[0111] Scheme 1: Preparation of Triol

[0112]

Chem.

[0113] Scheme 2: Preparation of Nicotinate

[0114]

Chem.

[0115] Compositions and Pharmaceutical Preparations Provided herein is a composition comprising one or more pharmaceutically acceptable excipients, and one or more compounds and / or salts thereof, wherein the compound has a structure represented by Formula 1, 2, 2a, 2b, and / or 2c.

[0116] Also provided herein is a composition comprising compounds of Formulas 1-2c, including Compounds 1-31. In some embodiments of the composition, the compound is in an amorphous solid form. In other embodiments, the compound is in a crystalline solid form. In some embodiments, the compound is dissolved in a solvent or carrier.

[0117] In some embodiments, the pharmaceutically acceptable excipient is selected from antiadherents, binders, coatings, dyes, disintegrants, flavoring agents, lubricants, glidants, preservatives, sorbents, sweeteners, syrups, elixirs, dispersants, diluents, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents, thickening agents, and vehicles, and combinations thereof. In some embodiments, the excipient is a solid excipient.

[0118] In some embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 5 wt%, at least about 10 wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, at least about 45 wt%, at least about 50 wt%, at least about 55 wt%, or at least about 60 wt% of the composition. In some embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, or at least about 40 wt%, preferably at least about 30 wt% of the composition. In other embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 50 wt% of the composition.

[0119] In some embodiments, the composition is in a solid form selected from tablets, pills, capsules, caplets, troches, granules, powders, sachets, inhalable powders, chewables, aromatic tablets, and lozenges. In certain embodiments, the composition is in the form of a tablet. In other embodiments, the composition is in the form of a hard or soft gelatin capsule.

[0120] The compounds of the invention are formulated with conventional carriers and excipients that can be selected based on ordinary practice. Tablets may contain excipients, lubricants, fillers, binders, and the like. All formulations optionally contain excipients, such as those described in "Handbook of Pharmaceutical Excipients" (1986). Suitable excipients are also listed in the U.S. Food and Drug Administration's Inactive Ingredients Database. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0121] While pharmaceutical active ingredients can be administered alone, it may be preferable to provide them as pharmaceutical formulations. The formulations of the present invention for both veterinary and human use contain at least one active ingredient as defined above, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. Some examples of materials that can act as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sesame oil, castor oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0122] The formulations of the present invention suitable for oral administration can be provided as individual units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient as a powder or granules. The active ingredient can also be administered as a bolus, a lick or a paste.

[0123] Tablets are prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine a free-flowing form, such as a powder or granules, of the active ingredient which has been optionally mixed with a binder, a lubricant, an inert diluent, a preservative, a surfactant or a dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can optionally be coated or scored and are optionally formulated to provide for a slow or controlled release of the active ingredient therefrom.

[0124] The pharmaceutical preparation according to the present invention comprises the compound according to the present invention, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. For example, if oral use is intended, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions can contain one or more agents, including sweetening agents, flavoring agents, coloring agents and preservatives, to provide palatable preparations. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0125] Preparations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin or olive oil.

[0126] The aqueous suspension of the present invention contains an active material in an additive mixture with excipients suitable for the manufacture of the aqueous suspension. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and gum acacia, and dispersing agents or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), and condensation products of partial esters derived from fatty acids and hexitol anhydrides and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. The liquid formulation can also include eye drops or other delivery forms to the surface of the eye or adjacent locations such as the tear duct. The liquid formulation can include an intravenous formulation, an excipient, and a carrier such as physiological saline or a buffer solution, and there may also be a package or container for such a formulation for injection or infusion etc.

[0127] The dispersible powders and granules of the present invention suitable for the preparation of an aqueous suspension by the addition of water provide an active ingredient in an additive mixture with a dispersing agent or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing agents or wetting agents, and suspending agents are exemplified by those disclosed above. Additional excipients such as sweetening agents, flavoring agents and colorants can also be present.

[0128] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the subject being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans can contain from about 1 mg to about 1000 mg of active material, formulated with a suitable and convenient amount of carrier material that can vary from about 5% to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide readily measurable amounts for administration.

[0129] Formulations suitable for intralung or nasal administration reach the alveolar sacs by being administered by rapid inhalation through the nasal passage or by inhalation through the mouth and have a particle size in the range of, for example, about 0.1 to about 500 microns, such as about 0.5, about 1, about 30 or about 35 microns. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents.

[0130] The formulations are provided in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried state that requires only the addition of a sterile liquid carrier, such as water, immediately prior to use. Immediate injection solutions and suspensions are prepared from sterile powders, granules and tablets of the types described previously. Preferred unit dose formulations contain the daily or unit sub-daily dose of the active ingredient as listed above herein, or a suitable fraction thereof.

[0131] In addition to the components specifically described above, it should be understood that the formulations of this invention can include other agents conventional in the art, taking into account the type of formulation, for example, those suitable for oral administration can include flavoring agents.

[0132] In some embodiments, the amount of the compound of Formulae 1-2c in the composition is from about 0.001 wt% to 100 wt%.

[0133] In some embodiments, the compounds of Formulas 1-2c are the sole pharmaceutical active ingredient in the composition. Alternatively, the compounds of Formulas 1-2c are formulated in the composition with one or more additional pharmaceutical active ingredients. When formulated as the sole pharmaceutical active ingredient, the compounds of Formulas 1-2c can be administered individually or as part of a regimen using one or more separately formulated pharmaceutical active ingredients.

[0134] When co-administered in the same formulation or as part of a regimen using one or more separately formulated pharmaceutical active ingredients, the additional pharmaceutical active ingredients can be selected from compounds in the NAD+ pathway such as nicotinic acid (NA), nicotinamide (Nam), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid mononucleotide (NaMN), nicotinic acid riboside (NAR), nicotinamide adenine dinucleotide (NAD + / NADH), nicotinamide adenine dinucleotide phosphate (NADP), and nicotinic acid adenine dinucleotide (NaAD). In some embodiments, the additional pharmaceutical active ingredient is an amorphous solid. In some embodiments, the additional pharmaceutical active ingredient is a crystalline solid. In some embodiments, the additional pharmaceutical active ingredient is amorphous NMN. In some embodiments, the additional pharmaceutical active ingredient is crystalline NMN.

[0135] In some embodiments, the additional pharmaceutical active ingredient is 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (BCG), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxybilirubin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide,It is a chemotherapeutic agent selected from levamisole, romustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonaporphyrin, topotecan, trametinib, trastuzumab, tretinoin, verubecestat, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA).

[0136] In other embodiments, suitable chemotherapeutic agents include the following: FK866, ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents include the following: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonaporphyrin.

[0137] Other types of chemotherapeutic agents include tumor immunotherapeutic agents such as abagovomab, adecatumumab, afucosumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epirubicinumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lanbritumomab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, tisilimumab, samalizumab and tremelimumab.

[0138] In some embodiments, the pharmaceutical active ingredient is selected from PARP inhibitors known to repair DNA damage, such as olaparib, veliparib, niraparib, NMS-P118, talazoparib and rucaparib.

[0139] Methods of treatment, diseases, disorders and conditions Provided herein is a method of modulating NAD levels in a subject in need of modulation of NAD levels, comprising administering a compound or a salt thereof, and a composition thereof, as disclosed herein.

[0140] Provided herein is a method of treating a disease or disorder associated with NAD biosynthesis, comprising administering a compound or a salt thereof, and a composition thereof, as disclosed herein.

[0141] Provided herein are methods of using the disclosed compounds and pharmaceutical compositions thereof. The disclosed compounds and pharmaceutical compositions thereof can be useful for a variety of therapeutic applications, including, for example, treating and / or reducing a variety of diseases and disorders such as diseases or disorders associated with aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular diseases, blood coagulation disorders, inflammation, cancer, and / or flushing. The methods include administering the disclosed compounds and / or pharmaceutical compositions thereof to a subject in need thereof. The disclosed compounds and pharmaceutical compositions thereof can be useful for decreasing NAD levels in other tissues or cells while increasing or maintaining NAD levels in certain tissues or cells. In various embodiments, the disclosed compounds and pharmaceutical compositions thereof can be used to selectively decrease NAD levels in some tissues or cells while decreasing NAD levels to a lesser extent in other tissues or cells.

[0142] In certain embodiments, a compound or pharmaceutical composition as disclosed herein can be used for treating or preventing a disease or condition induced or exacerbated by cellular aging in a subject, a method of decreasing the rate of aging of a subject, for example, after the onset of aging, a method of extending the lifespan of a subject, a method of treating or preventing a disease or condition associated with lifespan, a method of treating or preventing a disease or condition associated with the proliferative capacity of cells, and a method of treating or preventing a disease or condition resulting from cellular injury or cell death. In certain embodiments, the method does not act by decreasing the incidence of diseases that shorten the lifespan of a subject. In certain embodiments, the method does not act by reducing the mortality rate caused by a disease, such as cancer.

[0143] In certain embodiments, a compound or pharmaceutical composition as disclosed herein can be administered to a subject to generally increase the lifespan of the subject's cells and to protect the subject's cells against stress and / or apoptosis. Treating a subject with a compound described herein can be similar to hormesis, i.e., subjecting the organism to a mild stress that is beneficial to the organism and can extend their lifespan.

[0144] The disclosed compounds and their pharmaceutical compositions can be administered to subjects that have recently received or are likely to receive a dose of radiation or a toxin. In one embodiment, the dose of radiation or toxin is received as part of a work-related or medical procedure, such as working at a nuclear power plant, flying an airplane, an X-ray, a CAT scan, or the administration of a radioactive dye for medical imaging, and in such embodiments, the compound is administered as a prophylactic measure. In other embodiments, the radiation or toxin exposure is received unintentionally, e.g., as a result of an industrial accident, living in a location with natural radiation, a terrorist act, or a war involving radioactive or toxic materials. In such cases, the disclosed compounds and their pharmaceutical compositions are preferably administered as soon as possible after exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.

[0145] In other embodiments, the disclosed compounds and their pharmaceutical compositions can be useful for treating age-related disorders, such as cancer. Illustrative cancers that can be treated using the disclosed compounds and their pharmaceutical compositions include cancers of the brain and kidney, hormone-dependent cancers including breast, prostate, testicular, and ovarian cancers, lymphomas, and leukemias. Other diseases that can be treated include autoimmune diseases, such as systemic lupus erythematosus, scleroderma, and arthritis, where autoimmune cells are to be eliminated. Viral infections, such as herpes, HIV, adenovirus, and HTLV-1-related malignant and benign disorders can also be treated by administration of the disclosed compounds and their pharmaceutical compositions.

[0146] In some embodiments, the disclosed compounds and pharmaceutical compositions thereof can be used to treat patients suffering from neurodegenerative diseases and traumatic or mechanical injuries to the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include, but are not limited to, ataxia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), diffuse Lewy body disease, acanthocytosis, primary lateral sclerosis, eye diseases (optic neuritis), chemotherapy-induced neuropathy (e.g., from vincristine, paclitaxel, bortezomib), diabetes-induced neuropathy, and Friedreich's ataxia.

[0147] Administration of the disclosed compounds and pharmaceutical compositions thereof can increase insulin sensitivity and / or decrease insulin levels in a subject. Subjects in need of such treatment can be subjects with insulin resistance or other prodromal symptoms of type II diabetes, subjects with type II diabetes, or subjects at high risk of developing any of these conditions. For example, the subject can be a subject with insulin resistance, e.g., high circulating levels of insulin and / or related conditions, e.g., hyperlipidemia, lipogenesis deficiency, hypercholesterolemia, impaired glucose tolerance, high blood glucose levels, other manifestations of syndrome X, hypertension, atherosclerosis, and lipodystrophy.

[0148] In various embodiments, methods are disclosed herein for differentially modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissues or cell types. Such methods may include administering a compound or composition as disclosed herein, wherein the administration induces a differential response in NAD levels in a first tissue or cell type compared to a second tissue or cell type. In various embodiments, the differential response in NAD levels is selected from at least a 10% difference in NAD levels, at least a 20% difference in NAD levels, at least a 30% difference in NAD levels, at least a 40% difference in NAD levels, at least a 50% difference in NAD levels, at least a 60% difference in NAD levels, at least a 70% difference in NAD levels, at least an 80% difference in NAD levels, at least a 90% difference in NAD levels, at least a 100% difference in NAD levels, at least a 200% difference in NAD levels, at least a 300% difference in NAD levels, at least a 400% difference in NAD levels, at least a 500% difference in NAD levels, at least a 600% difference in NAD levels, at least a 700% difference in NAD levels, at least an 800% difference in NAD levels, at least a 900% difference in NAD levels, and at least a 1000% difference in NAD levels. In various embodiments, the differential response in NAD levels is an increase in NAD levels of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% in a first tissue or cell type compared to an untreated or pre-treatment NAD level, and a simultaneous decrease in NAD levels of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% in a second tissue or cell type compared to an untreated or pre-treatment NAD level.In various embodiments, the differential response of NAD levels is the maintenance of NAD levels within 10% of the NAD levels in the first tissue or cell type compared to the untreated NAD levels, and at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% simultaneous decrease in the NAD levels in the second tissue or cell type compared to the untreated NAD levels. In various embodiments, the differential response of NAD levels is at least a 10% reduction in the NAD levels in the first tissue or cell type compared to the untreated NAD levels, and a simultaneous decrease in the NAD levels in the second tissue or cell type compared to the untreated NAD levels, and the decrease in the second tissue or cell type is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% greater than the reduction in the first tissue or cell type. In various embodiments, the first tissue or cell type is a normal tissue or cell, and the second tissue or cell type is neoplastic or cancerous.

[0149] The methods of treating cancer disclosed herein include treating an individual in need thereof. Exemplary cancers that can be treated using the disclosed compounds and pharmaceutical compositions thereof include cancers of the brain and kidney, hormone-dependent cancers including breast, prostate, testicular and ovarian cancers, lymphomas, and leukemias. In various embodiments, the cancer may be a common type of cancer in males, such as lung cancer, prostate cancer, colorectal cancer and gastric cancer. In various embodiments, the cancer may be a common type of cancer in females, such as breast cancer, colorectal cancer, lung cancer and cervical cancer. In various embodiments, the cancer may be a skin cancer, such as melanoma, squamous cell carcinoma, or basal cell carcinoma. In various embodiments, the cancer may be a common type of cancer in children, such as acute lymphoblastic leukemia, brain tumor, or non-Hodgkin lymphoma. In various embodiments, the method exhibits a selective cell growth inhibitory or cytotoxic effect, which is indicated by a decrease in the viability of neoplastic or cancerous tissue or cells compared to untreated neoplastic or cancerous tissue or cells.

[0150] The method includes a situation where the first tissue or cell type is normal tissue or cells, and the method is a treatment for promoting the health or increasing the biological activity of the first tissue or cell type in an individual in need of such treatment. In various embodiments, the treatment does not induce an increased risk of cancer diagnosis in the individual being treated. Preferably, the treatment reduces the risk of cancer diagnosis in the individual receiving the treatment.

[0151] The various methods include treating or suppressing cancer in an individual in need of treatment or suppression of cancer, and the method includes administering a compound or composition as described herein. In various embodiments, methods are disclosed herein for increasing or maintaining healthy tissue or cells in an individual in need of increasing or maintaining healthy tissue or cells without increasing the risk of growth of neoplastic or cancerous tissue or cells, and such methods include administering a compound or composition as described herein.

[0152] In various embodiments, methods are described herein for increasing or maintaining healthy tissue or cells in an individual in need of increasing or maintaining healthy tissue or cells while suppressing the growth of neoplastic or cancerous tissue or cells, such methods comprising administering a compound or composition as described herein. In various embodiments, the disclosed methods include methods for increasing or maintaining nicotinamide adenine dinucleotide (NAD) levels in at least one healthy tissue or cell type, such methods comprising administering a compound or composition as described herein to a healthy tissue or cell type. In various embodiments, methods are described herein for reducing the viability of at least one cancerous tissue or cell type, such methods comprising administering a compound or composition as described herein to a cancerous tissue or cell type.

[0153] Furthermore, methods as described herein include methods for modulating the level of NAD in at least one tissue or cell type in a mixture of tissue or cell types, such methods comprising targeted delivery of a compound or composition as described herein to a desired tissue or cell type. In various embodiments, the targeted delivery is non-systemic.

[0154] The written description of the invention enables one of ordinary skill in the art to make and use what is presently considered to be the best mode thereof, while one of ordinary skill will recognize and appreciate the existence of variations, combinations, and equivalents to the specific embodiments, methods, and examples herein. The invention, therefore, should be limited not by the described embodiments, methods, and examples, but by all embodiments and methods within the scope and spirit of the invention.

[0155] [Examples] Synthesis Examples General Procedure A: One-Pot Preparation of Crude Triol with Purification of Product by Precipitation (See Example 1)

[0156] General Procedure B: One-Pot Preparation of Crude Triol and Purification of the Product by Chromatography (see Example 9)

[0157] [Example 1] Compound 1 Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridin-3-carboxamido)benzoate.

[0158] [Chemical Structure] Trimethylsilyl trifluoromethanesulfonate (TMS-triflate, 4.8 mL, 26.5 mmol, 1.2 equiv) was added dropwise over 5 min under Ar to a stirred mixture of methyl 4-(nicotinamide)benzoate (5.9 g, 23 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (8.1 g, 25.4 mmol, 1.1 equiv) in anhydrous acetonitrile (CH3CN, 100 mL). The reaction mixture was stirred at room temperature for 1 h, and then the reaction was determined to be complete when HPLC analysis of an aliquot showed less than 10% nicotinamide present. The reaction mixture was diluted with anhydrous MeOH (50 mL) and concentrated on a rotary evaporator to remove most of the CH3CN. The mixture was diluted with MeOH (100 mL) and cooled in an ice bath. Thionyl chloride (SOCl2, 5.8 mL, 80.5 mmol, 3.5 equiv) was added dropwise and the reaction mixture was stirred at 5 °C in a refrigerator for 16 h. The reaction was determined to be complete when HPLC analysis of an aliquot showed less than 5% mono- and diacetate intermediates present. The crude product was precipitated by adding the solution to 1.3 L of vigorously stirred MTBE in a 2 L Erlenmeyer flask. The precipitated solid was filtered, washed with a large amount of MTBE, dried in a suction funnel, and then further dried under high vacuum to give the product (7.7 g, 62%) as a white solid. 11H NMR (D2O): δ 9.64 (s, 1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.29 (dd, 1H), 8.02 (d, 2H), 7.70 (d, 2H), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.04 (apparent dd, 1H), 3.87 (m, 4H or 5H). MS(ESI+) m / z = 389.1

[0159] [Example 2] Compound 2 N-(4-carbamoylphenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamide.

[0160] [Chemical formula] Following general procedure A: TMS-triflate (1.2 eq) was added to a stirred mixture of N-(4-carbamoylphenyl)nicotinamide (1.1 g, 4.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) in anhydrous acetonitrile (40 mL). The mixture was stirred at room temperature for 2 h, the solvent was removed, and the residue was treated with 3 eq of SOCl2 in 40 mL of MeOH and then stirred at 5 °C for 24 h. The mixture was concentrated to half of its original volume, MTBE (50 mL) was added dropwise to precipitate the product. The solid was filtered through a sintered glass funnel, washed with 2 × 10 mL portions of MeOH (pre-cooled to -20 °C), and then with several portions of MTBE. The solid was dried under high vacuum for several hours to give the product (1.25 g, 49%) as a white solid. 11H NMR (D2O): δ 9.87 (s, 1H), 9.47 (apparent d, 1H), 9.17 (apparent d, 1H), 8.36 (t, 1H), 7.94 (dd, 4H), 6.23 (d, 1H), 4.46 (m, 2H), 4.34 (m, 1H), 3.97 (ab q, 2H). MS(ESI+) m / z = 374.1

[0161] [Example 3] Compound 3 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(methylcarbamoyl)phenyl)-1λ 4 -pyridine-3-carboxamide.

[0162] [Chemical Structure] Following general procedure B: TMS-triflate (1.7 mL, 0.55 mmol, 1.2 equiv) was added to a 2-hour stirred mixture of N-(4(methylcarbamoylphenyl)nicotinamide (1.1 g, 0.46 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in anhydrous acetonitrile (40 mL). Subsequent workup and treatment with 3 equiv of SOCl2 in MeOH, followed by stirring at 5 °C for 24 hours, gave a crude product as a semi-solid material after trituration. The material was dissolved in a minimum of 10% MeOH in DCM and loaded onto a 40 g ISCO automated chromatography cartridge. Elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM gave the product (1.1 g, 62%) as a white solid. 1NMR (D2O): δ 11.6 (s, 1H), 9.79 (s, 1H), 9.46 (d, 2H), 9.27 (d, 2H), 8.47 (m, 1H), 8.41 (t, 1H), 7.92 (dd, 4H), 6.25 (d, 1H), 4.40 (t, 1H), 4.27 (m, 1H), 4.18 (t, 1H), 3.79 (ab q, 2H), 2.78 (s, 3H). MS(ESI+) m / z = 388.1

[0163] [Example 4] Compound 4 ((2R,3S,4R,5R)-3,4-Dihydroxy-5-(3-((4-(methoxycarbonyl)phenyl)carbamoyl)-1λ 4 -pyridin-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate.

[0164] [Chemical Structure] 2 g (4.1 mmol) of Compound 1 was placed in a dry 100 mL flask. The flask was flushed with argon and 10 mL of trimethyl phosphate was added. The resulting solution was cooled to 0 °C and treated with POCl3 (1.25 g, 8.2 mmol, 2 equiv). The flask was sealed and left standing at -10 °C in a freezer. After 2.5 h, the homogeneous solution was treated with triethylamine (206 mg, 2.0 mmol) over several minutes and left standing overnight in the freezer. The reaction mixture was cooled in an ice bath and the well-stirred suspension was treated with water (1.5 g, 82 mmol) over several minutes, followed by solid NaHCO3 (2.4 g, 28.7 mmol), and stirring was continued at 0 °C for 90 min. The reaction mixture was treated with 100 mL of CH3CN containing 33 mmol of 90% formic acid to produce a white solid. The solid was recovered by filtration, washed with CH3CN, and placed under high vacuum to obtain the crude product as an off-white solid (3.7 g). This material was purified by medium-pressure chromatography on a column containing 50 g of aminopropyl-functionalized silica. The product was dissolved in 25 mL of 60% / 40% MeOH-CH3CN containing 100 mM formic acid, and the column was equilibrated with the same solvent mixture. The product-containing fractions were combined and concentrated, co-evaporated from water (3 × 25 mL), frozen, and lyophilized to obtain the product (300 mg, 16%) as a white solid. 1 1H NMR (D2O): δ 9.4 (s, 1H), 9.2 (m, 1H), 8.9 (d, 1H), 8.2 (m, 1H), 7.9 (d, 2H), 7.6 (d, 2H), 6.1 (d, 1H), 4.6 (m, 1H), 4.5 (m, 1H), 4.4 (q, 1H), 4.2 (dq, 1H), 4.1 (dq, 1H), 3.8 (s, 3H). 31 31P NMR (D2O): 0.24 ppm. MS(ESI+) m / z = 468.1

[0165] [Example 5] Compound 5 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-1λ 4 -pyridine-3-carboxamide.

[0166]

Chem.

[0167] [Example 6] Compound 6 Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-methyl-1λ 4 -pyridine-3-carboxamide)benzoate.

[0168] [Chemical formula] Into a dry 100 mL RB flask, 3.2 g of methyl 4-(N-methylnicotinamide)benzoate (11.8 mmol) was placed and the flask was flushed with argon. This was dissolved in 35 mL of anhydrous dioxane under a stream of argon and treated with 3.8 g of ribose tetraacetate (11.8 mmol). The resulting solution was cooled briefly with ice water, treated with 3.2 g of TMS-triflate (14.2 mmol), warmed to ambient temperature and stirred. After 2.5 hours, the reaction was allowed to proceed to approximately 90% completion. The solvent was removed by rotary evaporation and the residue was taken up in 50 mL of DCM. This was washed with saturated NaHCO3 and brine. The aqueous layer was back-extracted with DCM, the organic layers were combined, dried over Na2SO4, filtered and evaporated under high vacuum to give 6.9 g of an off-white foam. This was purified using a medium pressure LC system with a gradient of 0 - 15% MeOH in DCM using a 120 g silica cartridge. The product fractions were isolated, pooled, stripped and placed under high vacuum to give 5.6 g (70%) of the triacetate. 1 1H NMR (CDCl3): δ 9.3 (broad doublet of singlets, 1H); 9.2 (doublet, 1H); 8.0 (doublet, 2H); 7.3 (doublet, 2H); 6.6 (doublet, 1H); 5.3 (multiplet, 1H); 5.2 (multiplet, 1H); 4.7 (multiplet, 1H); 4.5 (doublet of doublets, 1H); 4.4 (doublet of doublets, 1H); 3.9 (singlet, 3H); 3.6 (singlet, 3H); 2.2 (singlet, 3H); 2.1 (singlet, 3H); 2.0 (singlet, 3H).

[0169] 5.6 g of the above triacetate (8.2 mmol) was placed in 250 mL of RB, and the flask was flushed with argon. This was dissolved in 75 mL of anhydrous MeOH, and the resulting solution was cooled on ice and treated dropwise with 2.94 g of SOCl2 (24.7 mmol). The sealed reaction vessel was left standing in a refrigerator at 10 °C. After 18 hours, the solvent was removed in vacuo, the residue was triturated with MTBE, and then placed under high vacuum to obtain 4.7 g as a white solid. This was purified on a 40 g silica ISCO cartridge using a gradient of 0 - 15% MeOH in DCM. The product fractions were pooled and stripped to obtain 2.5 g as an off - white foam. 1 1H NMR (CDCl3): δ 9.0 (d, 1H); 8.1 (d, 1H); 7.8 (m, 3H); 7.2 (d, 2H); 5.8 (d, 1H); 4.2 (m, 2H); 4.1 (d, 2H); 3.8 - 3.6 (4H); 3.4 (s, 3H); 3.2 (s, 3H).

[0170] [Example 7] Compound 7 Methyl 4 - (1 - ((2R,3R,4S,5R)-3,4 - dihydroxy - 5 - (hydroxymethyl)tetrahydrofuran - 2 - yl)-1λ 4 - pyridine - 3 - carboxamido)-3 - methoxy - benzoate.

[0171] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 3-methoxy-4-(nicotinamide)benzoate (1.6 g, 5.63 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in anhydrous acetonitrile (40 mL), and the resulting mixture was stirred for 2 h. Workup as described above and subsequent treatment with 3 equiv of SOCl2 in MeOH, followed by stirring at 5 °C for 24 h gave the crude product as a semi-solid after trituration. The crude product was purified using ISCO (40 g cartridge) eluting with a gradient of 30% MeOH in DCM from DCM to give the product (715 mg, 23%) as an off-white solid. 1 1H NMR (CD3OD): δ 9.84 (s, 1H), 9.67 (d, 1H), 9.12 (d, 1H), 8.31 - 8.36 (m, 2H), 7.72 - 7.74 (m, 2H), 6.25 (d, 1H), 4.42 - 4.52 (m, 2H), 4.36 (m, 1H), 4.04 (s, 3H), 3.96 (ab q, 2H), 3.91 (s, 3H). MS(ESI+) m / z = 419.1

[0172] [Example 8] Compound 8 Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridin-3-carboxamido)-3-fluorobenzoate.

[0173] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 3-fluoro-4-(nicotinamide)benzoate (610 mg, 2.31 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (800 mg, 2.5 mmol, 1.1 equiv) in anhydrous acetonitrile (40 mL), and the mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was treated with 3 equiv of SOCl2 in MeOH, followed by stirring at 5 °C for 24 h. After workup as described above and removal of excess HCl by co-evaporation with DCM, the crude product was obtained as a semi-solid. The crude product was purified by ISCO (24 g cartridge) eluting with a gradient of 30% MeOH in DCM from DCM to give the product (400 mg, 31%) as a light brown solid. 1 1H NMR (CD3CN): δ 9.66 (s, 1H), 9.30 (br s, 1H), 9.26 (d, 1H), 8.98 (d, 1H), 8.26 (t, 2H), 7.93 (d, 1H), 7.87 (d, 1H), 6.14 (d, 1H), 4.47 (t, 1H), 4.13 (m, 1H), 3.94 (ab q, 2H), 3.92 (s, 1H). MS(ESI+) m / z = 407.1

[0174] [Example 9] Compound 9 Ethyl 3-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridin-3-carboxamido)benzoate.

[0175] [Chemical formula] TMS-triflate (2.9 mL, 15.7 mmol, 1.2 equiv) was added dropwise to a stirred mixture of ethyl 3-(nicotinamido)benzoate (3.85 g, 14.3 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (8.1 g, 25.4 mmol, 1.1 equiv) in anhydrous DCM (80 mL) under Ar. The reaction mixture was stirred at room temperature for 1 h, after which it was found by HPLC analysis that only 10% of the reaction was complete due to the insolubility of nicotinamide. The reaction mixture was diluted with anhydrous dioxane (30 mL) and additional TMS-triflate (3.0 mL, 1.1 equiv) was added. The reaction mixture was stirred for 1 h, at which point it was found by HPLC analysis that the reaction was complete. The mixture was concentrated on a rotary evaporator to approximately 20 mL, diluted with anhydrous EtOH (50 mL), cooled in an ice bath, and treated dropwise with SOCl2 (4.2 mL, 57.3 mmol, 4 equiv). The mixture was stirred at 5 °C in a refrigerator for 3 days, then concentrated on a rotary evaporator to approximately 30 mL, triturated with MTBE, and the crude product was precipitated as a semi-solid material. The product was further triturated with MTBE to afford an off-white solid (2 g). 1 g of this material was purified using an ISCO Combi Flash® automated chromatography system with a 24 g silica gel cartridge and adding a minimum of 5% MeOH in DCM. Elution was carried out using a gradient from 5% MeOH in DCM to 30% MeOH in DCM. The pure fractions were pooled and concentrated, then co-stripped with DCM and placed under high vacuum for several hours to afford the pure product (700 mg, overall yield 24%) as a white solid. 11H NMR (D2O): δ 9.64 (s, 1H), 9.30 (d, 1H), 9.04 (d, 1H), 8.42 (s, 1H), 8.27 (apparent t, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H), 6.16 (d, 1H), 4.46 (apparent t, 1H), 4.33 - 4.43 (m, 2 or 3H), 4.31 (apparent t, 1H), 3.92 (ab q, 2H), 1.97 (q, 2H). MS(ESI+) m / z = 403.1

[0176] [Example 10] Compound 10 Ethyl 2-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)benzoate.

[0177] [Chemical formula] Trimethylsilyl trifluoromethanesulfonate (TMS-triflate, 3.3 mL, 17.8 mmol, 1.2 equiv) was added dropwise over 5 min under Ar to a stirred mixture of methyl 2-(nicotinamide)benzoate (3.8 g, 14.8 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (5.2 g, 16.3 mmol, 1.1 equiv) in anhydrous DCM (35 mL). The reaction mixture was stirred at ambient temperature for 1.5 h and the completion of the reaction was determined by HPLC. The mixture was cooled in an ice bath, diluted with anhydrous MeOH (50 mL), and thionyl chloride (SOCl2, 3.22 mL, 44.4 mmol, 3 equiv) was added dropwise. The solution was left standing at 5 °C in a refrigerator for 24 h. The mixture was concentrated to about 20 mL on a rotary evaporator and the product was precipitated by the addition of 100 mL of MTBE. After decanting the solution, the residue was triturated twice with MTBE to give a light brown solid. Attempts to purify a 2 g sample by chromatography were unsuccessful as the product decomposed on the column. 1.2 g of the solid was dissolved in anhydrous EtOH (10 mL) and the product was precipitated by the addition of 40 mL of MTBE. After successive trituration with MTBE, the solid was collected by filtration and washed with MTBE. After drying overnight under high vacuum, the product (780 mg) was obtained as an off-white solid with 95% purity. 1 H NMR (DMSO-d6): δ 11.74 (s, 1H), 9.80 (s, 1H), 9.52 (d, 1H), 9.13 (d, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.74 (t, 1H), 7.38 (t, 1H), 6.29 (d, 1H), 4.38 (t, 1H), 4.23 (m, 1H), 3.88 (s, 3H). MS(ESI+) m / z = 389.1

[0178] [Example 11] Compound 11 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(hydroxymethyl)phenyl)-1λ4 -Pyridine-3-carboxamide.

[0179]

Chem.

[0180] [Example 12] Compound 12 N-(4-(Diethylcarbamoyl)phenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -Pyridine-3-carboxamide.

[0181]

Chem.

[0182] [Example 13] Compound 13 N-(4-cyanophenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamide.

[0183] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 eq) was added to a stirred mixture of N-(4-cyanophenyl)nicotinamide (1.5 g, 5.63 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) in DCM (40 mL), and the mixture was subsequently stirred at ambient temperature for 3 h. Treatment with SOCl2 (3 eq) in MeOH followed by evaporation of the solvent and stirring at 5 °C for 16 h gave the crude product as a semi-solid material after workup as described above. The residue was absorbed into MeOH in DCM at a minimum of 20% and loaded onto a 40 g ISCO column eluting with a gradient from 10% MeOH in DCM to 40% MeOH in DCM to give 1.15 g (57%) of the pure product as an off-white solid. 1 1H NMR (D2O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m / z = 356.1

[0184] [Example 14] Compound 14 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(trifluoromethyl)phenyl)-1λ 4 -pyridine-3-carboxamide.

[0185] [Chemical formula] Follow general procedure B: TMS-triflate (1.5 mL, 8.04 mmol, 1.2 equiv) was added to a stirred mixture of N-(4-(trifluoromethyl)phenyl)nicotinamide (1.5 g, 6.7 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (2.4 g, 7.4 mmol, 1.1 equiv) in DCM (40 mL). Subsequent treatment with SOCl2 (3 equiv) in MeOH and stirring at 5 °C for 16 h, followed by workup as described above, gave the crude product as an off-white solid. Half of this material was chromatographed on ISCO (40 g cartridge, eluting with a gradient from DCM to 30% MeOH in DCM) to give the product (300 mg) as a white solid. 1 1H NMR (D2O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m / z = 399.1

[0186] [Example 15] Compound 15 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridin-3-carboxamido)benzoic acid.

[0187] [Chemical formula] To a mixture of 4-(nicotinamide)benzoic acid (3.76 g, 9.59 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (3.20 g, 10.07 mmol) in anhydrous dioxane (40 mL) was added triethylamine (4.02 mL, 28.8 mmol, 3 equiv), and the mixture was stirred at room temperature for 15 min. TMS-triflate (6.94 mL, 38.4 mmol, 3 equiv) was added over 5 min, and the reaction was stirred for 20 min, after which HPLC analysis indicated completion of the reaction. The mixture was diluted with 40 mL of MTBE, the solution was poured into 300 mL of MTBE, and the resulting oil was allowed to settle. After decanting the solvent, the oil was triturated twice with 80 mL portions of MTBE. The residue was dissolved in EtOAc (50 mL), washed with 2 × 30 mL portions of water, and dried over anhydrous Na2SO4. Filtration and evaporation of the solvent gave 5.5 g of the crude triacetate intermediate. 2.23 g of this material was chromatographed on 600 g of silica gel eluting with a gradient from 5% MeOH in DCM to 30% MeOH in DCM to give the purified triacetate (1.3 g) as a white solid. Triacetate: 1 1H NMR (CD3CN): δ 9.68 (br s, 1H), 9,48 (d, 1H), 9.14 (d, 1H), 9.09 (dd, 1H), 8.33 (dd, 1H), 8.10 (d, 2H), 7.92 (d, 2H), 6.45 (m, 1H), 5.53 (d, 1H), 5.43 (t, 1H), 4.81 (q, 1H), 4.53 (dd, 1H), 4.50 (dd, 1H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

[0188] Triacetate (1.3 g, 2.0 mmol) was dissolved in 4 mL of anhydrous MeOH and added to a well-stirred ice-cold solution of 1N NaOMe (6 mL, 6.0 mmol, 3 eq) in MeOH under Ar. The mixture was stirred for 20 min, then a cold solution of 1N HCl (6 mL, 6.0 mmol, 3 eq) in MeOH was added all at once. The color of the solution changed from dark orange to yellow and a solid precipitated from the solution (the pH of the solution was 2). The product was filtered, washed thoroughly with MTBE and then dried under high vacuum to give the product (369 mg, 49%) as a pale pink solid. 1 1H NMR (D2O): δ 9.65 (s, 1H), 9.27 (d, 1H), 9.03 (d, 1H), 8.28 (t, 1H), 8.01 (q, 2H), 7.71 (br d, 2H), 6.25 (d, 1H), 4.52 (t, 1H), 4.47 (q, 1H), 4.35 (t, 1H), 4.03 (dd, 1H), 3.88 (dd, 1H). MS(ESI+) m / z = 375.1

[0189] [Example 16] Compound 16 Methyl 2-chloro-4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)benzoate.

[0190] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 2-chloro-4-(nicotinamide)benzoate (610 mg, 2.31 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in DCM (40 mL). After stirring for 2 h, 20 mL of anhydrous CH3CN was added to obtain a clear solution, and the reaction mixture was stirred for an additional 1 h at ambient temperature. The solvent was removed under reduced pressure, the residue was dissolved in MeOH, cooled, and treated with SOCl2 (3 equiv) in MeOH. The mixture was stirred for 16 h, and the crude product was obtained by post-treatment as described above and purified by ISCO to give a white solid (600 mg, 26%). 1 1H NMR (D2O): δ 9.64 (s, 1H), 9.28 (d, 1H), 9.03 (d, 1H), 8.29 (apparent t, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.57 (dd, 1H), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (apparent dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m / z = 423.1

[0191] [Example 17] Compound 17 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(oxazol-2-yl)phenyl)-1λ 4 -pyridine-3-carboxamide.

[0192] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a 2-hour stirred mixture of N-(4-(oxazol-2-yl)phenyl)nicotinamide (900 mg, 3.4 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.2 g, 3.73 mmol, 1.1 equiv) in anhydrous acetonitrile (40 mL). After removal of the solvent under reduced pressure, the residue was dissolved in MeOH, treated with 3 equiv of SOCl2, and stirred at 5 °C for 16 h. Subsequent workup as described above gave the crude product as a light brown solid. Purification by ISCO (40 g cartridge, gradient elution from DCM to 30% MeOH in DCM) gave the product as a white solid (650 mg, 48%). 1 1H NMR (D2O): δ 11.74 (br s, 1H), 9.81(br s, 1H), 9.46 (d, 1H), 9.26 (d, 1H), 8.40 (t, 1H), 8.23 (d, 1H), 8.03 - 8.12 (m, 5H), 7.37 (br s, 1H), 6.25 (d, 1H), 4.43 (t, 1H), 4.28 (m, 1H), 4.20 (t, 1H), 3.79 (ab q, 2H). MS(ESI+) m / z = 398.1

[0193] [Example 18] Compound 18 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(2-methyl-1,3-dioxoisoindolin-5-yl)-1λ 4 -pyridine-3-carboxamide.

[0194] [Chemical Structure] Follow general procedure B: TMS-triflate (1.91 mL, 10.34 mmol, 1.2 equiv) was added to a stirred mixture of N-(2-methyl-1,3-dioxoisoindolin-5-yl)nicotinamide (2.46 g, 8.75 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (3.04 g, 9.56 mmol, 1.1 equiv) in CH3CN (80 mL). Stirred at ambient temperature for 3 h, followed by removal of the solvent and treatment with SOCl2 (3 equiv) in MeOH, stirred for 16 h, and triturated with MTBE to give the crude product as a light brown solid. Purification was achieved by ISCO (40 g cartridge, elution with a gradient from DCM to 30% MeOH in DCM). The pure fractions were combined, the solvent was evaporated under reduced pressure, and the product (1.05 g, 29%) was obtained as an off-white solid. 1 1H NMR (D2O): δ 9.69 (s, 1H), 9.31 (d, 1H), 9.07 (d, 1H), 8.34 (t, 1H), 8.08 (s, 1H), 7.83 (dd, 2H), 6.26 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H), 3.07 (s, 3H). MS(ESI+) m / z = 414.1

[0195] [Example 19] Compound 19 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(2-methyl-3-oxoisoindolin-5-yl)-1λ 4 -pyridine-3-carboxamide.

[0196] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of N-(2-methyl-3-oxoisoindolin-5-yl)nicotinamide (1.25 g, 4.7 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in anhydrous CH3CN (50 mL). The mixture was stirred at ambient temperature for 3 h, then the solvent was evaporated and the residue was treated with SOCl2 (3 equiv) in MeOH at 5 °C for 24 h and triturated to give the crude product as an off-white solid. Purification by ISCO (40 g cartridge, eluting with a gradient from DCM to 40% MeOH in DCM) gave the pure product (650 mg, 35%) as a white solid. 1 1H NMR (D2O): δ 9.65 (s, 1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.30 (t, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 7.66 (d, 1H), 7.57 (d, 1H), 6.26 (d, 1H), 5.42 (s, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 3.95 (ab q, 2H), 3.10 (s, 1H). MS(ESI+) m / z = 400.2

[0197] [Example 20] Compound 20 N-(3-carbamoylphenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamide.

[0198] [Chemical formula] TMS-triflate (1.3 mL, 7.1 mmol, 1.2 equiv) was added to a stirred mixture of N-(3-carbamoylphenyl)nicotinamide (1.42 g, 6.75 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (2.2 g, 6.8 mmol, 1.1 equiv) in CH3CN (60 mL) at room temperature. After stirring for 2 h, the solvent was removed and the residue was taken up in ethyl acetate. The solution was transferred to a separatory funnel and washed successively with 5% aqueous NaHCO3, water and brine, then dried over anhydrous Na2SO4. The solution was filtered and concentrated, and the residue was purified by ISCO (40 g cartridge) eluting with 20% MeOH in DCM from DCM. The fractions containing the product were pooled and concentrated to give the triacetate intermediate (405 mg) as a foam. This material was dissolved in anhydrous MeOH (20 mL), cooled in an ice bath and treated with 3 equiv of SOCl2. The solution was stirred at 5 °C for 24 h. The solution was triturated with MTBE to precipitate the product as a white solid, which was collected by filtration. The product was washed with several portions of MTBE on a Büchner funnel and then placed under high vacuum to remove traces of HCl. The product (140 mg, 6%) was obtained as a white solid. 1 1H NMR (D2O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 6.25 (d, 1H), 4.51 (apparent t, 1H), 4.47 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H). MS(ESI+) m / z = 374.1

[0199] [Example 21] Compound 21 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1λ 4 -pyridine-3-carboxamide.

[0200] [Chemical formula] Follow general procedure B: TMS-triflate (0.75 mL, 4.1 mmol, 1.2 eq) was added to a stirred mixture of N-(3-oxo-1,3-dihydroisobenzofuran-5-yl)nicotinamide (0.85 g, 3.4 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.2 g, 3.7 mmol, 1.1 eq) in CH3CN (25 mL). The mixture was stirred at ambient temperature for 1.5 h, then the solvent was removed and the residue was treated with SOCl2 (3.5 eq) in MeOH. The solution was then stirred at 5 °C for 24 h. MTBE was slowly added to the solution to precipitate the crude product, which was triturated with MTBE. The residue was co-stripped with DCM and then with CH3CN to remove traces of HCl. The residue was dissolved in a minimum of 20% MeOH in DCM and loaded onto a 24 g ISCO cartridge. Elution with 5% to 30% MeOH in DCM followed by evaporation of the pure fractions gave the pure product (505 mg, 38%). 1 H NMR (D2O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.06 (d, 1H), 8.32 (t, 1H), 8.12 (s, 1H), 7.89 (d, 1H), 7.66 (d, 1H), 6.26 (d, 1H), 5.43 (s, 2H), 4.54 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H). MS(ESI+) m / z = 387.1

[0201] [Example 22] Compound 22 Methyl 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carbonyl)indoline-5-carboxylate.

[0202] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 eq) was added to a stirred mixture of methyl 1-nicotinoylindoline-5-carboxylate (0.5 g, 1.78 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) in CH3CN (16 mL). After stirring for 2 h at ambient temperature, the solvent was removed, the residue was dissolved in MeOH, cooled and treated with SOCl2 (3 eq). After stirring at 5 °C for 16 h, trituration with MTBE gave the crude product as an off-white solid. Purification was achieved in standard fashion by ISCO (40 g cartridge, elution with a gradient from 10% MeOH in DCM to 30% MeOH in DCM) to give the product (330 mg, 45%) as an off-white solid. 1 1H NMR (D2O): δ 9.45 (br s, 1H), 9.25 (d, 1H), 8.85 (d, 1H), 8.3 (t, 1H), 7.70 - 8.10 (m, 3H), 6.23 (br s, 1H), 4.47 (m, 2H), 4.35 (m, 1H), 3.92 - 4.20 (m, 3H), 3.85 (s, 3H), 3.16 (m, 2H). MS(ESI+) m / z = 415.2

[0203] [Example 23] Compound 23 Methyl (4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-carboxamido)benzoyl)glycinate.

[0204] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 eq) was added to a stirred mixture of methyl (4-(nicotinamide)benzoyl)glycinate (0.5 g, 1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) in CH3CN (15 mL). The mixture was stirred at ambient temperature for 2 h, the solvent was removed and the residue was treated with SOCl2 (3.5 eq) in MeOH and the solution was stirred at 5 °C for 16 h. Since HPLC at that point showed 10% residual mono-acetate, additional SOCl2 (0.1 mL) was added and stirring was continued for 6 h. After trituration with MTBE, the crude product was obtained as an off-white solid. Purification by ISCO (12 g cartridge, elution with a gradient from 5% MeOH in DCM to 30% MeOH in DCM) gave the product (155 mg, 22%) as an off-white solid. 1 H NMR (D2O): δ 9.65 (br s, 1H), 9.26 (d, 1H), 9.03 (m, 1H), 8.27 (t, 1H), 7.65 - 7.88 (m, 4H), 6.24 (d, 1H), 4.50 (t, 1H), 4.45 (t, 1H), 4.35 (m, 1H), 4.15 (br s, 1H), 3.95 (ab q), 3.75 (s, 3H). MS(ESI+) m / z = 446.2

[0205] [Example 24] Compound 24 Ethyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)benzoate.

[0206] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of ethyl 4-(nicotinamide)benzoate (0.5 g, 1.85 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (20 mL). After stirring for 3 h at ambient temperature, the solvent was evaporated and the residue was taken up in anhydrous EtOH (20 mL) and cooled in an ice bath. SOCl2 (3.5 equiv) was added dropwise and the solution was left at 5 °C for 72 h. After work-up as described above, the crude product was obtained as a semi-solid. The crude product was purified by ISCO (24 g cartridge, eluting with a gradient of 5 - 30% MeOH in DCM with 10% MeOH in DCM added) eluting over 15 min. The pure fractions were pooled, stripped and traces of solvent removed under high vacuum. The product (145 mg, 19%) was obtained as an off-white solid. 1 1H NMR (DMSOd6): δ 11.75 (s, 1H), 9.79 (s, 1H), 9.46 (d, 1H), 8.38 (t, 1H), 8.04 (m, 4H), 6.24 (d, 1H), 4.42 (t, 1H), 4.22 - 4.35 (m, 3H), 4.18 (t, 1H), 3.80 (ab q, 2H), 1.33 (t, 3H). MS(ESI+) m / z = 403.2

[0207] [Example 25] Compound 25 Methyl 5-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)picolinate.

[0208] [Chemical formula] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 5-(nicotinamido)picolinate (1.21 g, 4.8 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (50 mL). After stirring for 3 h at ambient temperature, the solvent was evaporated and the residue was taken up in anhydrous MeOH (40 mL), cooled in an ice bath and treated with SOCl2 (3.5 equiv). After stirring at 5 °C for 24 h, the solution was concentrated to 10 mL and the product was precipitated with MTBE. The product was filtered through a sintered glass funnel and washed successively with 2 × 5 mL portions of ice-cold MeOH and then excess MTBE. After removing traces of solvent under high vacuum, the product (650 mg, 35%) was isolated as a white solid. 1 1H NMR (D2O): δ 9.63 (s, 1H), 9.26 (d, 1H), 9.03 (d, 1H), 8.26 (apparent t, 1H), 7.84 (br s, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 6.23 (d, 1H), 4.47 (t, 1H), 4.42 (s, 3H), 4.33 (apparent t, 1H), 3.94 (ab q, 2H). MS(ESI+) m / z = 390.1

[0209] [Example 26] Compound 26 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(1-oxoisoindolin-5-yl)-1λ 4 -pyridine-3-carboxamide.

[0210] [Chemical formula] Follow general procedure A: TMS-triflate (1.2 equiv) was added to a stirred mixture of N-(1-oxoisoindolin-5-yl)nicotinamide (0.56 g, 2.2 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (20 mL). After stirring for 1.5 h at ambient temperature, the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. SOCl2 (3.5 equiv) was added dropwise and the solution was stirred at 5 °C for 18 h. The product was precipitated with MTBE, the solvent was decanted, the solid was redissolved in MeOH and precipitated with MTBE. After trituration with MTBE, the solid (hygroscopic) was co-evaporated with CH3CN to remove traces of water and HCl. The pure product (600 mg, 71%) was obtained as an off-white solid. 1 H NMR (DMSO-d6): δ 11.9 (br s, 1H), 9.81 (d, 1H), 9.27 (apparent d, 1H), 9.16 (apparent d, 1H), 8.48 (m, 1H), 8.43 (apparent t, 1H), 8.18 (d, 1H), 6.24 (d, 1H), 4.40 (apparent t, 1H), 4.29 (m, 1H), 4.19 (apparent t, 1H), 3.87 (s, 2H), 3.81 (ab q, 2H). MS(ESI+) m / z = 386.1

[0211] [Example 27] Compound 27 2-(Dimethylamino)ethyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)benzoate.

[0212] [Chemical formula] TMS-triflate (3.0 g, 13.7 mmol) was added to a stirred solution of 2-(dimethylamino)ethyl 4-(nicotinamide)benzoate (1.8 g, 5.7 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.8 g, 5.7 mmol) in 40 mL of DCM over 5 minutes in an ice bath. The reaction mixture was warmed to ambient temperature and stirred overnight. The solvent was stripped and the residue was dissolved in EtOAc. This was washed with water, saturated NaHCO3 and brine, then dried over Na2SO4 and evaporated to dryness under vacuum to give 2.5 g of the triacetate as a solid. This compound was dissolved in 25 mL of anhydrous MeOH, cooled in an ice bath and then treated dropwise with 1.63 g (20.8 mmol, 3.65 eq) of acetyl chloride. The mixture was placed under argon and left at 10 °C overnight, then warmed to ambient temperature and stirred for 3 hours. The solvent was stripped until almost dry and the residue was triturated with hexane (2 × 150 mL), followed by MTBE (3 × 100 mL). The residue was taken up in MeOH (10 mL) and evaporated under high vacuum to give 2.1 g of a solid. The solid was suspended in 250 mL of acetone and treated with aqueous 5% NaHCO3 until neutral. After standing in the freezer for several hours, the mixture was filtered and the filtrate was evaporated to an oil and freeze-dried to give the product (650 mg, 43%) as a brown solid. 1 H NMR (D2O / CD3CN): δ 10.0 (s, 1H), 9.6 (s, 1H), 9.4 (dd, 1H), 8.7 (s, 1H), 8.5 (d, 2H), 8.2 (d, 2H), 6.5 (d, 1H), 4.75 (m, 4H), 4.3 (m, 1H), 4.2 (m, 1H), 3.4 (m, 2H), 2.9 (s, 6H). MS(ESI+) m / z= 446.2

[0213] [Example 28] Compound 28 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)-1λ 4-Pyridine-3-carboxamide.

[0214] [Chem.] Follow general procedure A: TMS-triflate (1.2 eq) was added to a stirred mixture of N-(4-(N,N-dimethylsulfamoyl)phenyl)nicotinamide (0.55 g, 1.8 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) in CH3CN (20 mL). After stirring for 2 h at ambient temperature, the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. SOCl2 (3.5 eq) was added dropwise and the solution was left standing at -5 °C in a freezer for 72 h. The solution was brought to room temperature and the product was precipitated with MTBE. The solvent was decanted from the product, the solid was dissolved in 5 mL of MeOH and stirred for 1 h at ambient temperature. A fine white precipitate formed, which was filtered through a sintered glass funnel and washed with ice-cold MeOH (5 mL) and then with MTBE. The pure product (220 mg, 28%) was obtained as an off-white solid. 1 1H NMR (D2O): δ 9.68 (br s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.83 (m, 4H), 6.25, (d, 1H), 4.43 - 4.57 (m, 2H), 4.36 (t, 1H), 3.95 (ab q, 2H), 2.65 (s, 6H). MS(ESI+) m / z = 438.1

[0215] [Example 29] Compound 29 Methyl 2-(4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)phenyl)acetate.

[0216] [Chem.] Follow general procedure B: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 2-(4-(nicotinamide)phenyl)acetate (0.50 g, 1.85 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in DCM (20 mL). After stirring for 30 min, only about 20% conversion was shown by HPLC analysis of an aliquot, so additional TMS-triflate (1.2 equiv) was added. The reaction mixture was stirred at ambient temperature for 1.5 h, the solvent was evaporated, and the residue was taken up in anhydrous MeOH (20 mL). SOCl2 (3.5 equiv) was added dropwise to the solution at 0 °C, and the reaction mixture was stirred at 5 °C for 16 h. HPLC analysis at that point showed the presence of about 25% of the mono- and diacetate intermediates, so additional SOCl2 (1 equiv) was added and stirring was continued for a further 5 h. After workup as described above and purification by ISCO in the usual manner, the product (340 mg, 46%) was obtained. 1 1H NMR (D2O): δ 9.65 (s, 1H), 9.26 (d, 1H), 9.04 (d, 1H), 8.27 (t, 1H), 7.45 (d, 2H), 7.35 (d, 2H), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.35 (t, 1H), 3.94 (ab q, 2H), 3.74 (s, 2H), 3.68 (s, 3H). MS(ESI+) m / z = 403.2

[0217] [Example 30] Compound 30 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(oxazol-5-yl)phenyl)-1λ 4 -pyridine-3-carboxamide.

[0218]

Chemical Structure

[0219] [Example 31] Compound 31 Methyl 6-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ 4 -pyridine-3-carboxamido)nicotinate.

[0220] [Chemical Structure] Follow general procedure A: TMS-triflate (1.2 equiv) was added to a stirred mixture of methyl 6-(nicotinamido)nicotinate (0.50 g, 1.95 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in anhydrous CH3CN (20 mL). After stirring for 2 h at ambient temperature, the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. The mixture was treated with SOCl2 (3.5 equiv) and stirred at 5 °C for 16 h. Since HPLC at that point still showed a mixture of about 10% mono- and di-acetate intermediates, additional SOCl2 (1 equiv) was added and stirring was continued for 5 h. The product was precipitated by the addition of MTBE to give a white solid, which was triturated several times with MTBE. The crude product was redissolved in 10 mL of anhydrous MeOH and precipitated with MTBE as described above. The product was filtered and washed with 2 x 5 mL portions of ice-cold MeOH followed by a large volume of MTBE. After drying under high vacuum for several hours, the product was obtained as a white solid (100 mg, 13%). 1 1H NMR (D2O): δ 9.72 (s, 1H), 9.28 (d, 1H), 9.08 (d, 1H), 8.93 (apparent d, 1H), 8.44 (dd, 1H), 8.32 (t, 1H), 8.10 (apparent d, 4H), 6.25 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.34 (t, 1H), 3.95 (ab q, 2H), 3.92 (s, 3H). MS(ESI+) m / z = 390.1

[0221] [Example 32] Compound 32

[0222] [Chemical Structure] Follow general procedure B: Add TMS-triflate (1.2 equiv) to a stirred mixture of the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (15 mL). Stir at ambient temperature for 2 h, remove the solvent and treat with SOCl2 (3.5 equiv) in MeOH, then stir the solution at 5 °C for 16 h. If 10% residual mono-acetate is indicated by HPLC, add additional SOCl2 (0.1 mL) and continue stirring for 6 h. Triturate with MTBE and obtain the crude product as a solid. Purify by ISCO (12 g cartridge, elution with a gradient from 5% MeOH in DCM to 30% MeOH in DCM) to obtain the product as a solid.

[0223] [Example 33] Compound 33

[0224] [Chemical formula] Follow general procedure B: Add TMS-triflate (1.2 equiv) to a stirred mixture of the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (15 mL). Stir at ambient temperature for 2 h, remove the solvent and treat with SOCl2 (3.5 equiv) in MeOH, then stir the solution at 5 °C for 16 h. If 10% residual mono-acetate is indicated by HPLC, add additional SOCl2 (0.1 mL) and continue stirring for 6 h. Triturate with MTBE and obtain the crude product as a solid. Purify by ISCO (12 g cartridge, elution with a gradient from 5% MeOH in DCM to 30% MeOH in DCM) to obtain the product as a solid.

[0225] [Example 34] Compound 34

[0226] [Chemical formula] Follow general procedure B: Add TMS-triflate (1.2 equiv) to a stirred mixture of the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (15 mL). Stir at ambient temperature for 2 h, remove the solvent and treat with SOCl2 (3.5 equiv) in MeOH, then stir the solution at 5 °C for 16 h. If HPLC shows a 10% residual mono-acetate, add additional SOCl2 (0.1 mL) and continue stirring for 6 h. After trituration with MTBE, obtain the crude product as a solid. Purify by ISCO (12 g cartridge, elution with a gradient from 5% MeOH in DCM to 30% MeOH in DCM) to obtain the product as a solid.

[0227] [Example 35] Compound 35

[0228] [Chemical formula] Follow general procedure B: Add TMS-triflate (1.2 equiv) to a stirred mixture of the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 equiv) in CH3CN (15 mL). Stir at ambient temperature for 2 h, remove the solvent and treat with SOCl2 (3.5 equiv) in MeOH, then stir the solution at 5 °C for 16 h. If HPLC shows a 10% residual mono-acetate, add additional SOCl2 (0.1 mL) and continue stirring for 6 h. After trituration with MTBE, obtain the crude product as a solid. Purify by ISCO (12 g cartridge, elution with a gradient from 5% MeOH in DCM to 30% MeOH in DCM) to obtain the product as a solid.

[0229] [Example 36] Compound 36

[0230] [Chemical formula] Place 4.1 mmol of Compound 17 in a dry 100 mL flask. Flash the flask with argon and add 10 mL of trimethyl phosphate. Cool the resulting solution to 0 °C and treat it with POCl3 (8.2 mmol, 2 equivalents). Seal the flask and let it stand at -10 °C in a freezer. After 2.5 hours, treat the homogeneous solution with triethylamine (2.0 mmol) over several minutes and let it stand overnight in the freezer. Cool the reaction mixture in an ice bath and treat the well-stirred suspension with water (82 mmol) over several minutes, followed by solid NaHCO3 (28.7 mmol), and continue stirring at 0 °C for 90 minutes. Treat the reaction mixture with 100 mL of CH3CN containing 33 mmol of 90% formic acid to produce a solid. Collect the solid by filtration, wash it with CH3CN, and place it under high vacuum to obtain the crude product. Purify this material by medium-pressure chromatography on a column containing 50 g of aminopropyl-functionalized silica. Dissolve the product in 25 mL of 60% / 40% MeOH-CH3CN containing 100 mM formic acid and equilibrate the column with the same solvent mixture. Combine and concentrate the product-containing fractions, co-evaporate them from water (3 × 25 mL), and freeze and lyophilize to obtain the product.

[0231] [Example 37] Compound 37

[0232] [Chemical Formula] Place 4.1 mmol of compound 13 in a dry 100 mL flask. Flush the flask with argon and add 10 mL of trimethyl phosphate. Cool the resulting solution to 0 °C and treat it with POCl3 (8.2 mmol, 2 equivalents). Seal the flask and let it stand at -10 °C in a freezer. After 2.5 h, treat the homogeneous solution with triethylamine (2.0 mmol) for several minutes and let it stand overnight in the freezer. Cool the reaction mixture in an ice bath and treat the well-stirred suspension with water (82 mmol) for several minutes, followed by solid NaHCO3 (28.7 mmol), and continue stirring at 0 °C for 90 min. Treat the reaction mixture with 100 mL of CH3CN containing 33 mmol of 90% formic acid to form a solid. Collect the solid by filtration, wash it with CH3CN, and place it under high vacuum to obtain the crude product. Purify this material by medium-pressure chromatography on a column containing 50 g of aminopropyl-functionalized silica. Dissolve the product in 25 mL of 60% / 40% MeOH-CH3CN containing 100 mM formic acid and equilibrate the column with the same solvent mixture. Combine and concentrate the product-containing fractions, co-evaporate from water (3 × 25 mL), and freeze and lyophilize to obtain the product.

[0233] Biological assay [Example B1] General assay - In a 96-well clear-bottom black plate, 2 × 10 3 of Hek293 (human fetal kidney) and HepG2 (human hepatocellular carcinoma) cells seeded per well were allowed to adhere O / N. The next day, the cells were treated with 2 mM of NMN or 500 μM of other compounds, and after 24 h of treatment, the cells were analyzed by CellTiter-Fluor and NAD assay.

[0234] Figures 1A and 1B show NAD(H) in cells after treatment with a control or a compound according to formula 1. Figure 1A is from Hek293 cells (human fetal kidney cells), while Figure 1B is from HepG2 cells (human hepatocellular carcinoma cells). In both Figures 1A and 1B, the Y-axis is the amount of NAD(H) / number of viable cells normalized to 1.0 for no treatment, and the X-axis is as follows: 1: (Control) - No treatment 2: (Control) - Treatment with nicotinamide mononucleotide (NMN) 3: (Control) - Treatment with PABA-methyl 4: Treatment with Compound 1 5: (Control) - Treatment with Compound A 6: Treatment with Compound 9 7: Treatment with Compound 7 8: Treatment with Compound 8 9: Treatment with Compound 6 10: Treatment with Compound 2 11: Treatment with Compound 4 12: Treatment with Compound 3 13: Treatment with Compound 5

[0235] [Example B2] Figures 2A, 2B, and 2C show NAD(H) in normal cells after treatment with a control or Compound 1 of formula 2a. Figure 2A is from AML12 (2K / well) cells (mouse normal liver cells), Figure 2B is from Hek293 cells (human fetal kidney cells), and Figure 2C is from primary hPBMC cells (human peripheral blood mononuclear cells). In Figures 2A and 2B, the Y-axis is the amount of NAD(H) / number of viable cells normalized to 1.0 relative to no treatment. In Figure 2C, the Y-axis shows the micrograms of NAD(H) / total protein normalized to 1.0 relative to no treatment.

[0236] In Figure 2A, the X-axis is as follows: 1: (Control) - No treatment 2: (Control) - Treatment with nicotinamide mononucleotide (NMN), 2 mM 3: (Control) - Treatment with nicotinamide mononucleotide (NMN), 0.5 mM 4: (Control) - Treatment with ethanol 5: Treatment with Compound 1, 0.5 mM 6: Treatment with Compound 1, 0.25 mM

[0237] In Figure 2B, the X-axis is as follows: 1: (Control) - No treatment 2: (Control) - Treatment with nicotinamide mononucleotide (NMN), 800 μM 3: (Control) - No treatment (Preparation 1) 4: Treatment with Compound 1, 800 μM (Preparation 1) 5: (Control) - No treatment (Preparation 2) 6: Treatment with Compound 1, 800 μM (Preparation 2)

[0238] In Figure 2C, the X-axis is as follows: 1: (Control) - No treatment 2: (Control) - Treatment with nicotinamide mononucleotide (NMN), 1 mM 3: Treatment with Compound 1, 1 mM

[0239] [Example B3] Figures 3A, 3B, 3C, and 3D show NAD(H) in cancer cells after treatment with a control or Compound 1 of Formula 1. Figure 3A is from B16-F10 cells (mouse melanoma), Figure 3B is from RAW264.7 cells (mouse tumor-derived macrophages), Figure 3C is from Jurkat cells (human acute T cell leukemia), and Figure 3D is from HepG2 cells (human hepatocellular carcinoma). In Figures 3B and 3D, the Y-axis is the amount of NAD(H) / number of viable cells normalized to 1.0 relative to no treatment. In Figures 3A and 3C, the Y-axis is the pg of NAD(H) / μg of total protein normalized to 1.0 relative to no treatment.

[0240] In Figure 3A, the X-axis is as follows: 1: (Control) No treatment 2: (Control) NMN 1 mM 3: (Control) NMN 250 μM 4: Compound 1, 250 μM 5: Compound 1, 500 μM 6: (Control) PABA, 250 μM 7: (Control) PABA, 500 μM 8: (Control) Methyl PABA, 250 μM 9: (Control) Methyl PABA, 500 μM

[0241] In Figure 3B, the X-axis is as follows: 1: (Control) No treatment 2: (Control) NMN, 2 mM 3: (Control) NMN, 500 μM 4: Compound 1, 500 μM 5: Compound 1, 250 μM

[0242] In Figure 3C, the X-axis is as follows: 1: (Control) No treatment 2: (Control) NMN, 2 mM 3: (Control) NMN, 1 mM 4: (Control) NMN, 500 μM 5: (Control) NMN, 250 μM 6: Compound 1, 500 μM 7: Compound 1, 250 μM

[0243] In Figure 3D, the X-axis is as follows: 1: (Control) No treatment 2: (Control) NMN 800 μM 3: (Control) No treatment (Preparation 1) 4: Compound 1, 800 μM (Preparation 1) 5: (Control) No treatment (Preparation 2) 6: Compound 1, 800 μM (Preparation 2)

[0244] [Example B4] Figures 4A and 4B show the NAD(H) levels and viability in normal cells (Hek293 cells / human fetal kidney cells) after treatment with a control or Compound 1 according to Formula 1, as an indicator of cytotoxicity / cell growth inhibition. In Figure 4A, the Y-axis shows the amount of NAD(H) / number of viable cells, normalized to 1.0 relative to no treatment, and the X-axis reflects the number of days of treatment. In Figure 4B, the Y-axis shows the number of cells as an indicator of viability, normalized to 1.0 relative to no treatment, and the X-axis reflects the number of days.

[0245] [Example B5] Figures 5A and 5B show the NAD(H) levels and viability in cancer cells (HepG2 cells / human hepatocellular carcinoma) after treatment with a control or Compound 1 according to Formula 1, as an indicator of cytotoxicity / cell growth inhibition. In Figure 5A, the Y-axis shows the amount of NAD(H) / number of viable cells, normalized to 1.0 relative to no treatment, and the X-axis reflects the number of days of treatment. In Figure 5B, the Y-axis shows the number of cells as an indicator of viability, normalized to 1.0 relative to no treatment, and the X-axis reflects the number of days.

[0246] In Figures 4A, 4B, 5A, and 5B, the following legends apply: i. (Control) Untreated ii. (Control) Nicotinamide mononucleotide (NMN) iii. Compound 1 iv. Compound 1 + NMN v. (Control) FK866 vi. (Control) FK866 + NMN

[0247] [Example B6] General assay for Figures 6A and 6B: 2×103 Hek293 (human fetal kidney) and HepG2 (human hepatocellular carcinoma) cells seeded per well were allowed to adhere overnight in a 96-well clear-bottom black plate. The next day, the cells were treated with 2 mM of NMN or 250 μM of other compounds, and after 24 hours of treatment, the cells were analyzed by CellTiter-Fluor and NAD assays.

[0248] Figure 6A shows NAD(H) levels in normal cells (Hek293 cells / human fetal kidney cells) after treatment with control or various compounds. In Figure 6A, the Y-axis shows the amount of NAD(H) / number of viable cells, normalized to 1.0 relative to no treatment.

[0249] Figure 6B shows NAD(H) levels in cancer cells (HepG2 cells / human hepatocellular carcinoma) after treatment with control or various compounds. In Figure 6B, the Y-axis shows the amount of NAD(H) / number of viable cells, normalized to 1.0 relative to no treatment.

[0250] In both Figure 6A and Figure 6B, the X-axis is as follows: 1: (control) - no treatment 2: (control) - treatment with nicotinamide mononucleotide (NMN) 3: (control) - treatment with PABA-nicotinamide (PABA nicotinate methyl ester) 4: (control) - treatment with DMSO vehicle 5: treatment with Compound 1 6: treatment with Compound 12 7: treatment with Compound 13 8: treatment with Compound 14 9: treatment with Compound 15 10: treatment with Compound 16 11: treatment with Compound 17 12: treatment with Compound 18 13: treatment with Compound 19 14: treatment with Compound 20 15: treatment with Compound 21 16: treatment with Compound 22 17: treatment with Compound 23 18: treatment with Compound 24 (Supplementary Note) (Appendix 1) Formula 1:

Chemical Structure

Chemical formula

Chemical formula

Chemical Structure

Chemical Structure

Chemical formula

Claims

1. Formula 1: 【Chemical 1】 A compound having a structure represented by and / or one or more salts thereof, wherein Ring A is an aromatic carbocyclic ring; X is H or a phosphate group; R 1 is H, C 1 ~C 6 alkyl group, and when combined with R 2 is selected from substituted or unsubstituted heterocycles which may be aromatic or non-aromatic; Each R 2 is independently selected from H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, and when combined with R 1 is selected from substituted or unsubstituted heterocycles which may be aromatic or non-aromatic; Each R 3 is independently H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, substituted or unsubstituted carboxamide, and when combined with R 4 optionally substituted or unsubstituted carbocyclic ring which may be aromatic or non-aromatic, and when combined with R 4 optionally substituted or unsubstituted heterocyclic ring which may be aromatic or non-aromatic; R 4 is H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, substituted or unsubstituted carboxamide, cyano group, substituted or unsubstituted sulfamoyl group, substituted or unsubstituted carbocyclic or heterocyclic ring which may be aromatic or non-aromatic, R 3 when combined with, a substituted or unsubstituted carbocyclic ring which may be aromatic or non-aromatic, and R 3 when combined with, a substituted or unsubstituted heterocyclic ring which may be aromatic or non-aromatic, selected from The compound.

2. Formula 2: [Chemical 2] A compound having a structure represented by and / or one or more salts thereof, wherein R 1 is H or C 1 ~C 6 is an alkyl group; Each R 2 is independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl group, substituted or unsubstituted C 1 -C 6 alkenyl group, substituted or unsubstituted C 1 -C 6 alkynyl group, and substituted or unsubstituted C 1 -C 6 alkoxy group; R 4 is H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, substituted or unsubstituted carboxamide, R 3 which, when combined with, may be substituted or unsubstituted carbocyclic ring, aromatic or non-aromatic, and R 3 which, when combined with, is selected from substituted or unsubstituted heterocyclic ring, aromatic or non-aromatic The compound according to Claim 1.

3. Formula 2a: 【Chemical Formula 3】 Having a structure represented by and / or one or more salts thereof, wherein R 3 independently, H, R 4 when combined with, a substituted or unsubstituted carbocyclic ring which may be aromatic or non-aromatic, and R 4 when combined with, is selected from a substituted or unsubstituted heterocyclic ring which may be aromatic or non-aromatic; R 3 and R 4 at least one of which is not H The compound according to Claim 2.

4. R 3 is H; R 4 is selected from carboxylic acids, substituted or unsubstituted C 1 -C 6 carboxyesters, and substituted or unsubstituted carboxamides, the compound according to claim 2 or 3.

5. The compound according to any one of Claims 2 to 4, selected from Compounds 1 to 5, 11, 12, 14, 15, 18, 19, 21, 23, 24, 26, 27, 29, 32, and 35: [Chemical Formula 4] 【Chem.】 。

6. Formula 2b: 【Chemical Formula 5】 Having a structure represented by and / or one or more salts thereof, wherein R 1 is H or C 1 -C 6 is an alkyl group; R 2 is selected from H and substituted or unsubstituted C 1 to C 6 alkoxy groups; R 3 is H; Furthermore, R 1 and R 2 is not H for at least one of them The compound according to Claim 2.

7. Compounds 6 and 7: 【Chemical Formula 6】 The compound according to Claim 6, selected from

8. Formula 2c: 【Chemical Formula 7】 Having a structure represented by and / or one or more salts thereof, wherein R 2 is selected from H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, and substituted or unsubstituted C 1 to C 6 alkynyl group; R 3 is selected from H, halogen, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, and substituted or unsubstituted carboxamide; R 4 is selected from H, substituted or unsubstituted C 1 to C 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 alkoxy group, carboxylic acid, substituted or unsubstituted C 1 to C 6 carboxyester, and substituted or unsubstituted carboxamide; Furthermore, R 2 and R 3 is not H for at least one of them The compound according to Claim 2.

9. Compounds 8, 9, 16, and 20: 【Chemical 8】 The compound according to Claim 8, selected from

10. Compounds 10, 13, 17, 22, 28, 30, 33, 34, 36, and 37: 【Chemical Formula 9】 【Chem.】 The compound according to Claim 1, selected from

11. wherein the salt is formed with a cation selected from H + Li + Na + K + Mg 2+ and Ca 2+ and / or wherein the salt is formed with an anion selected from acetate ion, trifluoromethanesulfonic acid (triflate) ion, halide ion, trifluoroacetate ion, formate ion, H 2 PO 4 - HPO 4 2- OH - HSO 4 - SO 4 2- NO 3 - HCO 3 - and CO 3 2- or wherein the salt is an zwitterion, the compound according to any one of claims 1 to 10.

12. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 11 and a pharmaceutically acceptable excipient or carrier.

13. Use in the manufacture of a medicament for differentially modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissue or cell types of the compound according to any one of Claims 1 to 11 or the pharmaceutical composition according to Claim 12, wherein the medicament induces a differential response of NAD levels in a first tissue or cell type and a second tissue or cell type.

14. The use according to Claim 13, wherein the differential response of NAD levels is selected from at least a 10% difference in NAD levels, at least a 20% difference in NAD levels, at least a 30% difference in NAD levels, at least a 40% difference in NAD levels, and at least a 50% difference in NAD levels.

15. The use according to claim 13, wherein the differential response of the NAD level is at least a 10% increase in the NAD level in the first tissue or cell type compared to the untreated NAD level and at least a 10% simultaneous decrease in the NAD level in the second tissue or cell type compared to the untreated NAD level.

16. The use according to claim 13, wherein the differential response of the NAD level is maintenance within 10% of the NAD level in the first tissue or cell type compared to the untreated NAD level and at least a 10% simultaneous decrease in the NAD level in the second tissue or cell type compared to the untreated NAD level.

17. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of cancer in an individual in need of treatment for cancer.

18. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for treating or suppressing cancer in an individual in need of treatment or suppression of cancer.

19. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for increasing or maintaining healthy tissue or cells in an individual in need of increasing or maintaining healthy tissue or cells while suppressing the growth of neoplastic or cancerous tissue or cells.

20. A method for synthesizing a compound according to any one of claims 1 to 11, the method comprising reacting an amine-containing precursor with a nicotinic acid riboside precursor under conditions that condense the precursors.

21. A pharmaceutical composition according to claim 12 for use in treating a disease or disorder associated with modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissue or cell types, the pharmaceutical composition inducing a differential response of NAD levels in a first tissue or cell type and a second tissue or cell type.

22. The pharmaceutical composition according to claim 21, wherein the differential response of the NAD level is selected from at least a 10% difference in NAD level, at least a 20% difference in NAD level, at least a 30% difference in NAD level, at least a 40% difference in NAD level, and at least a 50% difference in NAD level.

23. The pharmaceutical composition according to claim 21, wherein the differential response of NAD levels is at least a 10% increase in the NAD level in the first tissue or cell type compared to the untreated NAD level and at least a 10% simultaneous decrease in the NAD level in the second tissue or cell type compared to the untreated NAD level.

24. The pharmaceutical composition according to claim 21, wherein the differential response of NAD levels is maintenance within 10% of the NAD level in the first tissue or cell type compared to the untreated NAD level and at least a 10% simultaneous decrease in the NAD level in the second tissue or cell type compared to the untreated NAD level.

25. The pharmaceutical composition according to claim 21, for use in treating cancer in an individual in need of treatment for cancer.

26. The pharmaceutical composition according to claim 21, for treating or suppressing cancer in an individual in need of treating or suppressing cancer.

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