WO2016145142A1 - 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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WO2016145142A1
WO2016145142A1 PCT/US2016/021688 US2016021688W WO2016145142A1 WO 2016145142 A1 WO2016145142 A1 WO 2016145142A1 US 2016021688 W US2016021688 W US 2016021688W WO 2016145142 A1 WO2016145142 A1 WO 2016145142A1
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alkyl
compound
optionally substituted
aryl
amino
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PCT/US2016/021688
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English (en)
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Dennis C. Liotta
George R. Painter
Gregory R. BLUEMLING
Abel De La Rosa
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Emory University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto.
  • the disclosure relates to sulfur-containing
  • nucleosides optionally conjugated to a phosphorus oxide or salts thereof.
  • the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester, a lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • the disclosure contemplates
  • 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 virus and adefovir dipivoxil for the treatment of hepatitis B virus infections.
  • Administration of three or more antiretroviral agents in combination e.g., Highly Active Antiretroviral Therapy (HAART), has significantly reduced the morbidity and mortality associated with HIV infection.
  • HAART Highly Active Antiretroviral Therapy
  • HAART Highly Active Antiretroviral Therapy
  • 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
  • dNKs deoxynucleoside kinases
  • dNMPKs deoxynucleoside monophosphate kinases
  • NDPK nucleoside diphosphate kinase
  • intracellular activation of these compounds is often compromised by the high substrate specificity of the host’s endogenous kinases.
  • the first and/or second phosphorylation, catalyzed by dNKs and dNMPKs often represent the rate-limiting steps in nucleoside analogue activation.
  • CMX157 hexadecyloxypropyl prodrug ester
  • 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 derivatives.Bushnev et al., ARKIVOC, 2010, (viii):263-277, report an asymmetric synthetic method for preparing sphingolipid derivatives. Dougherty et al., Org.
  • nucleotide and nucleoside therapeutic compositions relate thereto. Included are sulfur-containing nucleosides optionally conjugated to a phosphorus oxide or salts thereof, prodrugs or conjugate compounds or salts thereof comprising an amino acid ester, lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • sulfur-containing nucleosides optionally conjugated to a phosphorus oxide or salts thereof
  • prodrugs or conjugate compounds or salts thereof comprising an amino acid ester, lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • FIG. 1 illustrates certain embodiments of the disclosure.
  • Figure 2 illustrates exemplary thio-containing bases for certain embodiments provided herein.
  • 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
  • hINT1 histidine triad nucleotide binding protein 1
  • Figure 4 illustrates embodiments of mono- and diphosphate structural types.
  • Figure 5 illustrates schemes for the synthesis of conjugates.
  • Figure 6 is the X-ray crystal structure for EIDD-02023.
  • This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto.
  • the disclosure relates to sulfur containing
  • nucleosides optionally conjugated to a phosphorus oxide or salts thereof.
  • the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester, a lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.
  • the disclosure contemplates
  • compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer.
  • the disclosure relates to phosphorus oxide prodrugs of 2’- fluoronucleosides containing sulfur-containing bases for the treatment of positive-sense and negative-sense RNA viral infections through targeting of the virally encoded RNA-dependent RNA polymerase (RdRp).
  • RdRp virally encoded RNA-dependent RNA polymerase
  • This disclosure also provides the general use of lipids and sphingolipids to deliver nucleoside analogs for the treatment of infectious disease and cancer.
  • the disclosure relates to conjugate compounds or salts thereof comprising a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside, wherein the nucleotide or nucleoside contains a sulfur-containing base.
  • 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 or phosphoroamidate.
  • the lipid or sphingolipid is covalently bonded to the phosphorus oxide through an amino group or a hydroxyl group.
  • the nucleotide or nucleoside comprises a heterocycle comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein the substituted heterocycle is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl.
  • the heterocycle comprising two or more nitrogen
  • the sphingolipid is saturated or unsaturated 2-aminoalkyl or 2-aminooctadecane optionally substituted with one or more substituents.
  • the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3-ol optionally substituted with one or more substituents.
  • the sphingolipid is saturated or unsaturated 2-aminooctadecane-3-ol optionally substituted with one or more substituents.
  • sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3,5-diol optionally substituted with one or more substituents.
  • 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 anti-inflammatory 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, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), Dengue virus, chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuela
  • influenza A virus including subtype H
  • influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza viruses 1 and 3, rinder
  • encephalitis virus Japanese encephalitis virus, Rift Valley fever virus (RVFV), hantavirus, Dengue virus serotypes 1, 2, 3 and 4, West Nile virus, Tacaribe virus, Junin, rabies virus, ebola virus, marburg virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV).
  • HSV-1 herpes simplex virus-1
  • HSV-2 herpes simplex virus-2
  • VZV varicella zoster virus
  • EBV Epstein-
  • 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 provided.
  • a second antiviral agent such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, maraviroc, moroxydine
  • 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-Hodgkins 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, camptothecin, bortezomib, anagrelide, tamoxifen, toremif
  • 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.
  • 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.
  • 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, cyclic, linear or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 22 carbon atoms, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • Alkyl groups can be optionally substituted with one or more moieties selected from, for example, hydroxyl, amino, halo, deutero, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected, as necessary, as known to those skilled in the art, for example, as taught in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 3ed., John Wiley & Sons, 1999, hereby incorporated by reference.
  • lower alkyl refers to a C1 to C4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred.
  • halo or “halogen,” as used herein, includes chloro, bromo, iodo and fluoro.
  • 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, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • 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 ).
  • 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.
  • 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
  • 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, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • 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,
  • 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
  • intracellular activation of these compounds is often compromised by the high substrate specificity of the host’s endogenous kinases.
  • the first and/or second phosphorylation catalyzed by dNKs and dNMPKs, often represent the rate- limiting steps in nucleoside analog activation.
  • kinase bypass strategies have been developed.
  • McGuigan phosphoramidates are chemical conjugates used for kinase bypass. See Serpi et al., J Med Chem, 2012, 55(10):4629-4639.
  • the metabolism 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 (hINT1).
  • 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 nucleosides having sulfur containing bases conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of the following formula:
  • X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 1 is a phosphonate, phosphonophosphate, phosphonodiphosphate or phosphate, including monophosphate, diphosphate, triphosphate, and polyphosphate, or
  • the phosphonate or a phosphate in the polyphosphate is optionally a phosphoroborate, phosphorothioate, or phosphoroamidate;
  • phosphonate or a phosphate in the polyphosphate, phosphoroborate, phosphorothiolate, or phosphoroamidate is optionally substituted with one or more, the same or different R 8 ;
  • phosphonate or a phosphate in the polyphosphate, phosphoroborate, phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring;
  • R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 are independently H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkynyl), C(O)O(C 1-22 alkynyl), C(O)O(C 1
  • alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), deuterium, NO 2 , C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkynyl), C(O)O(C 1-22 alkenyl), O(C 1-22 acyl), O(C 1-22 alkyl), O(C 1-22 alkenyl), S(C 1-22 acyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S(C 1-22 alkyl), S
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 9 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl; and Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl.
  • X is selected from the group consisting of: CHMe, CMe 2 , CHF, and CF 2 .
  • R 3 and R 4 with the carbon atom they are attached to form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 9 .
  • R 6 and R 7 with the carbon atom they are attached to, form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 9 ;
  • R 5 is selected from the group consisting of: Me, CN, alkyl, alkenyl, and alkynyl.
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • nucleoside conjugated to a phosphorus moiety or pharmaceutically acceptable salt thereof has the following structure:
  • X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 1 is OH, monophosphate, diphosphate, or triphosphate
  • R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • Q is one of the following bases: ,
  • Z is alkyl, alkyenyl, acyl, lipid, or geranyl.
  • R 2 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 2 is H.
  • R 3 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 4 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 6 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 7 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • Lipid as used herein, 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 derived 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 derived from essential and non-essential fatty acids.
  • the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and non-essential fatty acids that have 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 derived from essential and non-essential fatty acids that have 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 derived from essential and non-essential fatty acids that is optionally substituted.
  • the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and non-essential fatty acids that is optionally substituted.
  • the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is optionally substituted.
  • the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is also optionally substituted.
  • the lipid is hexadecyloxypropyl.
  • the lipid is 2-aminohexadecyloxypropyl.
  • the lipid is 2-aminoarachidyl.
  • the lipid is 2-benzyloxyhexadecyloxypropyl.
  • the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.
  • the lipid is a sphingolipid having the formula:
  • R 10 of the sphingolipid 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 of the sphingolipid is hydrogen, a branched or strait chain C 1-12 alkyl, C 13-22 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 ;
  • R 13 of the sphingolipid 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, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethy
  • ethoxycarbonyl N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
  • R 12 of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n- butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl,1-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 of the sphingolipid 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 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 of the sphingolipid is hydrogen, a branched or strait chain C 1-12 alkyl, C 13-22 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 of the sphingolipid 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-
  • ethoxycarbonyl N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
  • R 12 of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n- butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl,1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C 12 -C 19 long chain alkyl.
  • Suitable sphingolipids include, but are not limited to, sphingosine, ceramide, or sphingomyelin, or 2-aminoalkyl optionally substituted with one or more substituents.
  • Suitable sphingolipids include, but are not limited to, 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-1,3-diol; (1S,3S)-1-((S)-pyrrolidin
  • Y is O or S
  • Y’ is OH, OR”, SR”, NHR”, NR” 2 , or BH - 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 3 , R 4 , R 6 , R 7 and R 8 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.
  • Y’ is selected from the group consisting of: OR”, SR”, NHR”, and NR” 2 .
  • Q is a heterocycle selected from the group consisting of pyrimidin-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4- aminopyrimidine-2-thione, 5-fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4- one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin- 6-thione, 2-amino-7-deaza-purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • R 3 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 4 is selected from the group consisting of H, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 6 is selected from the group consisting of H, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 7 is selected from the group consisting of H, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 8 is selected from the group consisting of H, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I. In one embodiment, R 8 is H.
  • the disclosure relates to compounds of one of the following formulae:
  • A is O or S
  • A’ is OH, OR”, SR”, NHR”, NR” H - 2, or B 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • Y is CH, N, or CR 2 ;
  • Z is CH, N, or CR 2 ;
  • R 3 , R 4 , R 6 , R 7 and R 10 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 2 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 .
  • A’ is selected from the group consisting of: OR”, SR”, NHR”, and NR” 2 .
  • R 2 is deuteron.
  • R 3 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 4 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 6 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 7 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 10 is selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 8 is H.
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In still another embodiment, R 6 is methyl. In yet another embodiment, R 7 is fluoro. In an still further embodiment, R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is trifluoromethyl.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is C ⁇ CH.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is CH 2 F.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is methyl.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is trifluorom ethyl.
  • R 7 is fluoro.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is methyl.
  • R 7 is hydroxyl.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is trifluoromethyl.
  • R 7 is hydroxyl.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is C ⁇ CH.
  • R 7 is hydroxyl.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is CH 2 F.
  • R 7 is hydroxyl.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is methyl.
  • R 7 is H.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is trifluoromethyl.
  • R 7 is H.
  • R 10 is H.
  • the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is N 3 . In still another embodiment, R 6 is H. In yet another embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 10 is C ⁇ CH.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 10 is CH 2 F.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is N 3 . In still another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is C ⁇ CH. In still another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is CH 2 F. In still another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is fluoro.
  • R 5 is H.
  • R 10 is H.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In still another embodiment, R 6 is methyl. In yet another embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In still another embodiment, R 6 is C ⁇ CH. In yet another embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In still another embodiment, R 6 is CH 2 F. In yet another embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 10 is fluoro.
  • R 6 is methyl.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 10 is fluoro.
  • R 6 is C ⁇ CH.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 10 is fluoro.
  • R 6 is CH 2 F.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In still another embodiment, R 6 is methyl. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In still another embodiment, R 6 is C ⁇ CH. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In still another embodiment, R 6 is CH 2 F. In yet another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In still another embodiment, R 6 is CH 3 . In yet another embodiment, R 7 is chloro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In still another embodiment, R 6 is fluoro. In yet another embodiment, R 7 is H. In an still further embodiment, R 10 is H.
  • the disclosure relates to compounds of one of the following formulae:
  • A is O or S
  • A’ is OH, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • Y is CH, N, or CR 2 ;
  • Z is CH, N, or CR 2 ;
  • R 3 , R 4 , R 6 , R 7 and R 10 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 2 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 .
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the disclosure relates to a compound of the following formula:
  • X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • R 2 , R 3 , R 4 , R 8 and R 9 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 8 and R 9 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 1 is one of the formula:
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Y 2 is OH, OR”, SR”, NHR”, NR” 2 , or BH - +
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl,
  • each R 6 is optionally substituted with one or more, the same or different, R 10 .
  • R 8 and R 9 with the carbon atom they are attached to, form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 10 .
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • R 2 , R 3 , R 4 , R 8 and R 9 are each independently selected from H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , CH 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • the disclosure relates to a compound of the following
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • R 1 is one of the formula:
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Y 2 is OH, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 2 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • W is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 3 , R 4 , R 7 , R 9 and R 14 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 7 and R 14 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ; and each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
  • R 8 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl,
  • each R 6 is optionally substituted with one or more, the same or different, R 10 .
  • R 7 and R 14 with the carbon atom they are attached to, form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and can be optionally substituted with one or more, the same or different, R 10 .
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • R 5 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is H. In yet another embodiment, R 7 is F and R 14 is H. In a further embodiment,
  • R 1 is , wherein Y is O, Y 1 is phenoxy and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H.
  • R 3 is H.
  • R 4 is H.
  • R 7 is F and R 14 is methyl.
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso- propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In yet another embodiment, R 7 is F and R 14 is trifluoromethyl. In a
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment R 7 is F. In another embodiment, R 14
  • R 1 is trifluoromethyl.
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is F. In another embodiment, R 14
  • R 1 is methyl.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is F and R 14 is ethynyl. In a further embodiment,
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso- propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is F and R 14 is monofluoromethyl. In a
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is H. In another embodiment,
  • R 14 is methyl.
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is H and R 14 is trifluoromethyl. In a
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 7 is hydroxyl.
  • R 14 is trifluoromethyl.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is methyl.
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is methyl.
  • R 1 is , wherein Y is O.
  • the compound is selected from:
  • a compound of the present invention is selected from one or more of the following:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is ethynyl.
  • R 1 is wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is monofluoromethyl. In a further embodiment, R 1 is
  • Y is O
  • Y 1 is phenoxy
  • R 6 is iso-propyl
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is H.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is methyl.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is ethynyl.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is monofluoromethyl. In a further embodiment, R 1 is
  • Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from: In exemplary embodiments, the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from: In exemplary embodiments, the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the disclosure relates to a compound of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • R 1 is one of the formula:
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Y 2 is OH, OR”, SR”, NHR”, NR” 2 , or BH - 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 2 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • W is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 3 , R 4 , R 7 , R 9 and R 14 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 7 and R 14 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
  • R 8 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • 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 heterocyclyl, wherein each R 6 is optionally substituted with one or more, the same or different, R 10 .
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another
  • R 14 is methyl.
  • R 1 is , wherein Y is O, Y 1 is phenoxy, and R 6 is iso-propyl.
  • the compound is selected from:
  • R 5 is H.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 7 is hydroxyl.
  • R 14 is methyl.
  • R 1 is , wherein Y is O and Y 1 is O-aryl.
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • nucleoside conjugated to a phosphorus moiety has the following structure:
  • R 1 is selected from one of the following:
  • R 4 is C 1-22 alkoxy, or C 1-22 alkyl, alkyl, branched alkyl, cycloalkyl, or alkyoxy;
  • R 5 is aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2- 22 alkynyl, or substituted heteroaryl.
  • nucleoside conjugated to a phosphorus moiety or pharmaceutically acceptable salt thereof has the following structure:
  • R 1 of Formula Im or In is selected from one of the following:
  • R 2 is alkyl, branched alkyl, or cycloalkyl
  • R 3 is aryl, biaryl, or substituted aryl
  • R 4 is C 1-22 alkoxy, or C 1-22 alkyl, alkyl, branched alkyl, cycloalkyl, or alkyoxy;
  • R 5 is aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2- 22 alkynyl, or substituted heteroaryl.
  • R 1 of Formula Im or In is selected from one of the following:
  • Lipid is as described herein;
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Y 2 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • R 5 is alkyl, branched alkyl, or cycloalkyl;
  • Aryl is as described herein;
  • R 6 is C 1-22 alkoxy, or C 1-22 alkyl, alkyl, branched alkyl, cycloalkyl, or alkyoxy;
  • R 7 is aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2- 22 alkynyl, or substituted heteroaryl.
  • nucleoside conjugated to a phosphorus moiety or pharmaceutically acceptable salt thereof has the following structure:
  • R 2 is selected from C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl;
  • R 6 is lipid, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, pivaloyloxymethyl,
  • R 4 is C 1-22 alkoxy, or C 1-22 alkyl, alkyl, branched alkyl, cycloalkyl, or alkyoxy.
  • the disclosure relates to a compound of the following formula:
  • X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 2 , R 3 , R 4 , R 8 and R 9 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 8 and R 9 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 1 is one of the formula:
  • Y is O or S
  • Y 1 is OH, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; and
  • Lipid is as described herein.
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • the disclosure relates to a compound of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • E is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 1 is one of the formula:
  • Y is O or S;
  • Y 1 is OH, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Lipid is as described herein;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 2 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • W is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 8 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 , R 4 , R 6 , R 7 and R 14 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 7 and R 14 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • the lipid is a sphingolipid having the formula:
  • R 10 of the sphingolipid 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 is 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; or
  • 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 is 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 of the sphingolipid is hydrogen, a branched or strait chain C 13-22 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 of the sphingolipid 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, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethy
  • ethoxycarbonyl N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
  • R 12 of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n- butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl,1-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 of the sphingolipid 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 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 of the sphingolipid is hydrogen, a branched or strait chain C 1-12 alkyl, C 13-22 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 ;
  • R 13 of the sphingolipid 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, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethy
  • ethoxycarbonyl N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
  • R 12 of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n- butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl,1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C 12 -C 19 long chain alkyl.
  • R 5 is H. In another embodiment, R 4 is hydroxyl. In still another embodiment, R 7 is hydroxyl. In yet another embodiment, R 14 is methyl. In a further embodiment,
  • R 3 is hydrogen.
  • R 1 is , wherein Y is O, Y 1 is–OH and lipid is a sphingolipid.
  • E is CH 2 .
  • the compound is selected from:
  • R 5 is H. In another embodiment, R 4 is hydroxyl. In still another embodiment, R 7 is hydroxyl. In yet another embodiment, R 14 is methyl. In a further embodiment,
  • R 3 is hydrogen.
  • R 1 is , wherein Y is O, Y 1 is–OH and lipid is a sphingolipid.
  • E is CD 2 .
  • the compound is selected from:
  • the disclosure relates to a compound of the following formula:
  • X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • R 1 is hydroxyl
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • R 2 , R 3 , R 4 , R 8 and R 9 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • R 8 and R 9 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • R 8 and R 9 are selected from H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl and cyano.
  • the disclosure relates to compounds of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • one of X is S or R 1 is SR 8 , or both X is S and R 1 is SR 8 ;
  • Y is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 7 and R 14 are each independently selected from are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • R 7 and R1 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ;
  • each R 8 is independently selected from deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ; each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • R 5 is H. In other embodiments, R 7 is F and R 14 is H. In exemplary embodiments, the compound is selected from:
  • R 5 is H.
  • R 7 is F and R 14 is methyl.
  • the compound is selected from:
  • the disclosure relates to compounds of the following formula:
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • the disclosure relates to compounds of one of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • Y is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 8 is independently selected from deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In a still further embodiment, R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In a still further embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C ⁇ CH. In a still further embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of: . In one embodiment, R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 F. In a still further another embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In a still further embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In a still further embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In a still further embodiment, R 7 is fluoro. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C ⁇ CH. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is CH 2 F.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In a still further embodiment, R 7 is H. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is trifluoromethyl.
  • R 7 is H.
  • the compound is selected from the group consisting of:
  • R 2 is N 3 .
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is C ⁇ CH.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is CH 2 F.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is N 3 .
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is C ⁇ CH.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is CH 2 F.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C ⁇ CH. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is H. In another embodiment, R 3 is H. In still another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 F. In a still further embodiment, R 7 is hydroxyl. In exemplary embodiments, the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is methyl.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is C ⁇ CH.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is CH 2 F.
  • R 7 is hydroxyl.
  • the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is methyl.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is C ⁇ CH.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is fluoro.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is CH 2 F.
  • R 7 is fluoro.
  • the compound is selected from the group consisting of:
  • R 2 is H.
  • R 3 is H.
  • R 4 is hydroxyl.
  • R 5 is H.
  • R 6 is fluoro.
  • R 7 is H.
  • the compound is selected from the group consisting of:
  • the disclosure relates to compounds of the following formula:
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ; R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • the disclosure relates to compounds of one of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ; wherein in Formula Ix and Iy, one of X is S or R 1 is SR 8 , or both X is S and R 1 is SR 8 ;
  • Y is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 3 and R 4 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • each R 8 is independently selected from deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compoun is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3 ’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 7 is H, D, N 3 , ethynyl, vinyl, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, CD 3 , hydroxymethyl or cyano;
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or vinyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or vinyl.
  • Z is CD
  • U is S and Z is CH.
  • U is O and Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl;
  • R 3 ’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formula:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3 ’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D,methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N;
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae: or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formuale:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 6 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the followin formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formuale:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • the nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • nucleoside conjugated to a phosphorus moiety is of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following: ;
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • the nucleoside conjugated to a phosphorus moiety is a compound of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3 ’ is aryl, biaryl, or substituted aryl
  • Z is CH, CD, or N
  • R 3 is H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
  • R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
  • R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.
  • Z is CH.
  • the nucleoside conjugated to a phosphorus moiety is a compound of the following formulae:
  • R 1 is H, monophosphate, diphosphate, triphosphate, or selected from one of the following:
  • R 2’ is alkyl, branched alkyl, or cycloalkyl
  • R 3’ is aryl, biaryl, or substituted aryl.
  • R 1 is selected from one of the following:
  • R 4 is alkyl, branched alkyl, cycloalkyl, or alkyoxy
  • R 5 is aryl, heteroaryl, substituted aryl, or substituted heteroaryl.
  • X is methylene (CH 2 ) and R 1 is one of the following:
  • R 12 C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl;
  • Y is O or S;
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” BH - 2, or 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; and
  • Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.
  • X is methylene (CH 2 ) and R 1 is one of the following:
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” - 2, or BH 3 M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; and
  • Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.
  • R 1 is selected from one of the following:
  • Lipid is as described herein;
  • Y is O or S
  • Y 1 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • Y 2 is OH, OAryl, OR”, SR”, NHR”, NR” 2 , or BH - 3M + ;
  • R is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl;
  • R 5 is alkyl, branched alkyl, or cycloalkyl;
  • Aryl is as described herein;
  • R 6 is C 1-22 alkoxy, or C 1-22 alkyl, alkyl, branched alkyl, cycloalkyl, or alkyoxy;
  • R 7 is aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2- 22 alkynyl, or substituted heteroaryl.
  • the present invention relates to a compound of the following formula:
  • E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, cycloalkyl;
  • R 2 , R 3 , R 6 and R 7 are independently selected from are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 11 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 11 ;
  • R 10 is aryl, heteroaryl, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl;
  • R 4 is C 1-22 alkyl, C 1-22 alkoxy, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl;
  • each R 11 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.
  • Y 3 is selected from the group consisting of OH, SR 10 , NHR 10 , and NR 10
  • E is selected from the group consisting of CHMe, CMe 2 , CHF, and CF 2
  • the Q heterocyclyl is selected from pyrimidin-2-one-4- thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5- fluoropyrimidin-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4- dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purin-6-thione, 2-amino-7-deaza- purin-6-thione or 2-amino-7-deaza-7-substituted-purin-6-thione.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • R 2 , R 3 , R 6 and R 7 are independently selected from the group consisting of H, D, CH 3 , CD 3 , CF 3 , CF 2 H, CFH 2 , OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F or I.
  • R 10 is alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl,cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • the disclosure relates to compounds of the following formula:
  • R 1 and R 2 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 8 ;
  • each R 8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • Y is O or S; and R is 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, aryl, or heteroaryl.
  • the disclosure relates to compounds of the formula:
  • R 1 and R 9 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ;
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 2 is H; alkyl, e.g. methyl; C(O)R’; C(O)OR’; or C(O)NHR’;
  • R 3 is H; hydroxyl; fluoro; OR’; OC(O)R’; OC(O)OR’; OC(O)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 or trisubstituted phenyl;
  • R 4 is a C 11-17 long alkyl chain, e.g. wherein n is 8-14 and o is 9-15; or or
  • n 4-10 and o is 5-11;
  • n 6-12;
  • R 5 is H, hydroxyl, fluoro, OR’, OC(O)R’, OC(O)OR’, or OC(O)NHR’.
  • Lipid is Lipid
  • R 6 is H; hydroxyl; fluoro; OR’; OC(O)R’; OC(O)OR’; or OC(O)NHR’
  • R 7 is H; hydroxyl; fluoro; OR’; OC(O)R’; OC(O)OR’; or OC(O)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; R 8 is a C 9-15 alkyl chain, e.g. wherein n is 8-14 or wherein“m+n” is 8-14.
  • the disclosure relates to compounds of the formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • Y is O or S
  • Y 1 is OH, OR 40 , SR 40 , NHR 40 , NR 40
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • W is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 6 , R 7 , and R 9 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different R 8 ; R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 8 ; and
  • each R 8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 40 is aryl, heteroaryl, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl;
  • R 4 is C 1-22 alkyl, C 1-22 alkoxy, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl.
  • U is S and Y and Z are CH.
  • U is O and Y and Z are CH.
  • the compound is selected from:
  • the present invention relates to a compound of the following formula:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • Y 2 is O or S
  • R 2 , R 3 , R 6 and R 7 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 8 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 8 ; and Q is a heterocyclyl comprising two or more nitrogen heteroatoms substituted with at least one thione, thiol or thioether, wherein Q is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl;
  • each R 8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 19 is C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl.
  • U is O and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4-position of said pyrimidine.
  • U is S and Q is a pyrimidine with at least one thione, thiol or thioether at the 2 and/or 4 position of said pyrimidine.
  • R 6 is selected from hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.
  • R 19 is selected from is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • the disclosure relates to compounds of formula:
  • R 6 and R 7 are each independently selected from are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 10 ; R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 10 ; and
  • each R 10 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • 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 12-19 long chain alkyl; cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl.
  • the disclosure relates to a compound of the following formulae:
  • R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl;
  • E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
  • Y is O or S
  • each X is independently O, S, NH, NR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • R 1 is OH, SH, NH 2 , OR 8 , SR 8 , NHR 8 , NHOH, NR 8 OH, NHOR 8 , or NR 8 OR 8 ;
  • W is CH, N, or CR 8 ;
  • Z is CH, N, or CR 8 ;
  • R 6 , R 7 and R 10 are each independently selected from H, D, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, allyl, ethynyl, vinyl, C 1-22 alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • R 6 and R 7 with the carbon atom they are attached to can form a spirocycle containing carbon, oxygen, sulfur, or nitrogen and be optionally substituted with one or more, the same or different, R 9 ;
  • R 8 is deutero, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogentated alkyl, hydroxyl alkyl, acyl, lipid, geranyl, C 1-22 alkyl optionally substituted with one or more, the same or different, R 9 ;
  • each R 9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
  • R 50 is C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl.
  • U is S and W and Z are CH. In other embodiments, U is O and W and Z are CH.
  • R 5 is H. In other embodiments, R 6 is methyl. In still other embodiments, R 7 is hydroxyl. In a preferred embodiment, R 5 is H, R 6 is methyl and R 7 is hydroxyl.
  • R 50 is alkyl, methyl, ethyl, propyl, n-butyl , branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.
  • the compound is selected from:

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Abstract

L'invention concerne des compositions thérapeutiques à base de nucléotides et nucléosides et leurs utilisations pour traiter des maladies infectieuses, des infections virales et le cancer, la base du nucléotide ou nucléoside renfermant au moins un thiol, une thione ou un thioéther.
PCT/US2016/021688 2015-03-10 2016-03-10 Compositions thérapeutiques renfermant des nucléotides et des nucléosides et utilisations associées WO2016145142A1 (fr)

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US9828410B2 (en) 2015-03-06 2017-11-28 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
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US10280192B2 (en) 2011-07-19 2019-05-07 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
US10307434B2 (en) 2009-07-06 2019-06-04 Wave Life Sciences Ltd. Nucleic acid prodrugs and methods of use thereof
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US10428019B2 (en) 2010-09-24 2019-10-01 Wave Life Sciences Ltd. Chiral auxiliaries
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