ALKYNE CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

FIELD

This disclosure relates to alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to nucleosides optionally conjugated to a phosphorus oxide or salts thereof. In certain embodiments, 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. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer.

BACKGROUND

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. However, there is a growing need for new antiviral agents to address the critical issues of resistance and penetration into viral sanctuaries (commonly referred to as privileged compartments). Permeability into privileged compartments may be partially responsible for the current inability of chemotherapy to totally clear a patient of HIV infection and the emergence of resistance.

Anti-viral agents that are unphosphorylated nucleotides and nucleotide derivatives need to be phosphorylated to actively inhibit viral replication. Nucleoside analogues enter a cell via two types of broad-specificity transporters, concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). Once inside, they utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinases (dNKs), deoxynucleoside monophosphate kinases (dNMPKs) and nucleoside diphosphate kinase (NDPK). However, intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and/or second phosphorylation, catalyzed by dNKs and dNMPKs, often represent the rate-limiting steps in nucleoside analogue activation. Thus, there is a need to identifying improved antiviral nucleoside analogues with structural features that are sufficiently activated by cellular kinases.

McGuigan et al., J Med Chem, 2005, 48(10), 3504-3515, report phenylmethoxyalaninyl phosphoramidate of abacavir as a prodrug leads to enhancement of antiviral potency. Painter et al., Antimicrob Agents Chemother, 2007, 51(10), 3505-3509, report promoting the oral availability of tenofovir with a hexadecyloxypropyl prodrug ester, designated CMX157.

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. Pat. No. 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. Lett. 2006, 8(4), 649-652, report the synthesis of 1-deoxysphingosine derivatives. Wiseman et al., Org. Lett. 2005, 7(15), 3155-3157, report 1-deoxy-5-hydroxysphingolipids in anticancer and stereoselective syntheses of 2-amino-3,5-diols.

References cited herein are not an admission of prior art.

SUMMARY

This disclosure relates to alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto. Included are 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.

DETAILED DESCRIPTION

In certain embodiments, the disclosure relates to phosphorus oxide prodrugs of 2′-alkyne containing nucleosides for the treatment of positive-sense and negative-sense RNA viral infections through targeting of the virally encoded RNA-dependent RNA polymerase (RdRp). This disclosure also provides the general use of lipids and sphingolipids to deliver nucleoside analogs for the treatment of infectious disease and cancer.

In certain embodiments, the disclosure relates to conjugate compounds or salts thereof comprising a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, 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. In certain embodiments, 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, wherein the substituted heterocycle is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl.

In certain embodiments, the sphingolipid is saturated or unsaturated 2-aminoalkyl or 2-aminooctadecane optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3-ol optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3,5-diol optionally substituted with one or more substituents.

In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising any of the compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer comprising a saccharide. In certain embodiments, 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.

In certain embodiments, 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. Typically, the subject is diagnosed with or at risk of an infection from a virus, bacteria, fungi, protozoa, or parasite.

In certain embodiments, 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. In certain embodiments, the subject is a mammal, for example, a human. In certain embodiments, the subject is diagnosed with a chronic viral infection. In certain embodiments, administration is under conditions such that the viral infection is no longer detected. In certain embodiments, the subject is diagnosed with a RNA virus, DNA virus, or retroviruses. In certain embodiments, 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.

In certain embodiments, the subject is diagnosed with 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), Venezuelan equine encephalitis virus (VEEV), Ross River virus, Barmah Forest virus, yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, ebola virus, marburg virus, 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).

In certain embodiments, the subject is diagnosed with 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, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV), hantavirus, Dengue virus serotypes 1, 2, 3 and 4, West Nile virus, Zika virus, Powassan 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).

In certain embodiments, 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.

In certain embodiments, the pharmaceutical compositions disclosed herein can be administered in combination with a any of U.S. Pat. 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In certain embodiments, pharmaceutical compositions disclosed herein are administered in combination with a second antiviral agent, such as ABT-450, ABT-267, ABT-333, ABT-493, ABT-530, abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, 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, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, the 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, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide, and/or lenalidomide or combinations thereof.

In certain embodiment, 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.

In certain embodiments, the disclosure relates to derivatives of compounds disclosed herein or any of the formula.

Additional advantages of the disclosure will be set forth in part in the description which follows. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

It is to be understood that this disclosure is not limited to the particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

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.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated.

As used herein, the term “phosphorus oxide” refers to any variety of chemical moieties that contain a phosphorus-oxygen (P—O or P═O) bond. When used as linking groups herein, the joined molecules may bond to oxygen or directly to the phosphorus atoms. The term is intended to include, but are not limited to phosphates, in which the phosphorus is typically bonded to four oxygens and phosphonates, in which the phosphorus is typically bonded to one carbon and three oxygens. A “polyphosphate” generally refers to phosphates linked together by at least one phosphorus-oxygen-phosphorus (P—O—P) bond. A “polyphosphonate” refers to a polyphosphate that contains at least one phosphorus-carbon (C—P—O—P) bond. In addition to containing phosphorus-oxygen bond, phosphorus oxides may contain a phosphorus-thiol (P—S or P═S) bond and/or a phosphorus-amine (P—N) bond, respectively referred to as phosphorothioate or phosphoroamidate. In phosphorus oxides, 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.

As used herein, “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. The term includes both substituted and unsubstituted alkyl groups. 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.

The term “lower alkyl,” as used herein, and unless otherwise specified, 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.

The term “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.

As used herein, “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. Representative 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.

As used herein, “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—CH₃).

“Alkoxy” refers to an alkyl group as defined above attached through an oxygen bridge. Examples of 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—CH₃).

“Alkanoyl” refers to an alkyl as defined above attached through a carbonyl bride (i.e., —(C═O)alkyl).

“Alkylsulfonyl” refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., —S(═O)₂alkyl) such as mesyl and the like, and “Arylsulfonyl” refers to an aryl attached through a sulfonyl bridge (i.e., —S(═O)₂aryl).

“Alkylsulfinyl” refers to an alkyl as defined above attached through a sulfinyl bridge (i.e. —S(═O)alkyl).

The term “substituted” refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents.” The molecule may be multiply substituted. In the case of an oxo substituent (“═O”), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NRaRb, —NRaC(═O)Rb, —NRaC(═O)NRaNRb, —NRaC(═O)ORb, —NRaSO₂Rb, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —OC(═O)NRaRb, —ORa, —SRa, —SORa, —S(═O)₂Ra, —OS(═O)₂Ra and —S(═O)₂ORa. 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.

The term “optionally substituted,” as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.

As used herein, “salts” refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of 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. In typical embodiments, the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

“Subject” refers any animal, preferably a human patient, livestock, rodent, monkey or domestic pet.

The term “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.

As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted with one or more substituents, a salt, in different hydration/oxidation states, e.g., substituting a single or double bond, substituting a hydroxy group for a ketone, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom or replacing an amino group with a hydroxyl group or vice versa. Replacing a carbon with nitrogen in an aromatic ring is a contemplated derivative. The derivative may be a prodrug. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in the chemical literature or as in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.

As used herein, 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.

As used herein, 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.

As used herein, 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 Analogues as Antiviral Agents

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). However, intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and/or second phosphorylation, catalyzed by dNKs and dNMPKs, often represent the rate-limiting steps in nucleoside analog activation. These significant blockades in the phosphorylation cascade of a given nucleoside analog will result in the lack of any observable activity in cellular assays. To circumvent these blockades, several kinase bypass strategies have been developed. For example, 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).

An alternative prodrug strategy to circumvent these blockades is to utilize sphingoid bases to mask nucleotide analog phosphates. 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. 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). The 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.

Compounds

In certain embodiments, the disclosure relates to nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R is OH, F, Cl, or NH₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;
R is OH, F, Cl, or NH₂;
W is N or CR⁷;
Z is N or CR⁸;
R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;
R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;
R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;
R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;
R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;
R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;
R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R is OH, F, Cl, or NH₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

embedded image

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

embedded image

or pharmaceutically acceptable salts thereof wherein,

X is OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

embedded image

or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

embedded image

or pharmaceutically acceptable salts thereof wherein,

W is N or CR;

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

embedded image

or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

embedded image

Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from one of the following formulae:

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Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;
Y³is OH, OAlkyl, or BH₃⁻M⁺;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;
R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;
R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;
R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe;

W is N or CR⁷;

Z is N or CR⁸;

Q is N or CR⁹;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁹is D, hydroxyl, thiol, amino, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe;

R¹is selected from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22or alkoxy, C_1-2alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano. In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe or OCH₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, halkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, thiol, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂or OCHMe;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

Z is N or CR⁸;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano. In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

W is N or CR⁷;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁷is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂, OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R²is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCHMe, OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCMe₂, OCHF, OCF₂, or OCD₂;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

In certain embodiments, the present invention relates to compounds of the following formula:

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or pharmaceutically acceptable salts thereof wherein,

X is OCH₂or OCHMe;

R¹is selected from H or from one of the following formulae:

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Y is O or S;

Y¹is OH, OAryl, OAlkyl, or BH₃⁻M⁺;

Y²is OH or BH₃⁻M⁺;

Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

R⁴is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

R⁵is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C_1-22alkoxy, C_1-22alkyl, C_2-22alkenyl, C_2-22alkynyl, or substituted heteroaryl;

R⁶is methyl, ethyl, tert-butyl, C_1-22alkoxy, C_1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy;

R⁸is H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, substituted amino, or cyano.