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WO2014124430A1 - Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées - Google Patents

Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées Download PDF

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Publication number
WO2014124430A1
WO2014124430A1 PCT/US2014/015763 US2014015763W WO2014124430A1 WO 2014124430 A1 WO2014124430 A1 WO 2014124430A1 US 2014015763 W US2014015763 W US 2014015763W WO 2014124430 A1 WO2014124430 A1 WO 2014124430A1
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alkyl
amino
methyl
halogen
hydroxy
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PCT/US2014/015763
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English (en)
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Dennis C. Liotta
George R. Painter
Gregory R. BLUEMLING
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Emory University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • nucleotide and nucleoside therapeutic compositions relate to nucleotide and nucleoside therapeutic compositions and uses related thereto.
  • the disclosure relates to halogenated nucleosides optionally conjugated to a phosphorus oxide or pharmaceutically acceptable salts thereof.
  • the disclosure relates to conjugate compounds or pharmaceutically acceptable salts thereof comprising an amino acid ester or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer.
  • Nucleoside and nucleotide phosphates and phosphonates are clinically useful as antiviral agents. Two examples are tenofovir disoproxil fumarate for the treatment of human
  • immunodeficiency virusand adefovir dipivoxil for the treatment of hepatitis B virus infections.
  • HAART Antiretroviral Therapy
  • privileged compartments Permeability into privileged compartments may be partially responsible for the current inability of chemotherapy to totally clear a patient of HIV infection and the emergence of resistance.
  • Nucleoside analogues enter a cell via two types of broad-specificity transporters, concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). Once inside, they utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinases (dNKs), deoxynucleoside monophosphate kinases (dNMPKs) and nucleoside diphosphate kinase
  • dNKs deoxynucleoside kinases
  • dNMPKs deoxynucleoside monophosphate kinases
  • NDPK nucleoside analogue
  • Sphingolipids play roles in cell-cell and cell-substratum interactions, and help regulate growth and differentiation by a variety of mechanisms, such as inhibition of growth factor receptor kinases and effects on numerous cellular signal transduction systems.
  • U.S. patent 6,610,835 discloses sphingosine analogues. It also discloses methods of treating infections and cancer. Pruett et al, J. Lipid Res. 2008, 49(8), 1621-1639, report on sphingosine and
  • nucleotide and nucleoside therapeutic compositions relate to nucleotide and nucleoside therapeutic compositions and uses related thereto.
  • the disclosure relates to halogenated nucleosides optionally conjugated to a phosphorus oxide or salts thereof.
  • the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer.
  • the disclosure relates to phosphorus oxide prodrugs of 2'- fluoronucleosides for the treatment of positive-sense and negative-sense RNA viral infections through targeting of the virally encoded RNA-dependent RNA polymerase (RdRp).
  • This disclosure also provides the general use of sphingolipids to deliver nucleoside analogs for the treatment of infectious disease and cancer.
  • the disclosure relates to conjugate compounds or salt thereof comprising a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • the phosphorus oxide is a phosphate, phosphonate, polyphosphate, or polyphosphonate, wherein the phosphate, phosphonate or a phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate orphosphoroamidate.
  • the sphingolipid is covalently bonded to the phosphorus oxide through an amino group or a hydroxy 1 group.
  • the nucleotide or nucleoside is a heterocycle comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein the substituted heterocyclyl is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl.
  • the nucleotide or nucleoside comprises pyrimidine-2,4- dione, 4-aminopyrimidin-2-one, purin-6-amine, 2-amino-purin-6-one, 5-methylpyrimidine-2,4- dione, 3-methylpyrimidine-2,4-dione, 4-amino-5-methylpyrimidin-2-one, 4- (methylamino)pyrimidin-2-one, 4-(dimethylamino)pyrimidin-2-one, 2-methyl-purin-6-amine, N- methyl-purin-6-amine, N,N-dimethyl-purin-6-amine, pyrrolo[2,3-d]pyrimidin-4-amine; N- cyclopropyl-pyrrolo[2,3-d]pyrimidin-4-amine, purin-2-amine, purine-2,6-diamine, purin-6-one, N 6 -cyclopropyl-purine-2,6-diamine, 2-fluoro-purin-6-amine, 5-
  • the sphingolipid is saturated or unsaturated 2-aminoalkyl or 2- aminooctadecane optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3-ol optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3,5-diol optionally substituted with one or more substituents. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising any of the compounds disclosed herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer comprising a saccharide.
  • the composition may contain a second active agent such as a pain reliever, anti-inflammatory agent, non-steroidal antiinflammatory agent, anti-viral agent, anti-biotic, or anti-cancer agent.
  • the disclosure relates to methods of treating or preventing an infection comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.
  • the subject is diagnosed with or at risk of an infection from a virus, bacteria, fungi, protozoa, or parasite.
  • the disclosure relates the methods of treating a viral infection comprising administering an effective amount of a pharmaceutical composition disclosed herein to a subject in need thereof.
  • the subject is a mammal, for example a human.
  • the subject is diagnosed with a chronic viral infection.
  • administration is under conditions such that the viral infection is no longer detected.
  • the subject is diagnosed with a RNA virus, DNA virus, or retroviruses.
  • the subject is diagnosed with a virus that is a double stranded DNA virus, sense single stranded DNA virus, double stranded RNA virus, sense single stranded RNA virus, antisense single stranded RNA virus, sense single stranded RNA retrovirus or a double stranded DNA retrovirus.
  • influenza A virus including subtype H1N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus
  • the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis.
  • compositions disclosed herein are administered in combination with a second antiviral agent such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir,
  • a second antiviral agent such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir,
  • tromantadine truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof.
  • the disclosure relates to methods of treating a cancer comprising administering an effective amount of a pharmaceutical composition disclosed herein to subject in need thereof.
  • the cancer is selected from bladder cancer, lung cancer, breast cancer, melanoma, colon and rectal cancer, non-hodgkin lymphoma, endometrial cancer, pancreatic cancer, kidney cancer, prostate cancer, leukemia, thyroid cancer, and brain cancer.
  • compositions are administered in combination with a second anti-cancer agent such as temozolamide, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, docetaxel, cis-platin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin, vinblastine, vindesine, vinorelbine, taxol, taxotere, etoposide, teniposide, amsacrine, topotecan,
  • a second anti-cancer agent such as temozolamide, bevacizumab, procarbazine, lomustine, vincris
  • camptothecin camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide, and/or lenalidomide or combinations thereof.
  • the disclosure relates to uses of compounds disclosed herein in the production or manufacture of a medicament for the treatment or prevention of an infectious disease, viral infection, or cancer.
  • the disclosure relates to derivatives of compounds disclosed herein or any of the formula.
  • the base may be a naturally occurring base, a modified, for example a methylated base, or any active derivatives thereof, such as those found in currently approved nucleoside bases found in antiviral or anticancer agents.
  • R may be HOH 2 C- as well as their mono-, di-, and triphosphates.
  • Ri is hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or C2 units (acetylenyl, ethyl, vinyl, cyano, etc.).
  • FIG. 2 illustrates bases for embodiments provided in Figure 1 or any of the
  • Figure 3 illustrates the unraveling of McGuigan prodrugs in vivo.
  • the metabolic unraveling of these prodrugs begins with an esterase-catalyzed cleavage of the carboxylic ester, followed by several chemical rearrangement steps resulting in an amino acid phosphoramidate.
  • the final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified to be the histidine triad nucleotide binding protein 1 (hF Tl)
  • Figure 4 illustrates embodiments of cyclobutyl nucleosides.
  • the base may be any base or derivative thereof disclosed herein.
  • R may be hydrogen, fluoro, hydroxy or azide, and n may be 1 or 2.
  • Figure 5 illustrates a scheme for the synthesis of cyclobutyl nucleosides, a) Zn-Cu couple, Et 2 0, reflux; b) NH 4 C1, EtOH; c) i: LDA, THF, -78°C ii: electrophile; d) nucleophile, ammonium salt; e) L-Selectride, THF; f) i: PPI1 3 , 4-nitrobenzoic acid, DIAD, THF ii: K 2 CO 3 , MeOH; g) brosyl chloride, Et 3 N, DCM; h) DBU, purine or pyrimidine, DMSO; i) pTSA, EtOH, R may be hydrogen, fluoro, hydroxy or azide, and n may be 1 or 2.
  • Figure 6 illustrates embodiments of mono- and diphosphate structural types.
  • Figure 7 illustrates schemes for the synthesis of conjugates.
  • Figure 8 illustrates the preparation of embodiments of the disclosure.
  • FIG. 9 illustrates certain embodiments of the disclosure.
  • Figure 10 is the X-ray crystal structure for compound 32 of Example 6. DETAILED DESCRIPTION OF THE INVENTION
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • the joined molecules may bond to oxygen or directly to the phosphorus atoms.
  • the term is intended to include, but are not limited to phosphates, in which the phosphorus is typically bonded to four oxygens and phosphonates, in which the phosphorus is typically bonded to one carbon and three oxygens.
  • a "polyphosphate” generally refers to phosphates linked together by at least one phosphorus-oxygen-phosphorus (P-O-P) bond.
  • a "polyphosphonate” refers to a polyphosphate that contains at least one phosphorus-carbon (C-P-O-P) bond.
  • P-N phosphorus-amine
  • the oxygen atom may form a double or single bond to the phosphorus or combinations, and the oxygen may further bond with other atoms such as carbon or may exist as an anion which is counter balanced with a cation, e.g., metal or quaternary amine.
  • alkyl means a noncyclic, linear or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 22 carbon atoms. Unsaturated alkyl groups contain from 2 to 22 carbon atoms.
  • the term “lower alkyl” or “Ci_ 4 alkyl” refers to an alkyl group that contains from 1 to 4 carbon atoms.
  • the term “higher alkyl” refers to an alkyl group that contains from 8 to 22 carbon atoms.
  • saturated, linear alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated, branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1- butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl- 1-butynyl, and the like.
  • Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or
  • Carbocyclyl groups that contain 3 to 30 carbon atoms
  • Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.
  • Heterocarbocycles or heterocarbocyclyl groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
  • Aryl means an aromatic carbocyclic monocyclic or polycyclic ring that contains 6 to 32 carbon atoms, such as phenyl or naphthyl.
  • Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
  • heteroaryl refers an aromatic heterocarbocycle having 1 to 4
  • heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems.
  • Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
  • heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl” includes N-alkylated derivatives such as a 1- methylimidazol-5-yl substituent.
  • heterocycle or “heterocyclyl” refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom.
  • the mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings.
  • Heterocycle includes heterocarbocycles, heteroaryls, and the like.
  • Alkylthio refers to an alkyl group as defined above attached through a sulfur bridge.
  • An example of an alkylthio is methylthio, (i.e., -S-CH 3 ).
  • Alkoxy refers to an alkyl group as defined above attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, and t-butoxy.
  • Alkylamino refers an alkyl group as defined above attached through an amino bridge.
  • An example of an alkylamino is methylamino, (i.e., -NH-CH 3 ).
  • Alkylsulfonyl refers to an alkyl as defined above attached through a sulfonyl bridge
  • Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
  • Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
  • salts refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof, including pharmaceutically acceptable salts thereof.
  • salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids.
  • Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric,
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
  • Subject refers any animal, preferably a human patient, livestock, rodent, monkey or domestic pet.
  • prodrug refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue.
  • the derivative may be structurally similar because it is lacking one or more atoms, substituted with one or more substituents, a salt, in different hydration/oxidation states, e.g., substituting a single or double bond, substituting a hydroxy group for a ketone, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom or replacing an amino group with a hydroxyl group or vice versa.
  • Replacing a carbon with nitrogen in an aromatic ring is a contemplated derivative.
  • the derivative may be a prodrug.
  • Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in the chemical literature or as in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.
  • the terms “prevent” and “preventing” include the full or partial inhibition of the recurrence, spread or onset of a referenced pathological condition or disease. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • the term "combination with” when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.
  • Nucleoside analogs utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinases (dNKs), deoxynucleoside monophosphate kinases (dNMPKs) and nucleoside diphosphate kinase (NDPK).
  • dNKs deoxynucleoside kinases
  • dNMPKs deoxynucleoside monophosphate kinases
  • NDPK nucleoside diphosphate kinase
  • Sphingoid bases have the potential for delivering nucleotide analog phosphates to critical tissues such as the brain.
  • the design concept driving the use of sphingoid bases to form nucleoside-lipid conjugates is based on observations that the sphingoid base analogs are: (a) well absorbed after oral administration, (b) resistant to oxidative catabolism in enterocytes, and (c) achieve high concentrations in the brain.
  • sphingoid base conjugates Based on data for intestinal uptake of traditional phospholipid drug conjugates in mice and our data for sphingoid base oral absorption in rats, our sphingoid base conjugates should be well absorbed and resist first pass metabolism. After absorption, sphingoid bases, including sphingosine-1 -phosphate, are transported in blood via both lipoproteins and free plasma proteins like albumin. Active epithelial cell uptake of sphingoid base phosphates has been demonstrated to occur via the ABC transporter, CFTR, but passive protein transport and endocytotic uptake are also possible; it is believed that extracellularly delivered drug conjugates would be processed similarly by target cells in the central nervous system (CNS) and the gut-associated lymphoid tissue (GALT).
  • CNS central nervous system
  • GALT gut-associated lymphoid tissue
  • rat sphingolipid PK studies mentioned above resulted in 24 hour tissue concentrations exceeding plasma Cmax concentrations by 10 to 300+ fold, with lung and brain levels being particularly high and without evidence of toxicity. This approach has significant potential for conjugate delivery of high drug concentrations to critical tissues.
  • the disclosure relates to halogenated nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof.
  • the disclosure relates to compounds of the following formula:
  • X is O or CH 2 or CD 2 ;
  • R 1 is a phosphonate, or polyphosphonate
  • the phosphonate is optionally a phosphorothioate or phosphoroamidate, and wherein the phosphonate, phosphorothiolate, or phosphoroamidate is optionally substituted with one or more, the same or different R 5 , and
  • phosphonate, phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring
  • phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring with the R 2 carbon;
  • R 2 is hydrogen, hydroxy, alkoxy, azide, or halogen;
  • R 3 is hydrogen, hydroxy, halogen, cyano, or Ci_ 22 alkyl optionally substituted with one or more, the same or different, R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • each R 5 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to compounds of the following formula:
  • X is O or CH 2 or CD 2 ;
  • R 1 is a phosphate or polyphosphate, wherein the phosphate or a phosphate in the polyphosphate is a phosphorothioate or phosphoroamidate, and
  • phosphate, phosphorothiolate, or phosphoroamidate is optionally substituted with one or more, the same or different R 5 , and
  • phosphate, phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring
  • phosphate, phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring with the R 2 carbon;
  • R 2 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 3 is hydrogen, hydroxy, halogen, cyano, or Ci_ 22 alkyl optionally substituted with one or more, the same or different, R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • each R 5 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to compounds of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is a hydroxy
  • R 2 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 3 is hydroxy, halogen, cyano, -CH 2 -R 5 , -CH(R 5 ) 2 , or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • each R 5 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 2 is hydrogen or hydroxy
  • R 3 is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • R 2 and R 3 are hydrogen.
  • the R 4 heterocyclyl is 7-deazapurine, 7-deaza-7-substituted purine, 5-azapyrimidine, tricyclic heterocycle, pyrazine, triazole, imidazole, or 5,6-dihydro-5- azapyrimidine, and heterocycles attached to the carbohydrate through a C-C bond.
  • X is methylene (CH 2 ) and R 1 is a phosphate, phosphonate, polyphosphate, or polyphosphonate substituent wherein the phosphate or a phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoroamidate, and the substituent is further substituted with hydrophobic group.
  • the hydrophobic group is a C 6 _ 22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
  • the hydrophobic group is a lipid optionally substituted with one or more, the same or different R 6 .
  • the lipid is a sphingolipid such as sphingosine, ceramide, or sphingomyelin, or 2-aminoalkyl optionally substituted with one or more substituents.
  • X is methylene (CH 2 ) and R 1 is a phosphate, phosphonate, polyphosphate, or polyphosphonate substituent wherein the phosphate or a phosphate in the polyphosphate or polyphosphonate is optionally a phosphoroborate, phosphorothioate, or phosphoroamidate, and the substituent is further substituted with a Lipid.
  • the Lipid is a C 6 -22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
  • the Lipid is a fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids.
  • the Lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids.
  • the Lipid is a fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that has one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur.
  • the Lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that has one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur.
  • the Lipid is a fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that is optionally substituted with one or more, the same or different R 6 .
  • the Lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that is optionally substituted with one or more, the same or different R 6 .
  • the Lipid is a fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that has one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is optionally substituted with one or more, the same or different R 6 .
  • the Lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derivied from essential and non-essential fatty acids that has one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is also optionally substituted with one or more, the same or different R 6 .
  • the Lipid is hexadecyloxypropyl.
  • the Lipid is 2-aminohexadecyloxypropyl.
  • the Lipid is 2-aminoarachidyl. In certain embodiments, the Lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.
  • the Lipid is a sphingolipid.
  • the sphingolipid is optionally substituted with one or more, the same or different R 6 .
  • the sphingolipid is sphingosine, ceramide, or sphingomyelin, or 2-aminoalkyl optionally substituted with one or more substituents.
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 10 is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogen or hydroxy or a structure of the following formula: CH 3 (CH 2 ) n CH 3 (CH 2 ) n '
  • n 8 to 14 or less than or equal to 8 to less than or equal to 14
  • o is 9 to 15 or less than or equal to 9 to less than or equal to 15
  • the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14
  • the total of m and o is 9 to 15 or less than or equal to 9 to less than or equal to 15;
  • n is 4 to 10 or less than or equal to 4 to less than or equal to 10
  • o is 5 to 11 or less than or equal to 5 to less than or equal to 11
  • the total of m and n is 4 to 10 or less than or equal to 4 to less than or equal to 10
  • the total of m and o is 5 to 11 or less than or equal to 5 to less than or equal to 11 ;
  • n 6 to 12 or n is less than or equal to 6 to less than or equal to 12, the total of m and n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12;
  • R 12 is hydrogen, a branched or strait chain Ci_i 2 alkyl, Ci 3 _ 22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more, the same or different R 13 ; and
  • R 13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the hydrophobic group is of the formula the formula: wherein,
  • R 10 is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogens or a structure of the following formula:
  • n 8 to 14 or less than or equal to 8 to less than or equal to 14, the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14;
  • R is hydrogen, a branched or strait chain Ci_i 2 alkyl, Ci 3 _ 22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more, the same or different R 13 ; and
  • R 13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • salts includes, for example, Li + , Na + , K + , Mg 2+ ,
  • trialkylammonium or other pharmaceutically acceptable salts.
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R is one of the formula:
  • Y is O or S;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C 2 - 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is O
  • R 1 is one of the formula:
  • Y is O or S
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is hydroxyl
  • R 3 is hydroxy, halogen, cyano, -CH 2 -R 5 , -CH(R 5 ) 2 , or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl,
  • each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl,
  • each R 6 is optionally substituted with one or more, the same or different, R 7 ;
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 3 is H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • aryl is phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, or 1-naphthyl, 2-naphthyl.
  • R 6 is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, l-propylbutyl,cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is one of the formula:
  • Y is O or S
  • Lipid is any of the formula described above or herein.
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethylsulfon
  • the disclosure relates to a compound of the following formula:
  • X is O
  • R 1 is one of the formula:
  • Lipid-P-C Lipid-P-O-P-C
  • Y is O or S
  • Lipid is any of the formula described above or herein;
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ; R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocycly
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is hydroxyl
  • R 3 is hydroxy, halogen, cyano, -CH 2 -R 5 , -CH(R 5 ) 2 , or C 2 _ 22 alkyl optionally substituted with one or more
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ; R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocycl
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the sphingolipid has the formula:
  • R 10 is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogen or hydroxy or a structure of the following formula:
  • n 8 to 14 or less than or equal to 8 to less than or equal to 14
  • o is 9 to 15 or less than or equal to 9 to less than or equal to 15
  • the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14
  • the total of m and o is 9 to 15 or less than or equal to 9 to less than or equal to 15;
  • n is 4 to 10 or less than or equal to 4 to less than or equal to 10
  • o is 5 to 11 or less than or equal to 5 to less than or equal to 11
  • the total of m and n is 4 to 10 or less than or equal to 4 to less than or equal to 10
  • the total of m and o is 5 to 11 or less than or equal to 5 to less than or equal to 11 ;
  • n 6 to 12 or n is less than or equal to 6 to less than or equal to 12, the total of m and n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12;
  • R 12 is hydrogen, a branched or strait chain Ci_i 2 alkyl, Ci3_ 22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more, the same or different R 13 ; and R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ ,
  • R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, l-ethylpropyl,l-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.
  • the sphingolipid has the formula:
  • R 10 is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogens or a structure of the following formula:
  • CH 3 (CH 2 ) n / CFaiCFzWCH ⁇ n is 8 to 14 or less than or equal to 8 to less than or equal to 14, the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14;
  • R 12 is hydrogen, a branched or strait chain Ci_i 2 alkyl, Ci 3 _ 22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more, the same or different R 13 ; and R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇
  • R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, l-ethylpropyl,l-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is one of the formula:
  • Y is O or S
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is O
  • R 1 is one of the formula:
  • Y is O or S
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is hydroxyl
  • R 3 is hydroxy, halogen, cyano, -CH 2 -R 5 , -CH(R 5 ) 2 , or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl,
  • each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl,
  • each R 6 is optionally substituted with one or more, the same or different, R 7 ;
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 3 is H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • aryl is phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 1-naphthyl, or 2-naphthyl.
  • R 6 is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, l-propylbutyl,cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • the sphingolipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to a compound of the following formula: HO F
  • X is CH 2 or CD 2 ;
  • R 1 is one of the formula:
  • Lipid— P-0 Lipid— P-C -
  • Y is O or S
  • Lipid is any of the formula described above or herein;
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 _ 22 alkyl optionally substituted with one or more the same or different R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a compound of the following formula:
  • X is O
  • R 1 is one of the formula:
  • Lipid-P-C - ⁇ Lipid-P-O-P-C - ⁇
  • Y is O or S
  • Lipid is any of the formula described above or herein;
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more the same or different R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamin
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • R 1 is hydroxy
  • R 3 is hydrogen, hydroxy, halogen, cyano, -CH 2 -R 5 , -CH(R 5 ) 2 , or C 2 _ 22 alkyl optionally substituted with one or more R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 or CD 2 ;
  • Y is O or S
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 _ 22 alkyl optionally substituted with more the same or different R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ;
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 40 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl,
  • each R 40 is optionally substituted with one or more, the same or different, R 41 ;
  • R 41 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 3 is hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • R 40 is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, l-propylbutyl,cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • lipid refers to any of the lipid compounds, derivatives or lipid formulas described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to a compound of the following formula:
  • X is CH2 or CD2
  • Y is O or S
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more the same or different R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ;
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 50 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R is optionally substituted with one or more, the same or different, R 51 ; and
  • R 51 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 3 is hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • R 50 is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl,
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to a compound of the following formula:
  • X is CH2 or CD2
  • Y is O or S
  • Lipid is any lipid described above or herein.
  • R 3 is hydrogen, hydroxy, halogen, cyano, or C 2 - 22 alkyl optionally substituted with one or more the same or different R 5 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 5 is optionally substituted with one or more, the same or different, R 6 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to compounds of the following formula:
  • X is O or CH 2 or CD 2 ;
  • R 1 is a phosphate, phosphonate, polyphosphate, polyphosphonate substituent wherein the phosphate or a phosphate in the polyphosphate or poly phosphonate is optionally a phosphorothioate or phosphoroamidate, and the substituent is further substituted with an amino acid ester or sphingolipid or derivative optionally substituted with one or more, the same or different, R 6 ;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 6 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to a compound of the following formula
  • X is CH 2 or CD 2 ;
  • Y 1 is O or S
  • Y 2 is O or S
  • Z is O or NH
  • R 2 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 3 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 20 is an alkyl of 6 to 22 carbons optionally substituted with one or more, the same or different R 26 ;
  • R 21 and R 22 are each the same or different at each occurrence hydrogen, alkyl, or alkanoyl, wherein R 21 and R 22 are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 24 and R 25 are each the same or different at each occurrence hydrogen, alkyl, or aryl, wherein R 24 and R 25 are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 26 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 26 is optionally substituted with one or more, the same or different, R 27 ;
  • R 27 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 27 is optionally substituted with one or more, the same or different, R 28 ; and
  • R 28 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 20 is an alkyl of between 8 and 16 carbons.
  • the disclosure relates to compounds of the following formula
  • the dotted line represents the presence of a single or double bond
  • X is CH 2 or CD 2 ;
  • Z is O or NH
  • Y 1 is O or S
  • Y 2 is O or S
  • R 2 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 3 is hydrogen, hydroxy, alkoxy, azide, or halogen
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 20 is an alkyl of 6 to 22 carbons optionally substituted with one or more, the same or different R 26 ;
  • R 21 , R 22 , and R 23 are each the same or different at each occurrence hydrogen, alkyl, or
  • alkanoyl wherein R , R , and R are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 24 and R 25 are each the same or different at each occurrence hydrogen, alkyl, or aryl, wherein R 243 ⁇ 4nd R 2"5 are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 26 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 26 is optionally substituted with one or more, the same or different, R 27 ;
  • R 27 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 27 is optionally substituted with one or more, the same or different, R 28 ; and R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino
  • the disclosure relates to the compound 2-amino-3- hydroxyoctadec-4-en-l-yldihydrogen (3-azido-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)tetrahydrofuran-2-yl)methyl diphosphate or pharmaceutically acceptable salts thereof.
  • the disclosure relates to a compound having the following formula:
  • X is O or NH
  • Y is O or S
  • Z is O or NH
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 33 and R 34 are each the same or different at each occurrence hydrogen, alkyl, or alkanoyl, wherein R 33 and R 34 are eachoptionally substituted with one or more, the same or different R 37 ;
  • R 35 is hydrogen, alkyl, or aryl wherein R 35 is optionally substituted with one or more, the same or different R 37 ;
  • FT is alkyl;
  • R is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 37 is optionally substituted with one or more, the same or different, R 38 ; and
  • R 38 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to compounds having the following formula:
  • X is O or NH
  • Y is O or S
  • Z is O or NH
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 31 , R 32 , R 33 , and R 34 are each the same or different at each occurrence hydrogen, alkyl,
  • R , R , R , and R are eachoptionally substituted with one or more, the same or different R 37 ;
  • R 35 is hydrogen, alkyl, or aryl wherein R 35 is optionally substituted with one or more, the same or different R 37 ;
  • R 3b is alkyl
  • R is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 37 is optionally substituted with one or more, the same or different, R 38 ; and
  • R 38 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to a the compound 2-amino-3,4- dihydroxyoctadecyl hydrogen ((3-(6-amino-purin-9-yl)-2-methylpropoxy)methyl)phosphonate or pharmaceutically acceptable salts thereof.
  • the disclosure relates to compounds of the following formula:
  • X is O or CH 2 ;
  • R 1 is a phosphate, phosphonate, polyphosphate, polyphosphonate substituent wherein the phosphate or a phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoroamidate, and the substituent is further substituted with an amino acid ester or a sphingolipid or derivative optionally substituted with one or more, the same or different, R 6 ;
  • R 2 is hydrogen, fluoro, hydroxy, alkoxy, or azide
  • R 3 is hydrogen, fluoro, hydroxy, alkoxy, or azide
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 6 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl ⁇ amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the disclosure relates to compounds of the following formula: Formula VA
  • Y 1 is O or S
  • Y 2 is O or S
  • R 2 is hydrogen, fluoro, hydroxy, or azide
  • R 3 is hydrogen, fluoro, hydroxy, or azide;
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 6 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 7 ; and
  • R 7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 24 and R 25 are each the same or different at each occurrence hydrogen, alkyl, or aryl, wherein R 24 and R 25 are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 26 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 26 is optionally substituted with one or more, the same or different, R 27 ;
  • R 27 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 27 is optionally substituted with one or more, the same or different, R 28 ; and
  • R 28 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the disclosure relates to compounds of the following formula:
  • Lipid is a lipid of any formula described above or herein;
  • Y 1 is O or S
  • Y 2 is O or S
  • R 2 is hydrogen, fluoro, hydroxy, or azide
  • R 3 is hydrogen, fluoro, hydroxy, or azide
  • R 4 is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with an oxo, amino, or carbamoyl, wherein R 4 is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 24 and R 25 are each the same or different at each occurrence hydrogen, alkyl, or aryl, wherein R 24 and R 25 are eachoptionally substituted with one or more, the same or different R 26 ;
  • R 26 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 26 is optionally substituted with one or more, the same or different, R 27 ;
  • R 27 is the same or different at occurrence alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 27 is optionally substituted with one or more, the same or different, R 28 ; and
  • R 28 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ , ⁇ -diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the lipid is any of the formula described above or herein.
  • R 4 is any of the heterocycles described above or herein.
  • the sphingolipid may be selected from: 2-aminooctadecane-3,5- diol; (2S,3S,5S)-2-aminooctadecane-3,5-diol; (2S,3R,5S)-2-aminooctadecane-3,5-diol; 2- (methylamino)octadecane-3,5-diol; (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol; 2- (dimethylamino)octadecane-3,5-diol; (2R,3S,5S)-2-(dimethylamino)octadecane-3,5-diol; 1- (pyrrolidin-2-yl)hexadecane-l,3-diol; (lS,3S)-l-((S)-pyrrol
  • the disclosure relates to compounds of Formula VIA:
  • R is:
  • Ri is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , + , or Mg 2+ ; or a quaternary amine, e.g.
  • Sphingoid is a sphingolipid
  • Aryl is phenyl; monosubstituted phenyl, e.g. 4-fluorophenyl, 4-chlorophenyl, or 4-bromophi disubstituted phenyl; trisubstituted phenyl; 1-naphthyl; or 2-naphthyl;
  • Y is O or S.
  • the disclosure relates to compounds of Formula VIB:
  • Ri is H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • Sphingoid is a sphingolipid
  • Aryl is phenyl; monosubstituted phenyl, e.g. 4-fluorophenyl, 4-chlorophenyl, or 4- bromophenyl; disubstituted phenyl; trisubstituted phenyl; 1-naphthyl; or 2-naphthyl;
  • Y is O or S
  • R 2 is linear or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, or 1-propylbutyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl.
  • the disclosure relates to compounds of Formula VIC:
  • Ri is H, fiuoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • Y is O or S;
  • R 2 is H; alkyl, e.g. methyl; C(0)R'; C(0)OR'; or C(0)NHR';
  • R 3 is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C12-19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • n 8-14 and
  • o 9-15;
  • n 4-10 and o is 5-11;
  • n 6-12;
  • R 5 is H, hydroxyl, fluoro, OR', OC(0)R', OC(0)OR', or OC(0)NHR'.
  • the disclosure relates to compounds of Formula VID: R ⁇ Base
  • Ri is H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • Y is O or S;
  • Sphingoid is ;
  • Rg is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • Rv is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1- ethylpropyl, 1-propylbutyl, or a C 12 -19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • Rg is a C9-15 alkyl chain, e.g. wherein n is 8-14 or wherein "m+n" is 8-14.
  • the disclosure relates to compounds of Formula VIIA:
  • R is:
  • Ri is fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, ethyl, vinyl or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • trialkylammonium or other pharmaceutically acceptable salt cation
  • Sphingoid is a sphingolipid
  • Aryl is phenyl; monosubstituted phenyl, e.g. 4-fluorophenyl, 4-chlorophenyl, or 4- bromophenyl; disubstituted phenyl; trisubstituted phenyl; 1-naphthyl; or 2-naphthyl;
  • Y is O or S.
  • the disclosure relates to compounds of Formula VIIB:
  • R is:
  • Ri is acetylenyl
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • trialkylammonium or other pharmaceutically acceptable salt cation
  • Sphingoid is a sphingolipid
  • Aryl is phenyl; monosubstituted phenyl, e.g. 4-fluorophenyl, 4-chlorophenyl, or 4- bromophenyl; disubstituted phenyl; trisubstituted phenyl; 1-naphthyl; or 2-naphthyl;
  • Y is O or S.
  • the disclosure relates to compounds of Formula VIIC:
  • R is:
  • Ri is fluoromethyl, hydroxymethyl, difluoromethyl, trifiuoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • trialkylammonium or other pharmaceutically acceptable salt cation
  • Sphingoid is a sphingolipid
  • Aryl is phenyl; monosubstituted phenyl, e.g. 4-fiuorophenyl, 4-chlorophenyl, or 4- bromophenyl; disubstituted phenyl; trisubstituted phenyl; 1-naphthyl; or 2-naphthyl;
  • R 2 is straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1- ethylpropyl, or 1-propylbutyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl;
  • Y is O or S.
  • the disclosure relates to compounds of Formula VIID:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • trialkylammonium or other pharmaceutically acceptable salt cation
  • Y is O or S
  • Sphingoid is ;
  • R 2 is H; alkyl, e.g. methyl; C(0)R'; C(0)OR'; or C(0)NHR';
  • R 3 is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C12-19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • n 8-14
  • o 9-15;
  • n 4-10 and o is 5-11;
  • n 6-12;
  • R 5 is H, hydroxyl, fluoro, OR', OC(0)R', OC(0)OR', or OC(0)NHR'.
  • the disclosure relates to compounds of Formula VIIE
  • R is:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Cation is a metal cation, e.g. Li + , Na + , K + , or Mg 2+ ; or a quaternary amine, e.g.
  • Y is O or S;
  • Sphingoid is ;
  • Rg is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • R 7 is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C 12 -19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • Rg is a C9-15 alkyl chain, e.g. wherein n is 8-14 or wherein "m+n" is 8-14.
  • the disclosure relates to compounds of Formula VIII:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Y is O or S
  • R is straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1- ethylpropyl, 1-propylbutyl, or a C 12- 1 9 long chain alkyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl
  • benzyl is straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1- ethylpropyl, 1-propylbutyl, or a C 12- 1 9 long chain alkyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl
  • the disclosure relates to compounds of Formula IX:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Y is O or S
  • R is straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1- ethylpropyl, 1-propylbutyl, or a C 12- 1 9 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl.
  • the disclosure relates to compounds of Formula XA:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Y is O or S; R.
  • R 2 is H; alkyl, e.g. methyl; C(0)R'; C(0)OR'; or C(0)NHR';
  • R 3 is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C12-19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • n 8-14
  • o 9-15 or
  • n 4-10 and o is 5-11;
  • n 6-12;
  • R 5 is H, hydroxyl, fluoro, OR', OC(0)R', OC(0)OR', or OC(0)NHR'.
  • the disclosure relates to compounds of Formula XB:
  • Ri is H, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl or cyano;
  • Y is O or S
  • g is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • Rv is H; hydroxyl; fluoro; OR'; OC(0)R'; OC(0)OR'; or OC(0)NHR';
  • R' is H; straight or branched alkyl, e.g. methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C 12-1 g long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
  • Rg is a C9-15 alkyl chain, e.g. wherein n is 8-14 or
  • the disclosure relates to treating or preventing an infection by viruses, bacteria, fungi, protozoa, and parasites.
  • the disclosure relates to methods of treating a viral infection comprising administering a compound herein to a subject that is diagnosed with, suspected of, or exhibiting symptoms of a viral infection.
  • Viruses are infectious agents that can typically replicate inside the living cells of organisms.
  • Virus particles usually consist of nucleic acids, a protein coat, and in some cases an envelope of lipids that surrounds the protein coat.
  • the shapes of viruses range from simple helical and icosahedral forms to more complex structures.
  • Virally coded protein subunits will self-assemble to form a capsid, generally requiring the presence of the virus genome.
  • nucleoproteins proteins associated with nucleic acid
  • nucleocapsid proteins associated with viral nucleic acid
  • Viruses are transmitted by a variety of methods including direct or bodily fluid contact, e.g., blood, tears, semen, preseminal fluid, saliva, milk, vaginal secretions, lesions; droplet contact, fecal-oral contact, or as a result of an animal bite or birth.
  • a virus has either DNA or RNA genes and is called a DNA virus or a RNA virus respectively.
  • a viral genome is either single-stranded or double-stranded. Some viruses contain a genome that is partially double- stranded and partially single-stranded.
  • the strands are said to be either positive-sense (called the plus-strand) or negative-sense (called the minus-strand), depending on whether it is complementary to the viral messenger RNA (mRNA).
  • Positive-sense viral RNA is identical to viral mRNA and thus can be immediately translated by the host cell.
  • Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation.
  • DNA nomenclature is similar to RNA nomenclature, in that the coding strand for the viral mRNA is complementary to it (negative), and the non-coding strand is a copy of it (positive).
  • Antigenic shift, or reassortment can result in novel strains. Viruses undergo genetic change by several mechanisms. These include a process called genetic drift where individual bases in the DNA or RNA mutate to other bases. Antigenic shift occurs when there is a major change in the genome of the virus. This can be a result of recombination or reassortment. RNA viruses often exist as quasispecies or swarms of viruses of the same species but with slightly different genome nucleoside sequences.
  • viruses The genetic material within viruses, and the method by which the material is replicated, vary between different types of viruses.
  • the genome replication of most DNA viruses takes place in the nucleus of the cell. If the cell has the appropriate receptor on its surface, these viruses enter the cell by fusion with the cell membrane or by endocytosis. Most DNA viruses are entirely dependent on the host DNA and RNA synthesizing machinery, and RNA processing machinery. Replication usually takes place in the cytoplasm. RNA viruses typically use their own RNA replicase enzymes to create copies of their genomes.
  • viruses The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNAs from their genomes to produce proteins and replicate themselves, but different mechanisms are used to achieve this. Viral genomes may be single-stranded (ss) or double-stranded (ds), RNA or DNA, and may or may not use reverse transcriptase (RT).
  • ss single-stranded
  • ds double-stranded
  • RNA or DNA may or may not use reverse transcriptase (RT).
  • ssRNA viruses may be either sense (plus) or antisense (minus). This classification places viruses into seven groups: I, dsDNA viruses (e.g. adenoviruses, herpesviruses, poxviruses); II, ssDNA viruses (plus )sense DNA (e.g. parvoviruses); III, dsRNA viruses (e.g. reoviruses); IV, (plus)ssRNA viruses (plus)sense RNA (e.g. picornaviruses, togaviruses); V, (minus)ssRNA viruses (minus)sense RNA (e.g.
  • orthomyxoviruses Rhabdoviruses
  • VI ssRNA- RT viruses (plus)sense RNA with DNA intermediate in life-cycle (e.g. retroviruses)
  • VII dsDNA-RT viruses (e.g. hepadna viruses).
  • HIV Human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses.
  • the viral RNA genome is converted to double-stranded DNA by a virally encoded reverse transcriptase.
  • This viral DNA is then integrated into the cellular DNA by a virally encoded integrase, along with host cellular co-factors.
  • HIV-1 is sometimes termed LAV or HTLV-III.
  • helper T cells CD4+ T cells
  • macrophages macrophages
  • dendritic cells dendritic cells
  • Subjects with HIV typically develop malignancies associated with the progressive failure of the immune system.
  • the viral envelope is composed of two layers of phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and a HIV protein known as Env. Env contains glycoproteinsgpl20, and gp41.
  • the RNA genome consists of at structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS) and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat env and rev) encoding 19 proteins.
  • HIV-1 diagnosis is typically done with antibodies in an ELISA, Western blot, orimmunoaffinity assays or by nucleic acid testing (e.g., viral RNA or DNA amplification).
  • HIV is typically treated with a combination of antiviral agent, e.g., two nucleoside- analogue reverse transcription inhibitors and one non-nucleoside-analogue reverse transcription inhibitor or protease inhibitor.
  • the three drug combination is commonly known as a triple cocktail.
  • the disclosure relates to treating a subject diagnosed with HIV by administering a pharmaceutical composition disclosed herein in combination with two nucleoside-analogue reverse transcription inhibitors and one non-nucleoside-analogue reverse transcription inhibitor or protease inhibitor.
  • the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, and efavirenz. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir and raltegravir. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir and darunavir. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir and atazanavir.
  • the disclosure relates to methods of treating a subject by administering a lipid conjugated compound disclosed herein. In certain embodiments, the disclosure relates to methods of treating a subject by administering a sphingolipid conjugate.
  • Banana lectin (BanLec or BanLec-1) is one of the predominant proteins in the pulp of ripe bananasand has binding specificity for mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gpl20.
  • the disclosure relates to treating viral infections, such as HIV, by administering a compound disclosed herein in combination with a banana lectin.
  • the hepatitis C virus is a single-stranded, positive sense RNA virus. It is the only known member of the hepacivirus genus in the family Flaviviridae. There are six major genotypes of the hepatitis C virus, which are indicated numerically.
  • the hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell, and further encased in a lipid envelope. Two viral envelope glycoproteins, El and E2, are embedded in the lipid envelope.
  • the genome consists of a single open reading frame translated to produce a single protein.
  • This large pre-protein is later cut by cellular and viral proteases into smaller proteins that allow viral replication within the host cell, or assemble into the mature viral particles, e.g., El, E2, NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.
  • HCV leads to inflammation of the liver, and chronic infection leads to cirrhosis. Most people with hepatitis C infection have the chronic form. Diagnosis of HCV can occur via nucleic acid analysis of the 5'-noncoding region. ELISA assay may be performed to detect hepatitis C antibodies and RNA assays to determine viral load. Subjects infected with HCV may exhibit symptoms of abdominal pain, ascites, dark urine, fatigue, generalized itching, jaundice, fever, nausea, pale or clay-colored stools and vomiting.
  • Therapeutic agents in some cases may suppress the virus for a long period of time.
  • Typical medications are a combination of interferon alpha and ribavirin.
  • Subjects may receive injections of pegylated interferon alpha. Genotypes 1 and 4 are less responsive to interferon- based treatment than are the other genotypes (2, 3, 5 and 6).
  • the disclosure relates to treating a subject with HCV by administering a compound disclosed herein to a subject exhibiting symptoms or diagnosed with HCV.
  • the compound is administered in combination with interferon alpha and another antiviral agent such as ribavirin, and/or a protease inhibitor such as telaprevir or boceprevir.
  • the subject is diagnosed with genotype 2, 3, 5, or 6. In other embodiments, the subject is diagnosed with genotype 1 or 4.
  • the subject is diagnosed to have a virus by nucleic acid detection or viral antigen detection.
  • Cytomegalovirus belongs to the Betaherpesvirinae subfamily of Herpesviridae. In humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV- 5). Herpesviruses typically share a characteristic ability to remain latent within the body over long periods. HCMV infection may be life threatening for patients who are
  • the disclosure relates to methods of treating a subject diagnosed with cytomegalovirus or preventing a cytomegalovirus infection by
  • the subject is immunocompromised.
  • the subject is an organ transplant recipient, undergoing hemodialysis, diagnosed with cancer, receiving an immunosuppressive drug, and/or diagnosed with an HIV-infection.
  • the subject may be diagnosed with cytomegalovirus hepatitis, the cause of fulminant liver failure, cytomegalovirus retinitis
  • a compound disclosed herein is administerd in
  • an antiviral agent such as valganciclovir or ganciclovir.
  • the subject undergoes regular serological monitoring.
  • HCMV infections of a pregnant subject may lead to congenital abnormalities.
  • Congenital HCMV infection occurs when the mother suffers a primary infection (or reactivation) during pregnancy.
  • the disclosure relates to methods of treating a pregnant subject diagnosed with cytomegalovirus or preventing a cytomegalovirus infection in a subject at risk for, attempting to become, or currently pregnant by administering a compound disclosed herein.
  • CMV pp65 antigenemia test is an immunoaffmity based assay for identifying the pp65 protein of cytomegalovirus in peripheral blood leukocytes. CMV should be suspected if a patient has symptoms of infectious mononucleosis but has negative test results for
  • a virus culture can be performed at any time the subject is symptomatic.
  • Laboratory testing for antibody to CMV can be performed to determine if a subject has already had a CMV infection.
  • the enzyme-linked immunosorbent assay (or ELISA) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect hemagglutination, (PCR), and latex agglutination. An ELISA technique for CMV-specific IgM is available.
  • Hepatitis B virus is a hepadna virus.
  • the virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein.
  • the genome of HBV is made of circular DNA, but the DNA is not fully double-stranded. One end of the strand is linked to the viral DNA polymerase.
  • the virus replicates through an RNA intermediate form by reverse transcription. Replication typically takes place in the liver where it causes inflammation
  • hepatitis hepatitis.
  • the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people. Blood tests for these proteins and antibodies are used to diagnose the infection.
  • Hepatitis B virus gains entry into the cell by endocytosis. Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host chaperones. The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of viral mRNAs.
  • cccDNA covalently closed circular DNA
  • the virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome.
  • the hepatitis B surface antigen (HBsAg) is typically used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection if it is being cleared by the host.
  • the infectious virion contains an inner "core particle" enclosing viral genome.
  • the icosahedral core particle is made of core protein, alternatively known as hepatitis B core antigen, or HBcAg.
  • IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be used as a serological marker.
  • Hepatitis B e antigen (HBeAg) may appear. The presence of HBeAg in the serum of the host is associated with high rates of viral replication. Certain variants of the hepatitis B virus do not produce the 'e' antigen,
  • the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen and core antigen, (anti- HBs and anti HBc IgG).
  • the time between the removal of the HBsAg and the appearance of anti-HBs is called the window period.
  • a person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously.
  • Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers. Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase levels and inflammation of the liver which may be identified by biopsy.
  • PCR tests have been developed to detect and measure the amount of HBV DNA in clinical specimens.
  • Acute infection with hepatitis B virus is associated with acute viral hepatitis.
  • Acute viral hepatitis typically begins with symptoms of general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to development of jaundice.
  • Chronic infection with hepatitis B virus may be either asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), possibly leading to cirrhosis. Having chronic hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer).
  • CTLs virus-specific cytotoxic T lymphocytes
  • the adaptive immune response particularly virus-specific cytotoxic T lymphocytes (CTLs)
  • CTLs virus-specific cytotoxic T lymphocytes
  • CTLs By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs eliminate the virus .
  • liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.
  • Therapeutic agents can stop the virus from replicating, thus minimizing liver damage.
  • the disclosure relates to methods of treating a subject diagnosed with HBV by administering a compound disclosed herein disclosed herein.
  • the subject is immunocompromised.
  • the compound is administered in combination with another antiviral agent such as lamivudine, adefovir, tenofovir, telbivudine, and entecavir, and/or immune system modulators interferon alpha-2a and pegylated interferon alpha-2a (Pegasys).
  • the disclosure relates to preventing an HBV infection in an immunocompromised subject at risk of infection by administering a
  • the subject is at risk of an infection because the sexual partner of the subject is diagnosed with HBV.
  • an "infection” or "bacterial infection” refers to an infection caused by acinetobacter spp, bacteroides spp, burkholderia spp, Campylobacter spp, chlamydia spp, chlamydophila spp, Clostridium spp, enterobacter spp, enterococcus spp, escherichia spp, fusobacterium spp, gardnerella spp, haemophilus spp, helicobacter spp, lebsiella spp, legionella spp, moraxella spp, morganella spp, mycoplasma spp, neisseria spp, peptococcus spp peptostreptococcus spp, proteus spp, pseudomonas spp, salmonella spp, serratia spp., staphylococcus
  • an "infection” or "bacterial infection” refers to an infection caused by acinetobacter baumanii, acinetobacter haemolyticus, acinetobacter junii, acinetobacter johnsonii, acinetobacter Iwoffi, bacteroides bivius, bacteroides fragilis , burkholderia cepacia, Campylobacter jejuni, chlamydia pneumoniae, chlamydia urealyticus , chlamydophila pneumoniae, Clostridium difficile, enterobacter aerogenes, enterobacter cloacae, enterococcus faecalis, enterococcus faecium, escherichia coli, gardnerella vaginalis, haemophilus par influenzae, haemophilus influenzae, helicobacter pylori, Klebsiella
  • pneumoniae streptococcus pyogenes, stenotrophomonas maltophilia, ureaplasma urealyticum, vancomycin-resistant enterococcus faecium, vancomycin-resistant enterococcus faecalis, vancomycin-resistant staphylococcus aureus, vancomycin-resistant staphylococcus epidermis, mycobacterium tuberculosis, Clostridium perfringens, Klebsiella oxytoca, neisseria miningitidis, proteus vulgaris, or coagulase-negative staphylococcus (including staphylococcus lugdunensis, staphylococcus capitis, staphylococcus hominis, or staphylococcus saprophytic ).
  • infection refers to aerobes, obligate anaerobes, facultative anaerobes, gram-positive bacteria, gram-negative bacteria, gram- variable bacteria, or atypical respiratory pathogens.
  • the disclosure relates to treating a bacterial infection such as a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, or a urinary tract infection.
  • a bacterial infection such as a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, or a urinary tract infection.
  • the disclosure relates to treating a bacterial infection such as an infection caused by drug resistant bacteria.
  • the disclosure relates to treating a bacterial infection such as community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as penicillin-resistant streptococcus pneumoniae, methicillin- resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis and vancomycin-resistant enterococci, syphilis, ventilator-associated pneumonia, intra-abdominal infections, gonorrhoeae, meningitis, tetanus, or tuberculosis.
  • a bacterial infection such as community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomy
  • the disclosure relates to treating a fungal infections such as infections caused by tinea versicolor,microsporum, trichophyton, epidermophyton, candidiasis, cryptococcosis,or aspergillosis.
  • the disclosure relates to treating an infection caused by protozoa including, but not limited to, malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery.
  • an infection caused by protozoa including, but not limited to, malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery.
  • Certain compounds disclosed herein are useful to prevent or treat an infection of a malarial parasite in a subject and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith and can then be used in the preparation of a medicament for the treatment and/or prevention of such disease.
  • the malaria may be caused by Plasmodium falciparum, P. vivax, P. ovale, or P. malariae.
  • the compound is administered after the subject has been exposed to the malaria parasite.
  • a compound disclosed hereinis administered before the subject travels to a country where malaria is endemic.
  • the disclosure relates to the use of the compounds as topical microbicides. In certain embodiments, the disclosure relates to methods of treating a subject by using the lipid conjugates described herein as topical microbicides. In particular embodiments, the disclosure relates to methods of treating a subject by using the sphingo lipid conjugates described herein as topical microbicides.
  • the compounds or the above-mentioned pharmaceutical compositions may also be used in combination with one or more other therapeutically useful substances selected from the group comprising antimalarials like quinolines (e.g., quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine); peroxide antimalarials (e.g.,artemisinin, artemether, artesunate); pyrimethamine-sulfadoxine antimalarials (e.g., Fansidar); hydroxynaphtoquinones (e.g., atovaquone); acroline-type antimalarials (e.g., pyronaridine); and antiprotozoal agents such as ethylstibamine, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycine, propamidine, nifurtimox, melarsoprol, nimorazo
  • compounds disclosed herein can be used in combination one additional drug selected from the group consisting of chloroquine, artemesin, qinghaosu, 8- aminoquinoline, amodiaquine, arteether, artemether, artemisinin, artesunate, artesunic acid, artelinic acid, atovoquone, azithromycine, biguanide, chloroquine phosphate, chlorproguanil, cycloguanil, dapsone, desbutyl halofantrine, desipramine, doxycycline, dihydro folate reductase inhibitors, dipyridamole, halofantrine, haloperidol, hydroxychloroquine sulfate, imipramine, mefloquine, penfluridol, phospholipid inhibitors, primaquine, proguanil, pyrimethamine, pyronaridine, quinine, quinidine, quinacrineartemisinin, s
  • the disclosure relates to a method treating cancer comprising administering to a patient a compound disclosed herein.
  • the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof for uses in treating cancer.
  • the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate.
  • the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • leukaemias including ALL and CML
  • the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumors of the central nervous system and their metastases, and also for the treatment of glioblastomas.
  • compounds disclosed herein could be used in the clinic either as a single agent by itself or in combination with other clinically relevant agents. This compound could also prevent the potential cancer resistance mechanisms that may arise due to mutations in a set of genes.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the disclosure, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti- tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin- 4-a mine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
  • PI3K phosphotidylinositol 3-kinase
  • MEKl/2 mitogen activated protein kinase kinase
  • PPKB/Akt protein kinase B
  • Abl Abl tyrosine kinase family
  • dasatinib BMS-354825
  • imatinib mesylate GleevecTM
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody
  • bevacizumab [AvastinTM]
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ 3 function and angiostatin;
  • antisense therapies for example those which are directed to the targets listed above, such as an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro- drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine- transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies, and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid®].
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune cells such as cytokine- transfected dendritic cells
  • approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and le
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this disclosure, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below.
  • suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).
  • the compounds of the disclosure may also form internal salts, and such compounds are within the scope of the disclosure.
  • a compound of the disclosure contains a hydrogen-donating heteroatom (e.g., NH)
  • the disclosure also covers salts and/or isomers formed by the transfer of the hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydr
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH, 2002), incorporated herein by reference.
  • a prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds.
  • prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids. It is well within the ordinary skill of the art to make an ester prodrug, e.g., acetyl ester of a free hydroxyl group. It is well known that ester prodrugs are readily degraded in the body to release the corresponding alcohol. See e.g., Imai, Drug Metab Pharmacokinet. (2006)
  • compositions for use in the present disclosure typically comprise an effective amount of a compound and a suitable pharmaceutical acceptable carrier.
  • the preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the compounds may be formulated as a
  • composition comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient, and optionally one or more further pharmaceutically active compounds.
  • the pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the disclosure, e.g., about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used.
  • the compound will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable
  • an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses.
  • administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is made to U.S. Pat. No.
  • the compound can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, the compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the disclosure or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation may additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compounds for subcutaneous or intravenous administration, the compounds, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds may also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • the formulations When rectally administered in the form of suppositories, the formulations may be prepared by mixing the compounds of formula I with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds can be in various forms known to the art, including liquid form or in lotion form, either oil-in- water or water-in-oil emulsions, in aqueous gel compositions, in the form of foams, films, sprays, ointments, pessary, suppository, capsules, tablets, jellies, creams, liposomes or in other forms embedded in a matrix for the slow or controlled release of the biologically active material to the skin or surface onto which it has been applied or in contact.
  • the topical compositions of the present invention are aqueous compositions.
  • the topical compositions are aqueous gel compositions.
  • compositions can be extended release formulations.
  • Typical extended release formations utilize an enteric coating.
  • a barrier is applied to oral medication that controls the location in the digestive system where it is absorbed.
  • Enteric coatings prevent release of medication before it reaches the small intestine.
  • Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium
  • poly(acrylic acid); poly(hydroxyalkylmethacrylates) for example
  • HMC hydroxymethylcellulose
  • HEC hydroxyethylcellulose
  • CEC carboxyethylcellulose
  • EHEC ethylhydroxyethylcellulose
  • CHEC carboxymethylhydroxyethylcellulose
  • HPMC hydroxypropylmethyl-cellulose
  • HPEC hydroxypropylethylcellulose
  • Na CMC sodium carboxymethylcellulose
  • Certain of the above-mentioned polymers may further be crosslinked by way of standard techniques.
  • polymer will be determined by the nature of the active ingredient/drug that is employed in the composition of the disclosure as well as the desired rate of release.
  • a higher molecular weight will, in general, provide a slower rate of release of drug from the composition.
  • different degrees of substitution of methoxyl groups and hydroxypropoxyl groups will give rise to changes in the rate of release of drug from the composition. In this respect, and as stated above, it may be desirable to provide
  • compositions of the disclosure in the form of coatings in which the polymer carrier is provided by way of a blend of two or more polymers of, for example, different molecular weights in order to produce a particular required or desired release profile.
  • Microspheres of polylactide, polyglycolide, and their copolymers poly(lactide-co- glycolide) may be used to form sustained-release protein delivery systems.
  • Proteins can be entrapped in the poly(lactide-co-glycolide) microsphere depot by a number of methods, including formation of a water-in-oil emulsion with water-borne protein and organic solvent- borne polymer (emulsion method), formation of a solid-in-oil suspension with solid protein dispersed in a solvent-based polymer solution (suspension method), or by dissolving the protein in a solvent-based polymer solution (dissolution method).
  • emulsion method formation of a water-in-oil emulsion with water-borne protein and organic solvent- borne polymer
  • uspension method formation of a solid-in-oil suspension with solid protein dispersed in a solvent-based polymer solution
  • dissolution method dissolving the protein in a solvent-based polymer solution
  • Mono and diphosphate prodrugs have been prepared by several groups. See Jessen et al, Bioreversible Protection of Nucleoside Diphosphates, Angewandte Chemie-International Edition English 2008, 47 (45), 8719-8722, hereby incorporated by reference.
  • a pendant group that fragments rapidly (e.g. bis-(4- acyloxybenzyl)-nucleoside diphosphates (BAB-NDP) that is deacylated by an endogenous esterase) to generate a negative charge on the second phosphate.
  • BAB-NDP bis-(4- acyloxybenzyl)-nucleoside diphosphates
  • diphosphate and monothiodiphosphate prodrugs are shown in Figure 7. Standard coupling conditions are used to prepare sphingolipid-cyclobutyl nucleoside monophosphate prodrugs.
  • the corresponding diphosphate prodrugs may be prepared according to the protocols shown in Figure 7 and as provided in Smith et al, Substituted Nucleotide Analogs. U.S. Patent Application 2012/0071434; Skowronska et al., Reaction of
  • the sphingo lipid containing nucleosides tested for RdRp inhibition are 2'-
  • Fluoronucleosides when activated to their corresponding triphosphate inhibit RNAdependent RNA viral replication by acting as competitive substrate inhibitors of the virally encoded RdRp.
  • Compounds in this therapeutic class are useful in the treatment of viruses found in but not limited to the arenaviridae, bunyaviridae, flaviviridae, orthomyxoviridae, paramyxoviridae, and togaviridae viral families. Certain compounds disclosed herein are contemplated to have advantages such as a high genetic barrier for antiviral resistance; broad spectrum activity within viral families; and high oral bioavailability with targeted delivery to sites of infection.
  • the nucleoside analogs were designed with a 2 '-alpha-fluorine substituent to mimic natural ribonucleosides.
  • the C-F bond length (1.35 A) is similar to the C-0 bond length (1.43 A) and fluorine is a hydrogen-bond acceptor making the fluorine substituent an isopolar and isosteric replacement of a hydroxyl group.
  • fluorine is a hydrogen-bond acceptor making the fluorine substituent an isopolar and isosteric replacement of a hydroxyl group.
  • the 2',3'-dideoxy-2'-fluoronucleoside analogs covered by this disclosure lack a 3 '-hydroxyl group and are thus obligate chain terminators of viral replication.
  • nucleosides Once the nucleosides are converted to their triphosphates, they act as competitive substrate inhibitors of the virally encoded RdRp. After incorporation of the chain terminator into nascent RNA, viral replication ceases.
  • One advantage to obligate chain terminators is that they are not mutagenic to the host when treating chronic diseases.
  • HIV-1 (92HT599)
  • HIV-l (92HT599)
  • HIV-1 (92HT599)
  • Phytosphingosine-Tenofovir conjugate ( Figure 9) was found to exhibit good plasma stability (79.1% present after 120 minutes at 37°C at pH 7.4).
  • the Phytosphingosine-Tenofovir conjugate does not undergo oxidative catabolism (i.e., oxidation of the terminal methyl group, followed by sequential loss of two carbon fragments leading to inactive, water soluble derivatives) as does CMX-157.
  • oxidative catabolism i.e., oxidation of the terminal methyl group, followed by sequential loss of two carbon fragments leading to inactive, water soluble derivatives
  • CMX-157 Unlike phospholipids, no oxidative catabolism of the terminal methyl group of sphingoid bases has been observed with any sphingolipid derivatives.
  • AZTDP prodrugs were prepared, which are shown in Figure 9. Two of them, 16a and 16b, are alkylated glycerol and deoxyglycerol derivatives, the third, 17, is a "McGuigan" version of a diphosphate prodrug. A Sphingosine- AZTDP conjugate, 18 was also prepared.
  • Preliminary assessment of 18 indicates that it has good stability in human plasma and that it rapidly permeates the cell membrane of hepatocytes.
  • Reagents and conditions a) silylated base, TMSOTf, DCE; b) TBAF, THF; c) nucleobase, TDA-
  • Reagents and conditions a) NaN0 2 , HCl (aq) ; b) BH 3 SMe 2 ; c) TBDPSC1, DMAP, pyridine; d) i. LiHMDS, ii. NFSi; e) DIBAL; f) Ac 2 0, DMAP; g) HMPT, CC1 4
  • Reagents and conditions a) silylated base, TMSOTf, DCE; b) TBAF, THF; c) nucleobase, TDA- ⁇ , ⁇ , MeCN References:
  • the aqueous phase was back extracted with ethyl acetate (2 x 25 mL) and the combined organic phases dried over sodium sulfate, filtered and concentrated to dryness.
  • the crude material was purified by flash column chromatography (25 mm x 170 mm) over silica gel using 9: 1 hexanes: ethyl acetate to give 18 (540 mg, 46%) as a white foam.
  • the aqueous phase was back extracted with ethyl acetate (2 x 30 mL) and the combined organic phases dried over sodium sulfate, filtered and concentrated to dryness.
  • the crude material was purified by flash column chromatography (25 mm x 170 mm) over silica gel using 9: 1 hexanes: ethyl acetate to give 21 (767 mg, 54%) as a white foam.

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Abstract

L'invention concerne compositions thérapeutiques renfermant des nucléotides et des nucléosides et des utilisations associées. Dans certains modes de réalisation, l'invention concerne des nucléosides halogénés éventuellement conjugués avec un oxyde de phosphore ou leurs sels pharmaceutiquement acceptables. Dans certains modes de réalisation, l'invention concerne des composés conjugués ou leurs sels pharmaceutiquement acceptables comprenant un ester d'acide aminé ou un sphingolipide ou dérivé lié par un oxyde de phosphore à un nucléotide ou un nucléoside. Dans certains modes de réalisation, l'invention concerne des compositions pharmaceutiques comprenant ces composés et utilisées pour traiter des maladies infectieuses, des infections virales et le cancer.
PCT/US2014/015763 2013-02-11 2014-02-11 Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées WO2014124430A1 (fr)

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US20140248241A1 (en) * 2013-03-04 2014-09-04 Idenix Pharmaceuticals, Inc. 3'-deoxy nucleosides for the treatment of hcv
WO2015017713A1 (fr) * 2013-08-01 2015-02-05 Idenix Pharmaceuticals, Inc. Pronucléotides phosphoramidates avec acides aminés d de composés halogéno pyrimidines pour le traitement des hépatopathies
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