Alkyn-containing nucleotides and nucleoside therapeutic compositions and related uses thereof

Abstract

The present disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in the treatment of infectious diseases, viral infections, and cancer, wherein the base of the nucleotide or nucleoside contains at least one thiol, thione, or thioether.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to acetylenic-containing nucleotide and nucleoside therapeutic compositions and their related uses. In certain embodiments, the present disclosure relates to nucleosides optionally conjugated to phosphine oxides or salts thereof. In certain embodiments, the present disclosure relates to conjugate compounds or salts thereof comprising amino acid esters, lipids, or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphine oxides. In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising these compounds for the treatment of infectious diseases, viral infections, and cancer. BACKGROUND

[0002] 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 infection. The combined administration of three or more antiretroviral agents, such as highly active antiretroviral therapy (HAART), has significantly reduced morbidity and mortality associated with HIV infection. However, there is an increasing need for new antiviral agents to address the key issues of resistance and penetration into the viral sanctuary, often referred to as the special compartment. Penetrability of the special compartment can be a partial cause of the inability of current chemotherapy to completely clear HIV infected patients and the emergence of resistance.

[0003] There is a need to phosphorylate antiviral agents that are unphosphorylated nucleotides and nucleotide derivatives to actively inhibit viral replication. Nucleoside analogs enter cells through two types of broad-specificity transporters, the concentrative nucleoside transporter (CNT) and the equilibrative nucleoside transporter (ENT). Once inside, they utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinase (dNK), deoxynucleoside monophosphate kinase (dNMPK), and nucleoside diphosphate kinase (NDPK). However, intracellular activation of these compounds is often affected by the high substrate specificity of host endogenous kinases. In vitro and in vivo studies have demonstrated that the first and / or second phosphorylation catalyzed by dNK and dNMPK often represents the rate-limiting step in the activation of nucleoside analogs. Thus, there is a need to identify improved antiviral nucleoside analogs with structural features that are sufficiently activated by cellular kinases.

[0004] McGuigan et al., J Med Chem, 2005, vol. 48, no. 10, pp. 3504-3515, reported that phenylmethoxyalaninyl phosphoramidate of abacavir as a prodrug resulted in enhanced antiviral potency. Painter et al., Antimicrob Agents Chemother, 2007, vol. 51, no. 10, pp. 3505-3509, reported that oral availability of tenofovir was facilitated with a hexadecyloxypropyl prodrug ester, termed CMX157.

[0005] Sphingolipids play a role in cell-cell and cell-matrix interactions and help regulate growth and differentiation through various mechanisms, such as inhibiting growth factor receptor kinases and influencing many cellular signal transduction systems. US Patent 6,610,835 discloses sphingosine analogues. Methods for treating infections and cancer are also disclosed. Pruett et al., J. Lipid Res., 2008, Vol. 49, No. 8, pp. 1621-1639, reported on sphingosine and its derivatives. Bushnev et al., ARKIVOC, 2010, No. viii, pp. 263-277, reported an asymmetric synthetic method for preparing sphingolipid derivatives. Dougherty et al., Org. Lett., 2006, Vol. 8, No. 4, pp. 649-652, reported the synthesis of 1-deoxysphingosine derivatives. Wiseman et al., Org. Lett. 2005, Vol. 7, No. 15, pp. 3155-3157, reported the role of 1-deoxy-5-hydroxysphingolipids in anticancer activity and the stereoselective synthesis of 2-amino-3,5-diol.

[0006] The references cited in this article are not an endorsement of existing technology. Summary of the Invention

[0007] This disclosure relates to therapeutic compositions of nucleotides and nucleosides containing alkynes and their related uses. These include nucleosides, prodrugs, or conjugates or salts thereof optionally conjugated to phosphorus oxides or their salts, comprising amino acid esters, lipids, or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphorus oxides. Detailed Implementation

[0008] This disclosure relates to therapeutic compositions of nucleotides and nucleosides containing alkynes and their related uses. In some embodiments, this disclosure relates to nucleosides optionally conjugated to phosphorus oxides or salts thereof. In some embodiments, this disclosure relates to coupling compounds or salts thereof comprising amino acid esters, lipids, or sphingolipids or derivatives of nucleotides or nucleosides linked to phosphorus oxides. In some embodiments, this disclosure contemplates pharmaceutical compositions comprising these compounds for treating infectious diseases, viral infections, and cancer.

[0009] In some embodiments, this disclosure relates to a 2'-alkyne phosphorus oxide prodrug comprising a nucleoside that treats positive and negative sense RNA virus infections by targeting a virus-encoded RNA-dependent RNA polymerase (RdRp). This disclosure also provides general uses in lipids and sphingolipids to provide nucleoside analogs for the treatment of infectious diseases and cancer.

[0010] In certain embodiments, the disclosure relates to a conjugate compound or salt thereof comprising a sphingolipid or derivative linked to a nucleotide or nucleoside by a phosphine oxide. In certain embodiments, the phosphine oxide is a phosphonate, phosphinate, polyphosphonate, or polyphosphinate, wherein the phosphonate in the phosphonate, phosphinate, or polyphosphonate or polyphosphinate is optionally a phosphorothioate or phosphoramidate. In certain embodiments, the lipid or sphingolipid is covalently bound to the phosphine oxide through an amino or hydroxyl group.

[0011] The nucleotide or nucleoside comprises a heterocycle having two or more nitrogen heteroatoms, wherein the substituted heterocycle is optionally substituted with one or more alkyl, halogen, or cycloalkyl groups, which are the same or different.

[0012] In certain embodiments, the sphingolipid is a saturated or unsaturated 2- aminoalkyl or 2-aminooctadecane optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2- aminooctadecane-3-ol optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2- aminooctadecane-3,5-diol optionally substituted with one or more substituents.

[0013] In certain embodiments, the disclosure contemplates a pharmaceutical composition 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 sugar. In certain embodiments, the composition can comprise a second active agent such as an analgesic, anti-inflammatory agent, non-steroidal anti-inflammatory agent, antiviral agent, antibiotic, or anticancer agent.

[0014] In certain embodiments, the disclosure relates to a method of treating or preventing an infection comprising administering to a subject in need thereof an effective amount of a compound disclosed herein. Typically, the subject is diagnosed with or at risk of infection with a virus, bacteria, fungus, protozoan, or parasite.

[0015] In certain embodiments, the disclosure relates to a method of treating a viral infection comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein. 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, the administration is under conditions such that the viral infection is no longer detectable. In certain embodiments, the subject is diagnosed with an RNA virus, DNA virus, or retrovirus. In certain embodiments, the subject is diagnosed with a virus that is a double-stranded DNA virus, positive-sense single-stranded DNA virus, double-stranded RNA virus, positive-sense single-stranded RNA virus, negative-sense single-stranded RNA virus, positive-sense single-stranded RNA retrovirus, or double-stranded DNA retrovirus.

[0016] In certain embodiments, the subject is diagnosed with a type A influenza virus including subtypes H1N1, H3N2, H7N9, or H5N1, a type B influenza virus, a type C influenza virus, a rotavirus A, a rotavirus B, a rotavirus C, a rotavirus D, a rotavirus E, a human coronavirus, a SARS coronavirus, a MERS coronavirus, a human adenovirus types (HAdV-1 through 55), a type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 human papillomavirus (HPV), a parvovirus B19, a molluscum contagiosum virus, a JC virus (JCV), a BK virus, a Merkel cell polyomavirus, a coxsackie A virus, a norovirus, a rubella virus, a lymphocytic choriomeningitis virus (LCMV), a dengue virus, a chikungunya virus, an Eastern equine encephalitis virus (EEEV), a Western equine encephalitis virus (WEEV), a Venezuelan equine encephalitis virus (VEEV), a Ross River virus, a

[0017] In certain embodiments, the subject is diagnosed with influenza A virus including subtypes H1N1, H3N2, H7N9, or H5N1 (low pathogenicity), influenza B virus H5N1 (high pathogenicity), influenza C virus, Rotavirus A, Rotavirus B, Rotavirus C, Rotavirus D, Rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 through 55), types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 human papillomavirus (HPV), 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 virus, 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, Taccaribe virus, Junin virus, 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 sarcoma-associated herpesvirus, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, or Human Immunodeficiency Virus (HIV).

[0018] In certain embodiments, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immunodeficiency syndrome, or hepatitis.

[0019] In certain embodiments, the pharmaceutical compositions disclosed herein can be administered in combination with any of the following patents: US8466159; US8492386; US6056961, US6143752, US6403564, US6475985, US6689814, US6849254, US6936629, US6995174, US7012066, US7105499, US7125855, US7153848, US7202224, US7205330, US7244721, US7348425, US7423058, US7429572, US7470664, US7491794, US7514557, US7585845, US7592316, US7601820, US7608600, US7648998, US7728027, US7754699, US7772178, US7777395, US7793040, US7820671, US7893264, US7906619, US7910728, US7915291, US7939667, US7951787, US7951789, US7964580, US7973040, US8017771, US8067438, US8080654, US8088368, US8101765, US8106187, US8119602, US8148399, US8178491, US8216999, US8252923, US8466159, US8492386, US20020022015, US20020119122, US20020183690, US20030004119, US20030032590, US20030044824, US20030109697, US20030138403, US20030187000, US20030199518, US20040198840, US20040202641, US20050085528, US20050123628, US20050187170, US20050245502, US20050249702, US20050288245, US20060083785, US20060100148, US20060105063, US20060142238, US20060228333, US20060229293, US20060275366, US20060276404, US20060276406, US20060276407,US20060281689, US20060287248, US20060293267, US20070004635, US20070021351, US20070092512, US20070105781, US20070207949, US20070224167, US20070232527, US20070237818, US20070274951, US20070287664, US20080004236, US20080019950, US20080050336, US20080070861, US20080081791, US20080161232, US20080261906, US20080269205, US20080275005, US20080275141, US20090017457, US20090028824, US20090041716, US20090047245, US20090053263, US20090076100, US20090082366, US20090082414, US20090098123, US20090105471, US20090156545, US20090202476, US20090234102, US20090286843, US20090297518, US20090298916, US20100009970, US20100028301, US20100034839, US20100041617, US20100055055, US20100056770, US20100068182, US20100081672, US20100093792, US20100099695, US20100158866, US20100166661, US20100216725, US20100221217, US20100226885, US20100233122, US20100234585, US20100254942, US20100256217, US20100272682, US20100286083, US20100291034, US20100297080, US20100298257, US20100310512, US20100316594, US20100317568, US20100330173, US20110020272, US20110038833, US20110045001, US20110117055,US20110117057, US20110160149, US20110200582, US20110245484, US20110250176, US20110251152, US20110257122, US20110268697, US20110306541, US20110311482, US20110312973, US20110319323, US20120009148, US20120010170, US20120052046, US20120058084, US20120059033, US20120071434, US20120101049, US20120107278, US20120135949, US20120157404, US20120171157, US20120196272, US20120196794, US20120232247, US20130102526, US20130102557, US20130137084, US20130164261, USRE40525, USRE43298, CA2518115C, DE102005038768A1, EP1627641A1, EP1646639A2, EP1827450A2, EP1970372B1, JP2000212099A, KR20010068676A, MD2549F1, MD3477F1, MD20060037A, MXPA05012606A, RO118842B, RU2158604C2, RU2212248C1, RU2293572C1, RU2306134C2, RU2306934C1, RU2336096C1, RU2345787C2, RU2348412C1, RU2373952C1, RU2398582C1, RU2400229C1, RU2424794C1, RU2429877C1, UA64191A, UA68233A, WO1991009605A1, WO1994001125A1, WO1996018419A1, WO1996029336A1, WO1996036351A1, WO1997027866A1, WO1997033565A1, WO1998014181A1, WO1998019670A2, WO1998048621A1, WO1998049281A1, WO1999015194A1, WO1999018993A1, WO1999029321A1, WO1999030721A1,WO2000001715A1, WO2000023454A1, WO2000037097A1, WO2000037110A2, WO2000047240A1, WO2000061161A2, WO2001007454A1, WO2001012214A2, WO2001077091A2, WO2001079540A2, WO2002003886A1, WO2002010743A1, WO2002018369A2, WO2002030259A2, WO2002030455A2, WO2002032414A2, WO2002053096A2, WO2002055100A2, WO2002079234A1, WO2002089731A2, WO2002091989A2, WO2003002152A2, WO2003007981A1, WO2003024461A1, WO2003028754A1, WO2003028755A1, WO2003030923A1, WO2003037312A2, WO2003037908A1, WO2003040104A1, WO2003042377A1, WO2003049760A1, WO2003072135A2, WO2003101199A1, WO2003101478A1, WO2004019934A1, WO2004039996A1, WO2004043435A2, WO2004047673A2, WO2004073599A2, WO2004078127A2, WO2004078191A1, WO2004078194A1, WO2004094452A2, WO2004103396A1, WO2004112720A2, WO2005000308A2, WO2005010143A2, WO2005012327A2, WO2005016288A2, WO2005018330A1, WO2005023289A1, WO2005025583A2, WO2005037214A2, WO2005037274A1, WO2005038056A1, WO2005040816A1, WO2005042020A2, WO2005043118A2, WO2005062949A2, WO2005063281A2, WO2005067454A2, WO2005067963A1, WO2005102353A1, WO2005108418A1, WO2005123076A2,WO2006005610A1, WO2006016930A2, WO2006038088A1, WO2006039488A2, WO2006043153A2, WO2006046039A2, WO2006050250A2, WO2006063149A1, WO2006064026A1, WO2006067606A1, WO2006072347A2, WO2006084141A2, WO2006085747A1, WO2006089113A2, WO2006096285A2, WO2006110656A2, WO2006113937A2, WO2006119646A1, WO2006127289A1, WO2006127482A1, WO2006127757A2, WO2006130532A2, WO2006130626A2, WO2006130686A2, WO2006133092A1, WO2007021494A2, WO2007022459A2, WO2007049265A2, WO2007056016A2, WO2007058384A1, WO2007059221A2, WO2007062272A1, WO2007064691A1, WO2007075896A2, WO2007081974A2, WO2007098270A2, WO2007109080A2, WO2007109604A2, WO2007109605A2, WO2007111866A2, WO2007112028A2, WO2007138116A2, WO2007143164A1, WO2007146712A2, WO2007149382A2, WO2008005511A2, WO2008008502A1, WO2008017692A2, WO2008022006A2, WO2008024763A2, WO2008024843A2, WO2008033413A2, WO2008033466A2, WO2008039179A1, WO2008058393A1, WO2008063727A2, WO2008086161A1, WO2008089034A2, WO2008091763A1, WO2008092954A2, WO2008106151A2, WO2008106167A1, WO2008116194A2, WO2008118013A2, WO2008121634A3, WO2008124384A2,WO2008137126A2, WO2008137779A2, WO2008141227A1, WO2008143647A2, WO2008144072A1, WO2008153610A2, WO2009009951A1, WO2009015336A2, WO2009026292A1, WO2009032198A1, WO2009033183A2, WO2009038663A1, WO2009039127A1, WO2009039134A1, WO2009039248A2, WO2009043176A1, WO2009046369A2, WO2009061395A2, WO2009062737A1, WO2009082701A1, WO2009085267A1, WO2009085659A1, WO2009131696A1, WO2009134616A2, WO2009138146A2, WO2009149179A2, WO2009149377A1, WO2009150194A1, WO2009152589A1, WO2010017178A1, WO2010017432A1, WO2010020676A1, WO2010021681A2, WO2010024384A1, WO2010025380A2, WO2010027921A1, WO2010030359A2, WO2010031832A2, WO2010033443A1, WO2010034670A2, WO2010036799A1, WO2010038796A1, WO2010039801A2, WO2010042683A1, WO2010045266A1, WO2010049438A2, WO2010053942A1, WO2010076323A1, WO2010081082A2, WO2010093843A2, WO2010099458A1, WO2010101649A2, WO2010122538A1, WO2010132601A1, WO2010151472A1, WO2010151487A1, WO2010151488A1, WO2011009961A1, WO2011013019A1, WO2011014882A1, WO2011038224A1, WO2011041551A1, WO2011046811A1, WO2011053617A1, WO2011056630A2, WO2011056650A2,WO2011066082A2, WO2011066260A2, WO2011072370A1, WO2011079016A1, WO2011094489A1, WO2011112558A2, WO2011156578A1, WO2011156757A1, WO2012009503A1, WO2012015712A1, WO2012016995A1, WO2012018829A1, WO2012041771A1, WO2012050850A1, WO2012087596A1, WO2012139028A2, WO2012175733A1, WO2013000855A1, WO2013000856A1, WO2013024155A1, WO2013024158A1, WO2013025975A1, WO2013028953A1, WO2013040492A2, WO2013066753A1, US8680106, US8685984, US8809265, US8853176, US8889159, US8969357, US8993578, US20140080868US20140080886, US20150174194, WO2014152514A1, or WO2014152635A1.

[0020] In certain embodiments, the 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, daclatasvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonoformic acid, ganciclovir, ibacitabine, iminosine, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oblimersen, oseltamivir, ombitasvir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, tipranavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, virox, zalcitabine, zanamivir, or zidovudine, and combinations thereof.

[0021] In certain embodiments, the present disclosure relates to a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein. In certain embodiments, the cancer is selected from bladder cancer, lung cancer, breast cancer, melanoma, colon and rectum cancer, non-Hodgkin lymphoma, endometrial cancer, pancreatic cancer, kidney cancer, prostate cancer, leukemia, thyroid cancer, and brain cancer.

[0022] In certain embodiments, the composition is administered in combination with a second anti-cancer agent, such as temozolomide, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, docetaxel, cisplatin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin and plicamycin, vinblastine, vindesine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprolide, buserelin, megestrol, anastrozole, letrozole, vorozole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide, and / or lenalidomide, or combinations thereof.

[0023] In certain embodiments, the present disclosure relates to the use of a compound disclosed herein in the preparation or manufacture of a medicament for the treatment or prevention of an infectious disease, a viral infection, or a cancer.

[0024] In certain embodiments, the present disclosure relates to a derivative of a compound disclosed herein or any of the following formulae.

[0025] Additional advantages of the disclosure will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification or can be learned from practice of the disclosure. It is 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.

[0026] It is to be understood that the present disclosure is not limited to the particular implementations described. Also, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0027] 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 be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0028] 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 of this application. However, nothing herein is to 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 can be different from the dates that can be found, for example, an independent verification of the publication date should be made for any publication cited.

[0029] As will be apparent to those of ordinary skill in the art in the light of the present disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can 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.

[0030] The embodiments of the disclosure will employ, unless otherwise indicated herein, techniques of pharmacology, 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.

[0031] Note 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 the specification and the appended claims, reference will be made to a number of terms that shall have the following meanings unless a clearly different intent is apparent from the immediate context.

[0032] Before the various embodiments are described in detail, the following definitions are provided and should be used unless otherwise indicated.

[0033] As used herein, the term "phosphine oxide" refers to any species of chemical moiety containing a phosphorus-oxygen (P-O or P=O) bond. When used herein as a linking group, the molecule being linked can be bonded to the oxygen or directly to the phosphorus atom. The term is intended to include, but is 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. "Polyphosphates" refer generally to phosphates linked together by at least one phosphorus-oxygen-phosphorus (P-O-P) bond. "Polyphosphonates" refer to polyphosphates comprising at least one phosphorus-carbon (C-P-O-P) bond. In addition to containing phosphorus-oxygen bonds, phosphine oxides can also comprise phosphorus-thiol (P-S or P=S) bonds and / or phosphorus-amine (P-N) bonds, referred to as thiophosphates or phosphoramidates, respectively. In phosphine oxides, the oxygen atoms can form double or single bonds or combinations with the phosphorus, and the oxygens can be further bonded to other atoms such as carbon, or can exist as anions in equilibrium with cations (e.g., metal or quaternary ammonium).

[0034] As used herein, "alkyl" refers to acyclic, cyclic, straight-chain or branched, unsaturated or saturated hydrocarbons, such as those containing 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, deuterium, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, or any other available functional group that is unprotected or protected, as necessary, so as not to inhibit the pharmacological activity of the compound, as known to those of skill in the art, for example, as taught in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd edition, John Wiley & Sons, 1999, which is hereby incorporated by reference.

[0035] As used herein, and unless otherwise indicated, the term "lower alkyl" refers to C1to C4saturated straight-chain, branched, or, if appropriate, cyclic (e.g., cyclopropyl) alkyl groups, including both substituted and unsubstituted versions. Unless specifically stated otherwise in the application, lower alkyl is preferred when alkyl is an appropriate moiety.

[0036] As used herein, the term "halo" or "halogen" includes chloro, bromo, iodo, and fluoro.

[0037] Non-aromatic mono- or polycyclic alkyl groups are referred to herein as "carbocyclic" or "carbocyclyl" groups containing 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.

[0038] "Heterocarbocyclic" or "heterocarbocyclyl" is a carbocycle containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which can be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0039] "Aryl" means an aromatic carbocyclic ring, either single or multiple ring, containing 6 to 32 carbon atoms, such as phenyl or naphthyl. The ring system of a multiple ring can, but is not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.

[0040] "Heteroaryl" as used herein means an aromatic heterocarbocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom, including both single and multiple ring ring systems. The ring system of a multiple ring can, but is not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzoimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is contemplated to include N-alkylated derivatives, such as 1 -methylimidazol-5-yl substituents.

[0041] "Heterocycle" or "heterocyclyl" as used herein means a single and multiple ring ring system having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom. The single and multiple ring ring systems can be aromatic, non-aromatic, or a mixture of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.

[0042] "Alkylthio" means an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio group is methylthio, (i.e., -S-CH3).

[0043] "Alkoxy" means an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, and sec-pentyloxy. Preferred alkoxy groups are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, and t-butyloxy.

[0044] "Alkylamino" means an alkyl group as defined above attached through an amino bridge. An example of an alkylamino group is methylamino, (i.e., -NH-CH3).

[0045] "Alkanoyl" means an alkyl group as defined above attached through a carbonyl bridge, (i.e., -(C=0)alkyl).

[0046] "Alkylsulfonyl" means an alkyl group as defined above attached through a sulfonyl bridge, (i.e., -S(=0)2alkyl) such as methylsulfonyl and the like, and "arylsulfonyl" means an aryl group attached through a sulfonyl bridge, (i.e., -S(=0)2aryl).

[0047] "Aryloxy" means an aryl group, as previously defined, appended to the parent molecular moiety through an oxy (i.e., -O-) bridge.

[0048] The term "substituted" means a molecule in which at least one hydrogen atom is replaced with a substituent group. When substituted, one or more of the groups are "substituents." The molecule can be multiply substituted. In the case of an oxo substituent ("=0"), two hydrogen atoms are replaced. Exemplary substituents in this context can include halogen, hydroxyl, alkyl, alkoxy, nitro, cyano, oxygen, carbocyclyl, carbocyclylalkyl, heterocarbocyclyl, heterocarbocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=0)Rb, -NRaC(=0)NRaNRb, -NRaC(=0)ORb, -NRaS02Rb, -C(=0)Ra, -C(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -ORa, -SRa, -SORa, -S(=0)2Ra, -OS(=0)2Ra, and -S(=0)2ORa. In this context, Raand Rbcan be the same or different and independently hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocyclylalkyl, heterocarbocyclyl, heterocarbocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

[0049] As used herein, the term "optionally substituted" means that substitution is optional and thus the designated atom has the possibility of being unsubstituted.

[0050] As used herein, "salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by 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, alkyl amines, dialkyl amines; 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 the nontoxic 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.

[0051] "Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey, or household pet.

[0052] 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 can be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The solubility of a prodrug in a pharmaceutical composition can also be enhanced compared to the parent drug. A prodrug can be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

[0053] The term "derivative" as used herein refers to a structurally similar compound that retains sufficient functional properties of the identified analog. The derivative can be structurally similar because it lacks one or more atoms, is substituted with one or more substituents, is a salt, is in a different state of hydration / oxidation, e.g., a ketone is substituted with a hydroxyl, or because one or more atoms within the molecule are replaced, such as but not limited to, an oxygen atom is replaced with a sulfur or nitrogen atom or an amino group is replaced with a hydroxyl, or vice versa. Substitution of a carbon with a nitrogen in an aromatic ring results in the intended derivative. The derivative can be a prodrug. Derivatives can be prepared by various synthetic methods set forth in the chemical literature or appropriate adaptations in synthetic or organic chemistry textbooks, such as those provided in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Wiley, 6thedition (2007) Michael B. Smith or "Domino Reactions in Organic Synthesis", Wiley (2006) Lutz F. Tietze, which are hereby incorporated by reference.

[0054] The terms "prevent" and "preventing" as used herein include the total or partial inhibition of recurrence, spread, or onset of the referenced pathological condition or disease. The disclosure is not intended to be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

[0055] The terms "treat" and "treating" as used herein are not limited to situations in which the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments of the disclosure also contemplate treatment that merely reduces symptoms and / or delays disease progression.

[0056] The term "in combination with" as used herein when used to describe administration with an additional therapeutic agent means that the agent can be administered prior to, concurrently with, or after the additional therapeutic agent or a combination thereof.

[0057] Nucleoside analogs as antiviral agents

[0058] Nucleoside analogs utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinase (dNK), deoxynucleoside monophosphate kinase (dNMPK), and nucleoside diphosphate kinase (NDPK). However, intracellular activation of these compounds is often affected by the high substrate specificity of host endogenous kinases. In vitro and in vivo studies have demonstrated that the first and / or second phosphorylation catalyzed by dNK and dNMPK often represents the rate-limiting step in nucleoside analog activation. These significant bottlenecks in the phosphorylation cascade of a given nucleoside analog will result in a lack of any observable activity in cellular assays. To circumvent these bottlenecks, several kinase bypass strategies have been developed. For example, McGuigan phosphoramidates are chemical conjugates for kinase bypass. See Serpi et al., J Med Chem, 2012, 55(10):4629-4639. Metabolism of these prodrugs begins with esterase-catalyzed cleavage of the carboxylate ester, followed by several chemical rearrangement steps, yielding an amino acid phosphoramidate. The final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified as histidine triad nucleotide-binding protein 1 (hINT1).

[0059] Another prodrug strategy to circumvent these bottlenecks is to utilize sphingolipid bases to mask nucleotide analog phosphate esters. Sphingolipid bases have the potential to be used to deliver nucleotide analog phosphate esters to critical tissues such as the brain. The design concept that motivated the use of sphingolipid bases to form nucleoside-lipid conjugates was based on the observation that sphingolipid base analogs: (a) are well absorbed after oral administration, (b) are resistant to oxidative catabolism in the intestinal epithelium, and (c) achieve high concentrations in the brain. Based on intestinal absorption data for traditional phospholipid drug conjugates in mice and our rat sphingolipid base oral absorption data, our sphingolipid base conjugates should be well absorbed and resistant to first-pass metabolism. After absorption, sphingolipid bases, including sphingosine-1 -phosphate, are transported in the blood by lipoproteins and free plasma proteins such as albumin. It has been demonstrated that sphingolipid phosphate esters are taken up by actively living epithelial cells via the ABC transporter CFTR, but can also be passive protein transport and endocytic uptake; it is believed that extracellularly delivered drug conjugates will be similarly processed by target cells in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). The above rat sphingolipid PK study results, 24-hour tissue concentrations that exceed the plasma Cmax concentration by 10- to 300-fold, with particularly high levels in the lung and brain and no evidence of toxicity. This approach has the significant potential to deliver high drug concentrations of conjugates to critical tissues.

[0060] Compound

[0061] In certain embodiments, the disclosure relates to a nucleoside or a pharmaceutically acceptable salt thereof conjugated to a phosphorous moiety.

[0062] In some embodiments, the present invention relates to compounds of the following formula:

[0063]

[0064] Or its pharmaceutically acceptable salt, wherein:

[0065] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0066] R is OH, F, Cl, or NH2;

[0067] W is N or CR 7 ;

[0068] Z is N or CR 8 ;

[0069] R 1 Selected from H or one of the following formulas:

[0070]

[0071]

[0072] Y is either O or S;

[0073] Y 1 It is OH, O-aryl, O-alkyl, or BH3 - M + ;

[0074] Y 2 It is OH or BH3 - M + ;

[0075] The aryl group is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0076] R 2 It can be hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0077] R 4 It can be hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0078] R 5 The groups are hydrogen, deuterium, hydroxyl, cyano, azide, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, and C. 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 alkenyl, C 2-22alkynyl, or substituted heteroaryl;

[0079] R 6 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano; 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0080] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0081] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0082] In certain embodiments, the present application relates to a compound of the formula:

[0083]

[0084] or a pharmaceutically acceptable salt thereof, wherein:

[0085] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0086] R is OH, F, Cl, or NH2;

[0087] W is N or CR 7 ;

[0088] Z is N or CR 8 ;

[0089] R 1 is selected from H or one of the following formulas:

[0090]

[0091]

[0092] Y is O or S;

[0093] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M+ + ;

[0094] Y 2 is OH or BH3 - M+ ;

[0095] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0096] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0097] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0098] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0099] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0100] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0101] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0102] In certain embodiments, the present application relates to a compound of the formula:

[0103]

[0104] or a pharmaceutically acceptable salt thereof, wherein:

[0105] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0106] R is OH, F, Cl, or NH2;

[0107] W is N or CR 7 ;

[0108] R 1 is selected from H or one of the following:

[0109]

[0110] Y is O or S;

[0111] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0112] Y 2 is OH or BH3 - M + ;

[0113] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0114] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0115] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0116] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0117] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0118] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0119] R 8H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0120] In certain embodiments, the present application relates to a compound of the formula:

[0121]

[0122] or a pharmaceutically acceptable salt thereof, wherein:

[0123] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0124] W is N or CR 7 ;

[0125] Z is N or CR 8 ;

[0126] R 1 is selected from H or one of the following formulas:

[0127]

[0128] Y is O or S;

[0129] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0130] Y 2 is OH or BH3 - M + ;

[0131] Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0132] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0133] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0134] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C1-22 Alkyl, C 2-22 alkenyl, C 2-22 Alkyne group, or substituted heteroaryl group;

[0135] R 6 Methyl, ethyl, tert-butyl, C 1-22 Alkoxy, C 1-22 Alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0136] R 7 The following are the radicals: H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0137] R 8 It can be H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0138] In some embodiments, the present invention relates to compounds of the following formula:

[0139]

[0140] Or its pharmaceutically acceptable salt, wherein:

[0141] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0142] W is N or CR 7 ;

[0143] Z is N or CR 8 ;

[0144] R 1 Selected from H or one of the following formulas:

[0145]

[0146] Y is either O or S;

[0147] Y 1 It is OH, O-aryl, O-alkyl, or BH3 - M + ;

[0148] Y 2 It is OH or BH3 - M + ;

[0149] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0150] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0151] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0152] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0153] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0154] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0155] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0156] In certain embodiments, the present application relates to a compound of the formula:

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein:

[0159] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0160] W is N or CR 7 ;

[0161] R1 H or one of the following formulae:

[0162]

[0163]

[0164] Y is O or S;

[0165] Y 1 OH, Oaryl, Oalkyl, or BH3 - M + ;

[0166] Y 2 OH or BH3 - M + ;

[0167] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0168] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0169] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0170] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0171] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0172] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0173] R 8H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0174] In certain embodiments, the present application relates to a compound of the formula:

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein:

[0177] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0178] W is N or CR 7 ;

[0179] Z is N or CR 8 ;

[0180] R 1 is selected from H or one of the following formulas:

[0181]

[0182]

[0183] Y is O or S;

[0184] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0185] Y 2 is OH or BH3 - M + ;

[0186] Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0187] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0188] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0189] R 5hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0190] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0191] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0192] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0193] In certain embodiments, the present application relates to a compound of the formula:

[0194]

[0195] or a pharmaceutically acceptable salt thereof, wherein:

[0196] W is N or CR 7 ;

[0197] Z is N or CR 8 ;

[0198] R 1 is selected from H or one of the following formulas:

[0199]

[0200] Y is O or S;

[0201] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0202] Y 2 is OH or BH3 - M + ;

[0203] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0204] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0205] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0206] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0207] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0208] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0209] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0210] In certain embodiments, the present application relates to a compound of the formula:

[0211]

[0212] or a pharmaceutically acceptable salt thereof, wherein:

[0213] W is N or CR 7 ;

[0214] R 1 is selected from H or one of the following formulas:

[0215]

[0216] Y is O or S;

[0217] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0218] Y 2 is OH or BH3 - M + ;

[0219] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0220] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0221] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0222] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0223] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0224] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0225] In certain embodiments, the present application relates to a compound of the formula:

[0226]

[0227] or a pharmaceutically acceptable salt thereof, wherein:

[0228] R 1 is selected from H or one of the following formulas:

[0229]

[0230]

[0231] Y is O or S;

[0232] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0233] Y 2 is OH or BH3 - M + ;

[0234] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0235] R 2 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0236] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0237] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0238] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0239] In certain embodiments, the present application relates to a compound of the formula:

[0240]

[0241] or a pharmaceutically acceptable salt thereof, wherein:

[0242] R 1 is selected from one of the following formulas:

[0243]

[0244] Y is O or S;

[0245] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0246] Y 2 is OH or BH3 - M + ;

[0247] Y 3 is OH, Oalkyl, or BH3 - M + ;

[0248] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0249] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0250] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0251] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0252] In certain embodiments, the present application relates to compounds of the formula:

[0253]

[0254] or a pharmaceutically acceptable salt thereof, wherein:

[0255] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0256] W is N or CR 7 ;

[0257] Z is N or CR 8 ;

[0258] R 1selected from H or one of the following formulas:

[0259]

[0260]

[0261] Y is O or S;

[0262] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0263] Y 2 is OH or BH3 - M + ;

[0264] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0265] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0266] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0267] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0268] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0269] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0270] R 8H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0271] In certain embodiments, the present application relates to a compound of the formula:

[0272]

[0273] or a pharmaceutically acceptable salt thereof, wherein:

[0274] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0275] W is N or CR 7 ;

[0276] R 1 is selected from H or one of the following formulas:

[0277]

[0278] Y is O or S;

[0279] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0280] Y 2 is OH or BH3 - M + ;

[0281] Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0282] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0283] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0284] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0285] R 6 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano; 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0286] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0287] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0288] In certain embodiments, the present application relates to compounds of the formula:

[0289]

[0290] or a pharmaceutically acceptable salt thereof, wherein:

[0291] X is OCMe2, OCHF, OCF2, or OCD2;

[0292] W is N or CR 7 ;

[0293] Z is N or CR 8 ;

[0294] R 1 is selected from H or one of the following formulas:

[0295]

[0296] Y is O or S;

[0297] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0298] Y 2 is OH or BH3 - M + ;

[0299] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0300] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0301] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0302] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0303] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0304] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0305] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0306] In certain embodiments, the present application relates to a compound of the formula:

[0307]

[0308] or a pharmaceutically acceptable salt thereof, wherein:

[0309] X is OCHMe;

[0310] W is N or CR 7 ;

[0311] Z is N or CR 8 ;

[0312] R 1 is selected from H or one of the following formulas:

[0313]

[0314] Y is O or S;

[0315] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0316] Y 2 is OH or BH3 - M + ;

[0317] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0318] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0319] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0320] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0321] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0322] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0323] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0324] In certain embodiments, the present application relates to a compound of the formula:

[0325]

[0326] or a pharmaceutically acceptable salt thereof, wherein:

[0327] X is OCHMe;

[0328] W is N or CR 7 ;

[0329] Z is N or CR 8 ;

[0330] Q is N or CR 9 ;

[0331] R 1 is selected from H or one of the following:

[0332]

[0333]

[0334] Y is O or S;

[0335] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0336] Y 2 is OH or BH3 - M + ;

[0337] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0338] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0339] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0340] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0341] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0342] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0343] R 9 is D, hydroxyl, thiol, amino, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0344] In certain embodiments, the present application relates to a compound of the formula:

[0345]

[0346] or a pharmaceutically acceptable salt thereof, wherein:

[0347] X is OCHMe;

[0348] R 1 is selected from one of the following formulas:

[0349]

[0350]

[0351] Y is O or S;

[0352] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0353] Y 2 is OH or BH3 - M + ;

[0354] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0355] R 4hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C

[0356] R 5 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0357] R 6 methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0358] In certain embodiments, the present application relates to a compound of the formula:

[0359]

[0360] or a pharmaceutically acceptable salt thereof, wherein:

[0361] W is N or CR 7 ;

[0362] Z is N or CR 8 ;

[0363] R 1 selected from H or one of the following:

[0364]

[0365] Y is O or S;

[0366] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0367] Y 2 is OH or BH3 - M + ;

[0368] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0369] R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0370] R 4hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C

[0371] R 5 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkyl, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0372] R 6 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkyl, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0373] R 7 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0374] R 8 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0375] In certain embodiments, the present application relates to a compound of the formula:

[0376]

[0377] or a pharmaceutically acceptable salt thereof, wherein:

[0378] W is N or CR 7 ;

[0379] Z is N or CR 8 ;

[0380] R 1 is selected from H or one of the following formulas:

[0381]

[0382] Y is O or S;

[0383] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0384] Y 2 is OH or BH3 - M + ;

[0385] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0386] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0387] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0388] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0389] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0390] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0391] In certain embodiments, the present application relates to a compound of the formula:

[0392]

[0393] or a pharmaceutically acceptable salt thereof, wherein:

[0394] W is N or CR 7 ;

[0395] R 1 is selected from H or one of the following formulas:

[0396]

[0397]

[0398] Y is O or S;

[0399] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0400] Y 2 is OH or BH3 - M + ;

[0401] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0402] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0403] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0404] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0405] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0406] In certain embodiments, the present application relates to a compound of the formula:

[0407]

[0408] or a pharmaceutically acceptable salt thereof, wherein:

[0409] W is N or CR 7 ;

[0410] Z is N or CR 8 ;

[0411] R 1 is selected from H or one of the following:

[0412]

[0413] Y is O or S;

[0414] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0415] Y 2 is OH or BH3 - M + ;

[0416] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0417] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0418] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0419] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0420] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0421] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0422] In certain embodiments, the present application relates to compounds of the following formula:

[0423]

[0424] or a pharmaceutically acceptable salt thereof, wherein:

[0425] R 1 is selected from H or one of the following:

[0426]

[0427] Y is O or S;

[0428] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0429] Y 2 is OH or BH3 - M + ;

[0430] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0431] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0432] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0433] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0434] In certain embodiments, the present application relates to compounds of the following formula:

[0435]

[0436] or a pharmaceutically acceptable salt thereof, wherein:

[0437] W is N or CR 7 ;

[0438] Z is N or CR 8 ;

[0439] R 1 Selected from H or one of the following formulas:

[0440]

[0441] Y is either O or S;

[0442] Y 1 It is OH, O-aryl, O-alkyl, or BH3 - M + ;

[0443] Y 2 It is OH or BH3 - M + ;

[0444] The aryl group is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0445] R 4 It can be hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0446] R 5 The groups are hydrogen, deuterium, hydroxyl, cyano, azide, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, and C. 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 alkenyl, C 2-22 Alkynyl or substituted heteroaryl;

[0447] R 6 Methyl, ethyl, tert-butyl, C 1-22 Alkoxy, C 1-22 Alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0448] R 7 The following are the radicals: H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0449] R 8 It can be D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0450] In some embodiments, the present invention relates to compounds of the following formula:

[0451]

[0452] or a pharmaceutically acceptable salt thereof, wherein:

[0453] R 1 is selected from H or one of the following:

[0454]

[0455] Y is O or S;

[0456] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0457] Y 2 is OH or BH3 - M + ;

[0458] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0459] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0460] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0461] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0462] In certain embodiments, the present application relates to compounds of the following formula:

[0463]

[0464] or a pharmaceutically acceptable salt thereof, wherein:

[0465] R 1 is selected from H or one of the following:

[0466]

[0467] Y is O or S;

[0468] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0469] Y 2 is OH or BH3 - M + ;

[0470] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0471] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0472] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0473] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0474] R 7 is D, hydroxyl, thiol, amino, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0475] In certain embodiments, the present application relates to a compound of the formula:

[0476]

[0477] or a pharmaceutically acceptable salt thereof, wherein:

[0478] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0479] W is N or CR 7 ;

[0480] Z is N or CR 8 ;

[0481] R 1 is selected from H or one of the following:

[0482]

[0483] Y is O or S;

[0484] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0485] Y 2 is OH or BH3 - M + ;

[0486] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0487] R 2 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0488] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0489] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0490] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0491] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0492] R 8H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano. In certain embodiments, the present application relates to a compound of the formula:

[0493]

[0494] or a pharmaceutically acceptable salt thereof, wherein:

[0495] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0496] W is N or CR 7 ;

[0497] Z is N or CR 8 ;

[0498] R 1 is selected from H or one of the following formulas:

[0499]

[0500]

[0501] Y is O or S;

[0502] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0503] Y 2 is OH or BH3 - M + ;

[0504] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0505] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0506] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0507] R 6methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0508] R 7 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0509] R 8 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0510] In certain embodiments, the present application relates to a compound of the formula:

[0511]

[0512] or a pharmaceutically acceptable salt thereof, wherein:

[0513] W is N or CR 7 ;

[0514] Z is N or CR 8 ;

[0515] R 1 is selected from H or one of the following formulas:

[0516]

[0517]

[0518] Y is O or S;

[0519] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0520] Y 2 is OH or BH3 - M + ;

[0521] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0522] R 4hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C

[0523] R 5 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0524] R 6 methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0525] R 7 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0526] R 8 D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0527] In certain embodiments, the present application relates to a compound of the formula:

[0528]

[0529] or a pharmaceutically acceptable salt thereof, wherein:

[0530] W is N or CR 7 ;

[0531] R 1 selected from H or one of the following formulas:

[0532]

[0533] Y is O or S;

[0534] Y 1 OH, Oaryl, Oalkyl, or BH3 - M + ;

[0535] Y 2 OH or BH3 - M+ ;

[0536] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0537] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0538] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0539] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0540] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0541] In certain embodiments, the present application relates to a compound of the formula:

[0542]

[0543] or a pharmaceutically acceptable salt thereof, wherein:

[0544] X is OCMe2, OCHF, OCF2, or OCD2;

[0545] W is N or CR 7 ;

[0546] Z is N or CR 8 ;

[0547] R 1 is selected from H or one of the following formulas:

[0548]

[0549] Y is O or S;

[0550] Y 1 is OH, Oaryl, Oalkyl, or BH3- M + ;

[0551] Y 2 is OH or BH3 - M + ;

[0552] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0553] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0554] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0555] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0556] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0557] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0558] In certain embodiments, the present application relates to a compound of the formula:

[0559]

[0560] or a pharmaceutically acceptable salt thereof, wherein:

[0561] X is OCHMe or OCH2;

[0562] W is N or CR 7 ;

[0563] Z is N or CR 8 ;

[0564] R 1 is selected from H or one of the following:

[0565]

[0566]

[0567] Y is O or S;

[0568] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0569] Y 2 is OH or BH3 - M + ;

[0570] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0571] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0572] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0573] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0574] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0575] R 8D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0576] In certain embodiments, the present application relates to a compound of the formula:

[0577]

[0578] or a pharmaceutically acceptable salt thereof, wherein:

[0579] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0580] R 1 is selected from H or one of the following formulas:

[0581]

[0582]

[0583] Y is O or S;

[0584] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0585] Y 2 is OH or BH3 - M + ;

[0586] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0587] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0588] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0589] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0590] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0591] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0592] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0593] In certain embodiments, the present application relates to a compound of the formula:

[0594]

[0595] or a pharmaceutically acceptable salt thereof, wherein:

[0596] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0597] R 1 is selected from H or one of the following formulas:

[0598]

[0599] Y is O or S;

[0600] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0601] Y 2 is OH or BH3 - M + ;

[0602] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0603] R 2 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0604] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0605] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0606] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0607] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0608] In certain embodiments, the present application relates to a compound of the formula:

[0609]

[0610] or a pharmaceutically acceptable salt thereof, wherein:

[0611] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0612] R 1 is selected from H or one of the following formulas:

[0613]

[0614] Y is O or S;

[0615] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0616] Y 2 is OH or BH3 - M + ;

[0617] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0618] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0619] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0620] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0621] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0622] In certain embodiments, the present application relates to a compound of the formula:

[0623]

[0624] or a pharmaceutically acceptable salt thereof, wherein:

[0625] R 1 is selected from H or one of the following formulas:

[0626]

[0627]

[0628] Y is O or S;

[0629] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0630] Y 2 is OH or BH3 - M + ;

[0631] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0632] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0633] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0634] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0635] R 8 is H, D, thiol, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, or cyano.

[0636] In certain embodiments, the present application relates to a compound of the formula:

[0637]

[0638] or a pharmaceutically acceptable salt thereof, wherein:

[0639] X is OCMe2, OCHF, OCF2, or OCD2;

[0640] R 1 is selected from H or one of the following formulas:

[0641]

[0642] Y is O or S;

[0643] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0644] Y 2 is OH or BH3 - M + ;

[0645] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0646] R4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or a lipid;

[0647] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0648] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0649] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0650] In certain embodiments, the present application relates to a compound of the formula:

[0651]

[0652] or a pharmaceutically acceptable salt thereof, wherein:

[0653] X is OCH2or OCHMe;

[0654] R 1 is selected from H or one of the following:

[0655]

[0656]

[0657] Y is O or S;

[0658] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0659] Y 2 is OH or BH3 - M + ;

[0660] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0661] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0662] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0663] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0664] R 8 is H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, substituted amino, or cyano.

[0665] In certain embodiments, the present application relates to a compound of the formula:

[0666]

[0667] or a pharmaceutically acceptable salt thereof, wherein:

[0668] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0669] W is N or CR 7 ;

[0670] Z is N or CR 8 ;

[0671] R 1 is selected from H or one of the following formulas:

[0672]

[0673] Y is O or S;

[0674] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0675] Y 2 is OH or BH3 - M + ;

[0676] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0677] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0678] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0679] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0680] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0681] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0682] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0683] In certain embodiments, the present application relates to a compound of the formula:

[0684]

[0685] or a pharmaceutically acceptable salt thereof, wherein:

[0686] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0687] W is N or CR 7 ;

[0688] R 1 is selected from H or one of the following:

[0689]

[0690] Y is O or S;

[0691] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0692] Y 2 is OH or BH3 - M + ;

[0693] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0694] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0695] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0696] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0697] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0698] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0699] In certain embodiments, the present application relates to a compound of the formula:

[0700]

[0701] or a pharmaceutically acceptable salt thereof, wherein:

[0702] X is OCMe2, OCHF, OCF2, or OCD2;

[0703] W is N or CR 7 ;

[0704] R 1 is selected from H or one of the following formulas:

[0705]

[0706]

[0707] Y is O or S;

[0708] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0709] Y 2 is OH or BH3 - M + ;

[0710] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0711] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0712] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0713] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0714] R 7D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0715] In certain embodiments, the present application relates to a compound of the formula:

[0716]

[0717] or a pharmaceutically acceptable salt thereof, wherein:

[0718] X is OCMe2, OCHF, OCF2, or OCD2;

[0719] R 1 is selected from H or one of the following formulas:

[0720]

[0721] Y is O or S;

[0722] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0723] Y 2 is OH or BH3 - M + ;

[0724] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0725] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluorine, chlorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0726] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0727] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0728] R 6 is methyl, ethyl, t-butyl, C1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0729] In certain embodiments, the present application relates to a compound of the formula:

[0730]

[0731] or a pharmaceutically acceptable salt thereof, wherein:

[0732] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0733] W is N or CR 7 ;

[0734] Z is N or CR 8 ;

[0735] R 1 is selected from H or one of the following formulas:

[0736]

[0737] Y is O or S;

[0738] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0739] Y 2 is OH or BH3 - M + ;

[0740] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0741] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0742] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0743] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22alkynyl, or substituted heteroaryl;

[0744] R 6 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano; 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0745] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0746] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0747] In certain embodiments, the present application relates to a compound of the formula:

[0748]

[0749] or a pharmaceutically acceptable salt thereof, wherein:

[0750] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0751] W is N or CR 7 ;

[0752] R 1 is selected from H or one of the following formulas:

[0753]

[0754]

[0755] Y is O or S;

[0756] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0757] Y 2 is OH or BH3 - M + ;

[0758] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0759] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0760] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0761] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0762] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0763] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0764] In certain embodiments, the present application relates to a compound of the formula:

[0765]

[0766] or a pharmaceutically acceptable salt thereof, wherein:

[0767] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0768] R 1 is selected from H or one of the following formulas:

[0769]

[0770] Y is O or S;

[0771] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0772] Y 2 is OH or BH3- M + ;

[0773] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0774] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0775] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0776] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[0777] In certain embodiments, the present application relates to a compound of the formula:

[0778]

[0779] or a pharmaceutically acceptable salt thereof, wherein:

[0780] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0781] W is N or CR 7 ;

[0782] Z is N or CR 8 ;

[0783] R 1 is selected from H or one of the following formulas:

[0784]

[0785] Y is O or S;

[0786] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0787] Y 2 is OH or BH3 - M +;

[0788] The aryl group is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0789] R 4 It can be hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0790] R 5 The groups are hydrogen, deuterium, hydroxyl, cyano, azide, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, and C. 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 alkenyl, C 2-22 Alkynyl or substituted heteroaryl;

[0791] R 6 Methyl, ethyl, tert-butyl, C 1-22 Alkoxy, C 1-22 Alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0792] R 7 The following are the radicals: H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0793] R 8 The group can be D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, ynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano. In some embodiments, the invention relates to compounds of the following formula:

[0794]

[0795] Or its pharmaceutically acceptable salt, wherein:

[0796] X is OCMe2, OCHF, OCF2, or OCD2;

[0797] W is N or CR 7 ;

[0798] R 1 Selected from H or one of the following formulas:

[0799]

[0800]

[0801] Y is O or S;

[0802] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0803] Y 2 is OH or BH3 - M + ;

[0804] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0805] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0806] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0807] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0808] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[0809] In certain embodiments, the present application relates to a compound of the formula:

[0810]

[0811]

[0812] or a pharmaceutically acceptable salt thereof, wherein:

[0813] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0814] R 1selected from H or one of the following formulas:

[0815]

[0816] Y is O or S;

[0817] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0818] Y 2 is OH or BH3 - M + ;

[0819] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0820] R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl;

[0821] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0822] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0823] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0824] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[0825] R 8H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0826] In certain embodiments, the present application relates to a compound of the formula:

[0827]

[0828] or a pharmaceutically acceptable salt thereof, wherein:

[0829] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0830] R 1 is selected from H or one of the following formulas:

[0831]

[0832] Y is O or S;

[0833] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0834] Y 2 is OH or BH3 - M + ;

[0835] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0836] R 2 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluorine, hydroxymethyl, aminomethyl, ethenyl, or cyclobutyl;

[0837] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0838] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0839] R 6methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0840] R 8 H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0841] In certain embodiments, the present application relates to a compound of the formula:

[0842]

[0843] or a pharmaceutically acceptable salt thereof, wherein:

[0844] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[0845] R 1 selected from H or one of the following formulas:

[0846]

[0847]

[0848] Y is O or S;

[0849] Y 1 OH, Oaryl, Oalkyl, or BH3 - M + ;

[0850] Y 2 OH or BH3 - M + ;

[0851] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0852] R 4 hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0853] R 5 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22alkynyl, or substituted heteroaryl;

[0854] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0855] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0856] In certain embodiments, the present application relates to a compound of the formula:

[0857]

[0858]

[0859] or a pharmaceutically acceptable salt thereof, wherein:

[0860] R 1 is selected from H or one of the following formulas:

[0861]

[0862] Y is O or S;

[0863] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0864] Y 2 is OH or BH3 - M + ;

[0865] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0866] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0867] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22alkynyl, or substituted heteroaryl;

[0868] R 6 is hydrogen, methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0869] R 8 is H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, substituted amino, or cyano.

[0870] In certain embodiments, the present application relates to a compound of the formula:

[0871]

[0872] or a pharmaceutically acceptable salt thereof, wherein:

[0873] X is OCMe2, OCHF, OCF2, or OCD2;

[0874] R 1 is selected from H or one of the following formulas:

[0875]

[0876]

[0877] Y is O or S;

[0878] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0879] Y 2 is OH or BH3 - M + ;

[0880] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0881] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0882] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0883] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0884] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[0885] In certain embodiments, the present application relates to a compound of the formula:

[0886]

[0887]

[0888] or a pharmaceutically acceptable salt thereof, wherein:

[0889] X is OCH2or OCHMe;

[0890] R 1 is selected from H or one of the following formulas:

[0891]

[0892] Y is O or S;

[0893] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[0894] Y 2 is OH or BH3 - M + ;

[0895] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[0896] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[0897] R 5hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkyl, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[0898] R 6 is methyl, ethyl, t-butyl, C 1-22 alkyl, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[0899] R 8 H, D, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, substituted amino, or cyano.

[0900] In exemplary embodiments, the compound is selected from:

[0901]

[0902] In exemplary embodiments, the compound is selected from:

[0903]

[0904] In exemplary embodiments, the compound is selected from:

[0905]

[0906] In exemplary embodiments, the compound is selected from:

[0907]

[0908] In exemplary embodiments, the compound is selected from:

[0909]

[0910] In exemplary embodiments, the compound is selected from:

[0911]

[0912] In exemplary embodiments, the compound is selected from:

[0913]

[0914] In exemplary embodiments, the compound is selected from:

[0915]

[0916] In an exemplary embodiment, the compound is selected from:

[0917]

[0918] In an exemplary embodiment, the compound is selected from:

[0919]

[0920] In an exemplary embodiment, the compound is selected from:

[0921]

[0922] In an exemplary embodiment, the compound is selected from:

[0923]

[0924] In an exemplary embodiment, the compound is selected from:

[0925]

[0926] In an exemplary embodiment, the compound is selected from:

[0927]

[0928] In an exemplary embodiment, the compound is selected from:

[0929]

[0930] In an exemplary embodiment, the compound is selected from:

[0931]

[0932] In an exemplary embodiment, the compound is selected from:

[0933]

[0934] In an exemplary embodiment, the compound is selected from:

[0935]

[0936] In an exemplary embodiment, the compound is selected from:

[0937]

[0938] In an exemplary embodiment, the compound is selected from:

[0939]

[0940] In exemplary embodiments, the compound is selected from:

[0941]

[0942] In exemplary embodiments, the compound is selected from:

[0943]

[0944] In exemplary embodiments, the compound is selected from:

[0945]

[0946] In exemplary embodiments, the compound is selected from:

[0947]

[0948] In exemplary embodiments, the compound is selected from:

[0949]

[0950] In exemplary embodiments, the compound is selected from:

[0951]

[0952] In exemplary embodiments, the compound is selected from:

[0953]

[0954] In exemplary embodiments, the compound is selected from:

[0955]

[0956] In exemplary embodiments, the compound is selected from:

[0957]

[0958] In exemplary embodiments, the compound is selected from:

[0959]

[0960] In exemplary embodiments, the compound is selected from:

[0961]

[0962] In exemplary embodiments, the compound is selected from:

[0963]

[0964] In exemplary embodiments, the compound is selected from:

[0965]

[0966] In exemplary embodiments, the compound is selected from:

[0967]

[0968] In exemplary embodiments, the compound is selected from:

[0969]

[0970] In exemplary embodiments, the compound is selected from:

[0971]

[0972] In exemplary embodiments, the compound is selected from:

[0973]

[0974] In exemplary embodiments, the compound is selected from:

[0975]

[0976] In exemplary embodiments, the compound is selected from:

[0977]

[0978] In exemplary embodiments, the compound is selected from:

[0979]

[0980] In exemplary embodiments, the compound is selected from:

[0981]

[0982] In exemplary embodiments, the compound is selected from:

[0983]

[0984] In exemplary embodiments, the compound is selected from:

[0985]

[0986] In exemplary embodiments, the compound is selected from:

[0987]

[0988] In exemplary embodiments, the compound is selected from:

[0989]

[0990] In exemplary embodiments, the compound is selected from:

[0991]

[0992] In exemplary embodiments, the compound is selected from:

[0993]

[0994] In exemplary embodiments, the compound is selected from:

[0995]

[0996] In exemplary embodiments, the compound is selected from:

[0997]

[0998] In exemplary embodiments, the compound is selected from:

[0999]

[1000] In exemplary embodiments, the compound is selected from:

[1001]

[1002] In exemplary embodiments, the compound is selected from:

[1003]

[1004] In exemplary embodiments, the compound is selected from:

[1005]

[1006] In exemplary embodiments, the compound is selected from:

[1007]

[1008] In exemplary embodiments, the compound is selected from:

[1009]

[1010] In exemplary embodiments, the compound is selected from:

[1011]

[1012] In exemplary embodiments, the compound is selected from:

[1013]

[1014] In exemplary embodiments, the compound is selected from:

[1015]

[1016] In exemplary embodiments, the compound is selected from:

[1017]

[1018] In exemplary embodiments, the compound is selected from:

[1019]

[1020] In exemplary embodiments, the compound is selected from:

[1021]

[1022] In exemplary embodiments, the compound is selected from:

[1023]

[1024] In exemplary embodiments, the compound is selected from:

[1025]

[1026] In exemplary embodiments, the compound is selected from:

[1027]

[1028] In exemplary embodiments, the compound is selected from:

[1029]

[1030] In exemplary embodiments, the compound is selected from:

[1031]

[1032] In exemplary embodiments, the compound is selected from:

[1033]

[1034] In exemplary embodiments, the compound is selected from:

[1035]

[1036] In exemplary embodiments, the compound is selected from:

[1037]

[1038] In exemplary embodiments, the compound is selected from:

[1039]

[1040] In exemplary embodiments, the compound is selected from:

[1041]

[1042] In exemplary embodiments, the compound is selected from:

[1043]

[1044] In exemplary embodiments, the compound is selected from:

[1045]

[1046] In exemplary embodiments, the compound is selected from:

[1047]

[1048] In exemplary embodiments, the compound is selected from:

[1049]

[1050] In exemplary embodiments, the compound is selected from:

[1051]

[1052] In exemplary embodiments, the compound is selected from:

[1053]

[1054] In exemplary embodiments, the compound is selected from:

[1055]

[1056] In exemplary embodiments, the compound is selected from:

[1057]

[1058] In exemplary embodiments, the compound is selected from:

[1059]

[1060] In exemplary embodiments, the compound is selected from:

[1061]

[1062] In exemplary embodiments, the compound is selected from:

[1063]

[1064] In exemplary embodiments, the compound is selected from:

[1065]

[1066] In exemplary embodiments, the compound is selected from:

[1067]

[1068] In exemplary embodiments, the compound is selected from:

[1069]

[1070] In exemplary embodiments, the compound is selected from:

[1071]

[1072] In exemplary embodiments, the compound is selected from:

[1073]

[1074] In exemplary embodiments, the compound is selected from:

[1075]

[1076] In exemplary embodiments, the compound is selected from:

[1077]

[1078] In exemplary embodiments, the compound is selected from:

[1079]

[1080] In exemplary embodiments, the compound is selected from:

[1081]

[1082] In exemplary embodiments, the compound is selected from:

[1083]

[1084] In exemplary embodiments, the compound is selected from:

[1085]

[1086] In exemplary embodiments, the compound is selected from:

[1087]

[1088] In exemplary embodiments, the compound is selected from:

[1089]

[1090] In exemplary embodiments, the compound is selected from:

[1091]

[1092] In exemplary embodiments, the compound is selected from:

[1093]

[1094] In exemplary embodiments, the compound is selected from:

[1095]

[1096] In exemplary embodiments, the compound is selected from:

[1097]

[1098] In exemplary embodiments, the compound is selected from:

[1099]

[1100] In exemplary embodiments, the compound is selected from:

[1101]

[1102] In exemplary embodiments, the compound is selected from:

[1103]

[1104] In exemplary embodiments, the compound is selected from:

[1105]

[1106] In exemplary embodiments, the compound is selected from:

[1107]

[1108] In exemplary embodiments, the compound is selected from:

[1109]

[1110] In exemplary embodiments, the compound is selected from:

[1111]

[1112] In exemplary embodiments, the compound is selected from:

[1113]

[1114] In exemplary embodiments, the compound is selected from:

[1115]

[1116] In exemplary embodiments, the compound is selected from:

[1117]

[1118] In exemplary embodiments, the compound is selected from:

[1119]

[1120] In exemplary embodiments, the compound is selected from:

[1121]

[1122] In exemplary embodiments, the compound is selected from:

[1123]

[1124] In exemplary embodiments, the compound is selected from:

[1125]

[1126] In exemplary embodiments, the compound is selected from:

[1127]

[1128] In exemplary embodiments, the compound is selected from:

[1129]

[1130] In exemplary embodiments, the compound is selected from:

[1131]

[1132] In exemplary embodiments, the compound is selected from:

[1133]

[1134] In exemplary embodiments, the compound is selected from:

[1135]

[1136] In exemplary embodiments, the compound is selected from:

[1137]

[1138] In exemplary embodiments, the compound is selected from:

[1139]

[1140] In exemplary embodiments, the compound is selected from:

[1141]

[1142] In exemplary embodiments, the compound is selected from:

[1143]

[1144] In exemplary embodiments, the compound is selected from:

[1145]

[1146] In exemplary embodiments, the compound is selected from:

[1147]

[1148] In exemplary embodiments, the compound is selected from:

[1149]

[1150] In exemplary embodiments, the compound is selected from:

[1151]

[1152] In exemplary embodiments, the compound is selected from:

[1153]

[1154] In exemplary embodiments, the compound is selected from:

[1155]

[1156] In exemplary embodiments, the compound is selected from:

[1157]

[1158] In exemplary embodiments, the compound is selected from:

[1159]

[1160] In exemplary embodiments, the compound is selected from:

[1161]

[1162] In exemplary embodiments, the compound is selected from:

[1163]

[1164] In exemplary embodiments, the compound is selected from:

[1165]

[1166] In exemplary embodiments, the compound is selected from:

[1167]

[1168] In exemplary embodiments, the compound is selected from:

[1169]

[1170] In exemplary embodiments, the compound is selected from:

[1171]

[1172] In exemplary embodiments, the compound is selected from:

[1173]

[1174] In exemplary embodiments, the compound is selected from:

[1175]

[1176] In exemplary embodiments, the compound is selected from:

[1177]

[1178] In exemplary embodiments, the compound is selected from:

[1179]

[1180] In exemplary embodiments, the compound is selected from:

[1181]

[1182] In exemplary embodiments, the compound is selected from:

[1183]

[1184] In exemplary embodiments, the compound is selected from:

[1185]

[1186] In exemplary embodiments, the compound is selected from:

[1187]

[1188] In certain embodiments, the present application relates to a compound of the formula:

[1189]

[1190] or a pharmaceutically acceptable salt thereof, wherein:

[1191] R 1 is selected from one of the following formulas:

[1192]

[1193] Y is O or S;

[1194] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1195] Y 2 is OH or BH3 - M + ;

[1196] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1197] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1198] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1199] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1200] In certain embodiments, the present application relates to a compound of the formula:

[1201]

[1202] or a pharmaceutically acceptable salt thereof, wherein:

[1203] R 1 is selected from one of the following formulas:

[1204]

[1205] Y is O or S;

[1206] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1207] Y 2 is OH or BH3 - M + ;

[1208] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1209] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1210] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1211] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1212] In certain embodiments, the present application relates to a compound of the formula:

[1213]

[1214] or a pharmaceutically acceptable salt thereof, wherein:

[1215] X is OCH2, OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1216] Z is N or CR 8 ;

[1217] R 1 is selected from H or one of the following:

[1218]

[1219]

[1220] Y is O or S;

[1221] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1222] Y 2 is OH or BH3 - M + ;

[1223] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1224] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1225] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1226] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1227] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1228] In certain embodiments, the present application relates to compounds of the following formula:

[1229]

[1230] or a pharmaceutically acceptable salt thereof, wherein:

[1231] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1232] R 1 is selected from H or one of the following:

[1233]

[1234] Y is O or S;

[1235] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1236] Y 2 is OH or BH3 - M + ;

[1237] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1238] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1239] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1240] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1241] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1242] In certain embodiments, the present application relates to a compound of the formula:

[1243]

[1244] or a pharmaceutically acceptable salt thereof, wherein:

[1245] R 1 is selected from H or one of the following:

[1246]

[1247]

[1248] Y is O or S;

[1249] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1250] Y 2 is OH or BH3 - M + ;

[1251] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1252] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1253] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1254] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1255] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1256] In certain embodiments, the present application relates to a compound of the formula:

[1257]

[1258] or a pharmaceutically acceptable salt thereof, wherein:

[1259] R 1 is selected from one of the following formulas:

[1260]

[1261] Y is O or S;

[1262] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1263] Y 2 is OH or BH3 - M + ;

[1264] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1265] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1266] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1267] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1268] In certain embodiments, the present application relates to a compound of the formula:

[1269]

[1270] or a pharmaceutically acceptable salt thereof, wherein:

[1271] X is OCHMe, OCMe2, OCHF, or OCF2;

[1272] R1 H or one of the following:

[1273]

[1274]

[1275] Y is O or S;

[1276] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1277] Y 2 is OH or BH3 - M + ;

[1278] Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1279] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1280] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1281] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1282] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1283] In certain embodiments, the present application relates to a compound of the formula:

[1284]

[1285] or a pharmaceutically acceptable salt thereof, wherein:

[1286] X is OCHMe, OCMe2, OCHF, OCF2, or CD2;

[1287] R 1 Selected from H or one of the following formulas:

[1288]

[1289] Y is either O or S;

[1290] Y 1 It is OH, O-aryl, O-alkyl, or BH3 - M + ;

[1291] Y 2 It is OH or BH3 - M + ;

[1292] The aryl group is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1293] R 4 It can be hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1294] R 5 The groups are hydrogen, deuterium, hydroxyl, cyano, azide, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, and C. 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 alkenyl, C 2-22 Alkyne group, or substituted heteroaryl group;

[1295] R 6 Methyl, ethyl, tert-butyl, C 1-22 Alkoxy, C 1-22 Alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1296] R 8 It can be D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azide, halogen, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1297] In some embodiments, the present invention relates to compounds of the following formula:

[1298]

[1299] Or its pharmaceutically acceptable salt, wherein:

[1300] R 1 is selected from H or one of the following:

[1301]

[1302] Y is O or S;

[1303] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1304] Y 2 is OH or BH3 - M + ;

[1305] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1306] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1307] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1308] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1309] R 8 is D, hydroxyl, thiol, amino, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, or substituted amino.

[1310] In certain embodiments, the present application relates to a compound of the formula:

[1311]

[1312] or a pharmaceutically acceptable salt thereof, wherein:

[1313] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1314] W is N or CR 7 ;

[1315] R 1 is selected from H or one of the following:

[1316]

[1317]

[1318] Y is O or S;

[1319] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1320] Y 2 is OH or BH3 - M + ;

[1321] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1322] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1323] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1324] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1325] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1326] In certain embodiments, the present application relates to compounds of the following formula:

[1327]

[1328] or a pharmaceutically acceptable salt thereof, wherein:

[1329] W is N or CR 7 ;

[1330] R 1 is selected from H or one of the following:

[1331]

[1332] Y is O or S;

[1333] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1334] Y 2 is OH or BH3 - M + ;

[1335] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1336] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1337] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1338] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1339] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1340] In certain embodiments, the present application relates to compounds of the following formula:

[1341]

[1342] or a pharmaceutically acceptable salt thereof, wherein:

[1343] R 1 is selected from one of the following formulas:

[1344]

[1345]

[1346] Y is O or S;

[1347] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1348] Y 2 is OH or BH3 - M + ;

[1349] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1350] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1351] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1352] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1353] In certain embodiments, the present application relates to compounds of the following formula:

[1354]

[1355] or a pharmaceutically acceptable salt thereof, wherein:

[1356] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1357] W is N or CR 7 ;

[1358] R 1 is selected from H or one of the following:

[1359]

[1360] Y is O or S;

[1361] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1362] Y 2 is OH or BH3 - M + ;

[1363] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1364] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1365] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1366] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1367] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[1368] R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1369] In certain embodiments, the present application relates to compounds of the following formula:

[1370]

[1371] or a pharmaceutically acceptable salt thereof, wherein:

[1372] W is N or CR 7 ;

[1373] R 1 is selected from H or one of the following:

[1374]

[1375] Y is O or S;

[1376] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1377] Y 2 is OH or BH3 - M + ;

[1378] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1379] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1380] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1381] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1382] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[1383] R 8D, hydroxyl, thiol, amino, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1384] In certain embodiments, the present application relates to a compound of the formula:

[1385]

[1386] or a pharmaceutically acceptable salt thereof, wherein:

[1387] W is N or CR 7 ;

[1388] R 1 is selected from H or one of the following formulas:

[1389]

[1390]

[1391] Y is O or S;

[1392] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1393] Y 2 is OH or BH3 - M + ;

[1394] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1395] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1396] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1397] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1398] R 7 D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1399] In certain embodiments, the present application relates to a compound of the formula:

[1400]

[1401] or a pharmaceutically acceptable salt thereof, wherein:

[1402] R 1 selected from one of the following formulas:

[1403]

[1404] Y is O or S;

[1405] Y 1 OH, Oaryl, Oalkyl, or BH3 - M + ;

[1406] Y 2 OH or BH3 - M + ;

[1407] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1408] R 4 hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1409] R 5 hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1410] R 6 methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1411] In certain embodiments, the present application relates to a compound of the formula:

[1412]

[1413] or a pharmaceutically acceptable salt thereof, wherein:

[1414] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1415] R 1 is selected from H or one of the following:

[1416]

[1417]

[1418] Y is O or S;

[1419] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1420] Y 2 is OH or BH3 - M + ;

[1421] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1422] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1423] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1424] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1425] In certain embodiments, the present application relates to compounds of the following formula:

[1426]

[1427]

[1428] or a pharmaceutically acceptable salt thereof, wherein:

[1429] R 1 is selected from one of the following:

[1430]

[1431] Y is O or S;

[1432] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1433] Y 2 is OH or BH3 - M + ;

[1434] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1435] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1436] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1437] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1438] In certain embodiments, the present application relates to a compound of the following formula:

[1439]

[1440] or a pharmaceutically acceptable salt thereof, wherein:

[1441] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1442] R 1 is selected from H or one of the following:

[1443]

[1444]

[1445] Y is O or S;

[1446] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1447] Y 2 is OH or BH3 - M + ;

[1448] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1449] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1450] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1451] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1452] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1453] In certain embodiments, the present application relates to a compound of the formula:

[1454]

[1455]

[1456] or a pharmaceutically acceptable salt thereof, wherein:

[1457] R 1 is selected from one of the following formulas:

[1458]

[1459] Y is O or S;

[1460] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1461] Y 2 is OH or BH3 - M + ;

[1462] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1463] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1464] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1465] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1466] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1467] In certain embodiments, the present application relates to a compound of the formula:

[1468]

[1469] or a pharmaceutically acceptable salt thereof, wherein:

[1470] X is OCHMe, OCMe2, OCHF, OCF2, or OCD2;

[1471] R 1 is selected from H or one of the following formulas:

[1472]

[1473]

[1474] Y is O or S;

[1475] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1476] Y 2 is OH or BH3 - M + ;

[1477] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1478] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1479] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1480] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1481] R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano;

[1482] R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano.

[1483] In certain embodiments, the present application relates to compounds of the formula:

[1484]

[1485] or a pharmaceutically acceptable salt thereof, wherein:

[1486] R 1 is selected from H or one of the following:

[1487]

[1488] Y is O or S;

[1489] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1490] Y 2 is OH or BH3 - M + ;

[1491] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1492] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1493] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1494] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1495] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1496] In certain embodiments, the present application relates to compounds of the following formula:

[1497]

[1498] or a pharmaceutically acceptable salt thereof, wherein:

[1499] R 1 is selected from H or one of the following:

[1500]

[1501]

[1502] Y is O or S;

[1503] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1504] Y 2 is OH or BH3 - M + ;

[1505] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1506] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1507] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1508] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1509] In certain embodiments, the present application relates to a compound of the following formula:

[1510]

[1511]

[1512] or a pharmaceutically acceptable salt thereof, wherein:

[1513] R 1 is selected from H or one of the following:

[1514]

[1515] Y is O or S;

[1516] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1517] Y 2 is OH or BH3 - M + ;

[1518] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1519] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1520] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1521] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy;

[1522] R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluorine, chlorine, bromine, iodine, acyl, ester, formyl, alkoxy, substituted amino, or cyano.

[1523] In certain embodiments, the present application relates to a compound of the formula:

[1524]

[1525] or a pharmaceutically acceptable salt thereof, wherein:

[1526] R 1 is selected from one of the following formulas:

[1527]

[1528]

[1529] Y is O or S;

[1530] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1531] Y 2 is OH or BH3 - M + ;

[1532] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1533] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1534] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1535] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1536] In certain embodiments, the present application relates to a method for a compound of the formula:

[1537]

[1538] or a pharmaceutically acceptable salt thereof, wherein:

[1539] R 1 is selected from H or one of the following formulas:

[1540]

[1541] Y is O or S;

[1542] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1543] Y 2 is OH or BH3 - M+ ;

[1544] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1545] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1546] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1547] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1548] In certain embodiments, the present application relates to a method for a compound of the formula:

[1549]

[1550] or a pharmaceutically acceptable salt thereof, wherein:

[1551] R 1 is selected from H or one of the following formulas:

[1552]

[1553] Y is O or S;

[1554] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1555] Y 2 is OH or BH3 - M + ;

[1556] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1557] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1558] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1559] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1560] In certain embodiments, the present application relates to a method for a compound of the formula:

[1561]

[1562] or a pharmaceutically acceptable salt thereof, wherein:

[1563] R 1 is selected from H or one of the following formulas:

[1564]

[1565]

[1566] Y is O or S;

[1567] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1568] Y 2 is OH or BH3 - M + ;

[1569] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1570] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1571] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C2-22 alkynyl, or substituted heteroaryl;

[1572] R 6 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1573] In certain embodiments, the present application relates to a method for a compound of the formula:

[1574]

[1575]

[1576] or a pharmaceutically acceptable salt thereof, wherein:

[1577] R 1 is selected from H or one of the following formulas:

[1578]

[1579] Y is O or S;

[1580] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1581] Y 2 is OH or BH3 - M + ;

[1582] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1583] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1584] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1585] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1586] In certain embodiments, the present application relates to a method for a compound of the formula:

[1587]

[1588] or a pharmaceutically acceptable salt thereof, wherein:

[1589] R 1 is selected from H or one of the following formulas:

[1590]

[1591]

[1592] Y is O or S;

[1593] Y 1 is OH, Oaryl, Oalkyl, or BH3 - M + ;

[1594] Y 2 is OH or BH3 - M + ;

[1595] aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl;

[1596] R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid;

[1597] R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl;

[1598] R 6 is methyl, ethyl, t-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkoxy.

[1599] In certain embodiments, the present application relates to a compound having the following structure:

[1600]

[1601] In certain embodiments, the application relates to a method for a compound of the formula:

[1602]

[1603] In certain embodiments, the application relates to a method for a compound of the formula:

[1604]

[1605] In certain embodiments, the application relates to a method for a compound of the formula:

[1606]

[1607] In certain embodiments, the application relates to a method for a compound of the formula:

[1608]

[1609] In certain embodiments, the application relates to a method for a compound of the formula:

[1610]

[1611] In certain embodiments, the application relates to a method for a compound of the formula:

[1612]

[1613] As used herein, a lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

[1614] In certain embodiments, the lipid is a fatty alcohol, a fatty amine, or a fatty thiol derived from an essential and a non-essential fatty acid.

[1615] In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, a fatty amine, or a fatty thiol derived from an essential and a non-essential fatty acid.

[1616] In certain embodiments, the lipid is a fatty alcohol, a fatty amine, or a fatty thiol derived from an essential and a non-essential fatty acid having one or more carbon units replaced by oxygen, nitrogen, or sulfur.

[1617] In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, a fatty amine, or a fatty thiol derived from an essential and a non-essential fatty acid having one or more carbon units replaced by oxygen, nitrogen, or sulfur.

[1618] In certain embodiments, the lipid is an optionally substituted fatty alcohol, a fatty amine, or a fatty thiol derived from an essential and a non-essential fatty acid.

[1619] In some embodiments, lipids are optionally substituted unsaturated, polyunsaturated, ω-unsaturated or ω-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids.

[1620] In some embodiments, lipids are optionally substituted fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids, wherein one or more carbon units are replaced by oxygen, nitrogen, or sulfur.

[1621] In some embodiments, lipids are optionally substituted unsaturated, polyunsaturated, ω-unsaturated or ω-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids, wherein one or more carbon units are replaced by oxygen, nitrogen or sulfur.

[1622] In some implementations, the lipid is hexadecyloxypropyl.

[1623] In some embodiments, the lipid is 2-aminohexadecoxypropyl.

[1624] In some implementations, the lipid is 2-aminoarachidonic.

[1625] In some embodiments, the lipid is 2-benzyloxyhexadecyloxypropyl.

[1626] In some embodiments, the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, docosyl, or tetracosyl.

[1627] In some embodiments, the lipid is a sphingolipid having the following formula:

[1628]

[1629] in,

[1630] R of sphingolipids 8 Hydrogen, alkyl, C(=O)R 12 C(=O)OR 12 Or C(=O)NHR 12 ;

[1631] R of sphingolipids 9 For hydrogen, fluorine, OR 12 OC(=O)R 12 OC (=O) OR 12 Or OC (=O)NHR 12 ;

[1632] R of sphingolipids 10 It is a saturated or unsaturated alkyl chain with more than 6 and less than 22 carbons, which is optionally substituted by one or more halogens or hydroxyl groups or structures of the following formula:

[1633]

[1634] n is 8 to 14 or less than or equal to 8 to less than or equal to 14, o is 9 to 15 or less than or equal to 9 to less than or equal to 15, the sum of m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14, the sum of m and o is 9 to 15 or less than or equal to 9 to less than or equal to 15; or

[1635]

[1636] n is 4 to 10 or less than or equal to 4 to less than or equal to 10, o is 5 to 11 or less than or equal to 5 to less than or equal to 11, the sum of m and n is 4 to 10 or less than or equal to 4 to less than or equal to 10, the sum of m and o is 5 to 11 or less than or equal to 5 to less than or equal to 11; or

[1637]

[1638] n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12, the sum of m and n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12;

[1639] R of a sphingolipid 11 is OR 12 , OC(=O)R 12 , OC(=O)OR 12 , or OC(=O)NHR 12 ;

[1640] R of a sphingolipid 12 is hydrogen, a branched or straight chain C 1-12 alkyl, C 13-22 alkyl, cycloalkyl, or an aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more R 13 , which are the same or different; and

[1641] R of a sphingolipid 13halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfmyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[1642] In certain embodiments, the R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1- ethylpropyl, 1 -propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.

[1643] In certain embodiments, the sphingolipid has the formula:

[1644]

[1645] wherein,

[1646] the R 8 of the sphingolipid is hydrogen, hydroxyl, fluoro, OR 12 , OC(=O)R 12 , OC(=O)OR 12 , or OC(=O)NHR 12 ;

[1647] the R 9 of the sphingolipid is hydrogen, hydroxyl, fluoro, OR 12 , OC(=O)R 12 , OC(=O)OR 12 , or OC(=O)NHR 12 ;

[1648] the R 10 of the sphingolipid is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons, optionally substituted with one or more halogen or a structure of the formula:

[1649]

[1650] n is 8 to 14 or less than or equal to 8 to less than or equal to 14, the sum of m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14;

[1651] R of the sphingolipid 12 is hydrogen, branched or straight chain C 1-12 alkyl, C 13-22 alkyl, cycloalkyl or aryl selected from benzyl or phenyl, wherein the aryl is optionally substituted with one or more R 13 which are the same or different; and

[1652] R of the sphingolipid 13 halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfmyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[1653] In certain embodiments, R of the sphingolipid 12 is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1- ethylpropyl, 1 -propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C 12 -C 19 long chain alkyl.

[1654] Suitable sphingolipids include, but are not limited to, sphingosine, ceramide or sphingomyelin, or 2-aminoalkyl optionally substituted with one or more substituents.

[1655] Other suitable sphingolipids include, but are not limited to, 2-aminooctadecan-3,5-diol; (2S,3S,5S)-2-aminooctadecan-3,5-diol; (2S,3R,5S)-2-aminooctadecan-3,5-diol; 2-(methylamino)octadecan-3,5-diol; (2S,3R,5S)-2-(methylamino)octadecan-3,5-diol; 2-(dimethylamino)octadecan-3,5-diol; (2R,3S,5S)-2-(dimethylamino)octadecan-3,5-diol; l-(pyrrolidin-2-yl)hexadecan-l,3-diol; (lS,3S)-l-((S)-pyrrolidin-2-yl)hexadecan-l,3-diol; 2-amino-l l,l-difluorooctadecan-3,5-diol; (2S,3S,5S)-2-amino-l l,l-difluorooctadecan-3,5-diol; 11,11-difluoro-2-(methylamino)octadecan-3,5-diol; (2S,3S,5S)-l l,l-difluoro-2-(methylamino)octadecan-3,5-diol; N-((2S,3S,5S)-3,5-dihydroxyoctadecan-2-yl)acetamide; N-((2S,3S,5S)-3,5-dihydroxyoctadecan-2-yl)palmitamide; l-(l-aminocyclopropyl)hexadecan-l,3-diol; (lS,3R)-l-(l-aminocyclopropyl)hexadecan-l,3-diol; (lS,3S)-l-(l-aminocyclopropyl)hexadecan-l,3-diol; 2-amino-2-methyloctadecan-3,5-diol; (3S,5S)-2-amino-2-methyloctadecan-3,5-diol; (3S,5R)-2-amino-2-methyloctadecan-3,5-diol; (3S,5S)-2-methyl-2-(methylamino)octadecan-3,5-diol; 2-amino-5-hydroxy-2-methyloctadecan-3-one; (Z)-2-amino-5-hydroxy-2-methyloctadecan-3-one oxime; (2S,3R,5R)-2-amino-6,6-difluorooctadecan-3,5-diol; (2S,3S,5R)-2-amino-6,6-difluorooctadecan-3,5-diol; (2S,3R,5S)-2-amino-6,6-difluorooctadecan-3,5-diol; (2S,3R,5S)-2-amino-6,6-difluorooctadecan-3,5-diol; and (2S,3S,5S)-2-amino-18,18,18-trifluorooctadecan-3,5-diol; which can be optionally substituted with one or more substituents.

[1656] Infectious disease

[1657] The compounds provided herein can be used to treat viral infectious diseases. Examples of viral infections include, but are not limited to, infections caused by RNA viruses (including negative-strand RNA viruses, positive-strand RNA viruses, double-strand RNA viruses, and retroviruses) or DNA viruses. All strains, types, and subtypes of RNA viruses and DNA viruses are contemplated herein.

[1658] Examples of RNA viruses include, but are not limited to, picornaviruses, which include aphthoviruses (e.g., foot-and-mouth disease virus O, A, C, Asia 1, SAT1, SAT2, and SAT3), cardioviruses (e.g., encephalomyocarditis virus and Theiler’s murine encephalomyelitis virus), enteroviruses (e.g., poliovirus 1, 2, and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses 1-7, 9, 11-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10, and simian enteroviruses 1-18), equine rhinoviruses (e.g., equine rhinitis virus), hepaciviruses (e.g., human hepatitis A virus and simian hepatitis A virus), flavi viruses (e.g., bovine flavivirus and Akabane virus), parvoviruses (e.g., human parvovirus 1 and human parvovirus 2), rhinoviruses (e.g., rhinovirus A, rhinovirus B, rhinovirus C, HRV 16 , HRV 16 (VR-11757), HRV 14 (VR-284), or HRV 1A (VR-1559), human rhinoviruses 1-100, and bovine rhinoviruses 1-3), and teschoviruses (e.g., porcine teschovirus).

[1659] Additional examples of RNA viruses include caliciviruses, which include noroviruses (e.g., Norwalk virus), sapoviruses (e.g., Sapporo virus), lagoviruses (e.g., rabbit hemorrhagic disease virus and European brown hare syndrome), and vesiviruses (e.g., water vesicles of pig virus and cat calicivirus). Other RNA viruses include astroviruses, which include mammalian astroviruses and avian astroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (e.g., Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis virus, Eastern equine encephalitis virus, Everglades virus, Venezuelan equine encephalitis virus, Ross River virus, O'nyong'nyong virus, and Aura virus) and rubiviruses. Other examples of RNA viruses include flaviviruses (e.g., tick-borne encephalitis virus (Western, Siberian, and Far Eastern subtypes), Omsk hemorrhagic fever virus, Kunjin virus, Alkhurma virus, sheep jumper virus, Tyulenko virus, Aroa virus, M virus (types 1-4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Dengue virus (including genotypes 1-4), Zika virus, Powassan virus, Kokobera virus, Ntaya virus, Spykeri virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, Cell fusing agent virus, Pestivirus, GB virus A, GBV-A-like virus, GB virus C, hepatitis G virus, Hepatitis virus (Hepatitis C virus (HCV) all six genotypes), bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).

[1660] Other examples of RNA viruses are coronaviruses, which include human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63, and HCoV-OC43. Coronaviruses also include bat SARS-like CoV, Middle East respiratory syndrome coronavirus (MERS), turkey coronavirus, chicken coronavirus, cat coronavirus, and canine coronavirus. Other RNA viruses include arteriviruses (e.g., equine arterivirus, porcine reproductive and respiratory syndrome virus, mouse lactate dehydrogenase-elevating virus, and simian hemorrhagic fever virus). Other RNA viruses include rhabdoviruses, which include rabies viruses (e.g., rabies, Lagos bat virus, Mokola virus, Duvenhage virus, and European bat rabies virus), vesiculoviruses (e.g., VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Piribet virus, Cocal virus, Maraba virus, Isfahan virus, and Kíndi virus), and ephemeral fever viruses (e.g., bovine ephemeral fever virus, Adelaide River virus, and Berrimah virus). Additional examples of RNA viruses include filoviruses. These include Marburg virus and Ebola virus (e.g., EBOV-Z, EBOV-S, EBOV-IC, and EBOV-R).

[1661] Paramyxoviruses are also RNA viruses. Examples of these viruses are mumps viruses (e.g., mumps, parainfluenza virus 5, human parainfluenza virus type 2, Mapuella virus, and swine mumps virus), avian mumps viruses (e.g., Newcastle disease virus), respiratory viruses (e.g., Sendai virus, human parainfluenza virus types 1 and 3, bovine parainfluenza virus type 3), Hennipa virus (e.g., Hendra virus and Nipah virus), measles viruses (e.g., measles, cetacean measles virus, canine distemper virus, peste des petits ruminants virus, phozoonosis virus, and rinderpest virus), pneumoviruses (e.g., human respiratory syncytial virus (RSV) A2, B1, and S2, bovine respiratory syncytial virus, and mouse pneumonia virus), and metapneumoviruses (e.g., human metapneumovirus and avian metapneumovirus). Other paramyxoviruses include American shrew virus, tree shrew paramyxovirus, Menango virus, Tioman virus, Beilong virus, J virus, Mossman virus, Salem virus, and Nariwa virus.

[1662] Other RNA viruses include orthomyxoviruses. These viruses include influenza viruses and strains (e.g., influenza A, influenza A virus strain A / Victoria / 3 / 75, influenza A virus strain A / Puerto Rico / 8 / 34, influenza A H1N1 (including but not limited to A / WS / 33, A / NWS / 33 and A / California / 04 / 2009 strains), influenza B, influenza B virus strain Lee, and influenza C virus) H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7), as well as avian influenza (e.g., strains H5N1, H5N1Duck / MN / 1525 / 81, H5N2, H7N1, H7N7, and H9N2), togovirus, and salmon anemia virus. Bunyaviruses (e.g., Akabane virus, California encephalitis virus, Catch Valley virus, Snowshoe virus), Nairoviruses (e.g., Nairobi sheep virus, Crimean-Congo hemorrhagic fever virus swarm, and Hughes virus), sandfly viruses (e.g., Candiru virus, Pacuui virus, Rift Valley fever virus, sandfly virus, Naples virus, Tuscan virus, Sicilian virus, and Chagres virus), and Hantaviruses (e.g., Hantavirus, Doberva virus, Seoul virus, Puma virus, Sinopo virus, Oxbow Lake virus, Black Creek virus, Andean virus, and Sotopalaya virus) are also RNA viruses. Arenaviruses, such as lymphocytic choriomeningitis virus, Luyo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV, and WWAV, are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (δ) virus and hepatitis E virus are also RNA viruses.

[1663] Additional RNA viruses include reoviruses, rotaviruses, birnaviruses, chloroviruses, cystoviruses, leviviruses, partitiviruses, and totoviruses. Orbiviruses, such as African horse sickness virus, blue tongue virus, Changuinola virus, Chuno virus, Chobar Gorge Corriparta virus, epizootic hemorrhagic disease virus, equine encephalosis virus, North Australian encephalitis virus, Iri virus, Great Island virus, Lebombo virus, Otranto Valley virus, Palyam virus, Peruvian horse sickness virus, San Carlo River virus, Yuma virus, Whataroa virus, Wolloon virus, Wye River virus, and Wesselsbron virus are also RNA viruses. Retroviruses include alpha retroviruses (e.g., Rous sarcoma virus and avian leukosis virus), beta retroviruses (e.g., mouse mammary tumor virus, Mason-Pfizer monkey virus, and Jaagsiekte sheep retrovirus), gamma retroviruses (e.g., murine leukemia virus and feline leukemia virus), delta retroviruses (e.g., human T-cell leukemia virus (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1, and STLV-2), epsilon retroviruses (e.g., Walleye dermal sarcoma virus and Walleye epidermal hyperplasia virus 1), reticuloendotheliosis viruses (e.g., chicken syncytial virus), lentiviruses (e.g., human immunodeficiency virus (HIV) type 1, human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis- encephalitis virus, and visna maedi virus), and spumaviruses (e.g., human spumavirus and feline syncytial forming virus).

[1664] Examples of DNA viruses include polyomaviruses (e.g., simian virus 40, simian virus 12, BK virus, JC virus, Merkel cell polyomavirus, bovine polyomavirus, and lymphocytic choriomeningitis virus), papillomaviruses (e.g., human papillomavirus, bovine papillomavirus), adenoviruses (e.g., adenoviruses A-F, canine adenovirus type I, canine adenovirus type 2), circoviruses (e.g., porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (e.g., canine parvovirus), erythroviruses (e.g., adeno-associated viruses 1-8), betaparvovirus, alvirus, densovirus, iterovirus, brevidensovirus, circovirus, herpesviruses 1, 2, 3, 4, 5, 6, 7, and 8 (e.g., herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi’s sarcoma-associated herpesvirus, human herpesvirus-6 variant A, human herpesvirus-6 variant B, and macaque herpesvirus 1 (B virus)), poxviruses (e.g., variola, vaccinia, monkeypox, cowpox, tanapox, camel pox, pseudocowpox, pigeonpox, horsepox, fowlpox, turkeypox, and swinepox), and hepadnaviruses (e.g., hepatitis B and hepatitis B-like viruses). Chimeric viruses comprising more than one viral genome portion are also contemplated herein.

[1665] In some embodiments, the present disclosure relates to treating or preventing viral, bacterial, fungal, protozoal, and parasitic infections. In some embodiments, the present disclosure relates to methods of treating viral infections, comprising administering a compound herein to a subject diagnosed with, suspected of having, or exhibiting symptoms of a viral infection.

[1666] Viruses are infectious agents that can typically replicate within the living cells of an organism. Virions (viruses) are typically composed of a nucleic acid, a protein coat, and in some cases a lipid envelope surrounding the protein coat. Viruses range in shape from simple helical and icosahedral forms to more complex structures. The protein subunits encoded by the virus will self-assemble into a capsid, often requiring the presence of the viral genome. Complex viruses can encode proteins that aid in the construction of their capsids. The proteins associated with the nucleic acid are called nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called the nucleocapsid.

[1667] Viruses are spread by a variety of methods, including direct or bodily fluid contact, such as blood, tears, semen, pre-ejaculate, saliva, breast milk, vaginal secretions, lesions; droplet contact, fecal-oral contact, or as a result of animal bites or birthing. Viruses have DNA or RNA genes, and are referred to as DNA viruses or RNA viruses, respectively. Viral genomes are single- or double-stranded. Some viruses contain genomes that are partially double-stranded and partially single-stranded. For viruses with RNA or single-stranded DNA, the strands are considered positive-sense (called positive strands) or negative-sense (called negative strands), depending on whether it is complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is identical to the viral mRNA, and therefore can be immediately translated by the host cell. Negative-sense viral RNA is complementary to the mRNA, and therefore must be converted to positive-sense RNA by an RNA polymerase before translation. DNA nomenclature is similar to RNA nomenclature, as the coding strand of viral mRNA is complementary (negative) to its copy (positive).

[1668] Antigenic shift or reassortment can produce new strains. Viruses undergo genetic changes through several mechanisms. These include a process called genetic drift, in which individual bases in the DNA or RNA mutate to other bases. Antigenic shift occurs when there is a major change in the viral genome. This can be the result of recombination or reassortment. RNA viruses often exist as quasi-species or swarms of viruses of the same species, but with slightly different genomic nucleotide sequences.

[1669] The genetic material within the virus, as well as the method of replicating the material, varies by the type of virus. Genome replication for most DNA viruses occurs in the nucleus of the cell. These viruses enter the cell by fusing with the cell membrane or by endocytosis if the cell has the appropriate receptors on its surface. Most DNA viruses are completely dependent on the host DNA and RNA synthesis machinery and RNA processing machinery. Replication usually occurs in the cytoplasm. RNA viruses usually use their own RNA replicases to create copies of their genomes.

[1670] The Baltimore virus classification is based on the mechanism of mRNA production. Viruses must produce mRNA from their genome to produce proteins and self-replicate, but use different mechanisms to do so. Viral genomes can be single-stranded (ss) or double-stranded (ds), RNA or DNA, and can or can not use reverse transcriptase (RT). In addition, ssRNA viruses can be positive (+) or negative (-) sense. This classification divides viruses into seven groups: I, dsDNA viruses (e.g., adenovirus, herpesvirus, poxvirus); II, ssDNA viruses (+) positive sense DNA (e.g., parvovirus); III, dsRNA viruses (e.g., reovirus); four, (+) ssRNA viruses (+) positive sense RNA (e.g., picornavirus, togavirus); five, (-) ssRNA viruses (-) negative sense RNA (e.g., orthomyxovirus, rhabdovirus); VI, ssRNA-RT viruses (+) positive sense RNA with a DNA intermediate in the life cycle (e.g., retrovirus); and VII, dsDNA-RT viruses (e.g., hepadnavirus).

[1671] Human immunodeficiency virus (HIV) is a lentivirus (member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS). Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into a target cell, the viral RNA genome is converted to double-stranded DNA by a virus-encoded reverse transcriptase. This viral DNA is then integrated into cellular DNA by a virus-encoded integrase and host cell cofactors. There are two types of HIV. HIV-1 is sometimes called LAV or HTLV-III.

[1672] HIV primarily infects living cells in the human immune system, such as helper T cells (CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells. When the number of CD4+ T cells drops below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to infection by other viruses or bacteria. Subjects with HIV often develop malignancies associated with progressive failure of the immune system.

[1673] When newly formed virions bud from the cell, the viral envelope is composed of two layers of phospholipids taken from the human cell membrane. Embedded in the viral envelope are proteins from the host cell and HIV proteins called Env. Env contains glycoproteins gpl20 and gp41. The RNA genome is composed of structural markers (LTR, TAR, RRE, PE, SLIP, CRS, and INS) and 9 genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth, tev, which is a fusion of tat env and rev) that encode 19 proteins. Three of these genes, gag, pol, and env, contain the information needed to make the structural proteins for the new virion. HIV-1 diagnosis is usually by antibody in ELISA, Western blot, or immunoaffinity assays or by nucleic acid testing (e.g., viral RNA or DNA amplification).

[1674] HIV is typically treated with a combination of antiviral agents, such as two nucleoside analog reverse transcriptase inhibitors and one non-nucleoside analog reverse transcriptase inhibitor or a protease inhibitor. The three drug combination is often referred to as a triple cocktail. In certain embodiments, the present disclosure relates to treating a subject diagnosed with HIV by administering a pharmaceutical composition disclosed herein in combination with two nucleoside analog reverse transcriptase inhibitors and one non-nucleoside analog reverse transcriptase inhibitor or a protease inhibitor.

[1675] In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein emtricitabine, tenofovir, and efavirenz. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein emtricitabine, tenofovir, and rilpivirine. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein emtricitabine, tenofovir, ritonavir, and darunavir. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein emtricitabine, tenofovir, ritonavir, and atazanavir.

[1676] BanLec (BanLec or BanLec-1) is one of the major proteins in the pulp of a ripe banana and has binding specificity for mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gpl20. In certain embodiments, the present disclosure relates to treating viral infections, such as HIV, by administering a compound disclosed herein in combination with BanLec.

[1677] Hepatitis C virus is a single-stranded, positive-sense RNA virus. It is the only known member of the Hepacivirus genus in the Flaviviridae family. There are six major genotypes of Hepatitis C virus, denoted by numbers. The virion is composed of a core of genetic material (RNA) surrounded by an icosahedral protective shell and further encased in a lipid envelope. Two viral envelope glycoproteins, El and E2, are embedded in the lipid envelope. The genome consists of a single open reading frame that is translated to produce a single protein. This large preprotein is later cleaved by cellular and viral proteases into smaller proteins, allowing the virus to replicate within the host cell, or to assemble into mature virions, for example, El, E2, NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.

[1678] HCV causes inflammation of the liver, and chronic infection leads to cirrhosis. Most people infected with Hepatitis C have the chronic form. Diagnosis of HCV can be made by nucleic acid analysis of the 5'-noncoding region. ELISA assays can be performed to detect Hepatitis C antibodies, and RNA assays to determine viral load. Subjects infected with HCV can exhibit symptoms of abdominal pain, ascites, urine redness, fatigue, generalized itching, jaundice, fever, nausea, pallor or clay-colored stool, and vomiting.

[1679] In some cases, the therapeutic agent can suppress the virus for a long time. A typical drug is a combination of interferon alpha and ribavirin. Subjects can receive injections of pegylated interferon alpha. Genotypes 1 and 4 are less responsive to interferon-based therapy than other genotypes (2, 3, 5, and 6). In certain embodiments, the present disclosure relates to treating a subject having HCV by administering a compound disclosed herein to a subject exhibiting symptoms of HCV or diagnosed with HCV. In certain embodiments, the compound is administered in combination with interferon alpha and another antiviral agent such as ribavirin and / or a protease inhibitor such as telaprevir or boceprevir. In certain embodiments, the subject is diagnosed with genotype 2, 3, 5, or 6. In other embodiments, the subject is diagnosed with genotype 1 or 4.

[1680] In some embodiments, the subject is diagnosed with the virus by nucleic acid testing or viral antigen testing. Cytomegalovirus (CMV) belongs to the β-herpesvirus subfamily of the Herpesviridae family. In humans, it is commonly referred to as HCMV or human herpesvirus 5 (HHV-5). Herpesviruses typically have the characteristic ability to remain latent in the body for extended periods. HCMV infection can be life-threatening in immunocompromised patients. In some embodiments, this disclosure relates to methods of treating or preventing CMMV infection in a subject by administering the compounds disclosed herein. In some embodiments, the subject is immunocompromised. In typical embodiments, the subject is an organ transplant recipient, undergoing hemodialysis, diagnosed with cancer, receiving immunosuppressive drugs, and / or diagnosed with HIV infection. In some embodiments, the subject may be diagnosed with cytomegalovirus hepatitis, cause of acute liver failure, cytomegalovirus retinitis (retinal inflammation, detectable by ophthalmoscopy), cytomegalovirus colitis (colitis), cytomegalovirus pneumonia, cytomegalovirus esophagitis, cytomegalovirus mononucleosis, polyradiculopathy, transverse myelitis, and subacute encephalitis. In some embodiments, the compounds disclosed herein are administered in combination with antiviral agents such as valganciclovir or ganciclovir. In some embodiments, the subject undergoes regular serum monitoring.

[1681] HCMV infection in pregnant subjects can lead to congenital abnormalities. Congenital HCMV infection occurs when the mother experiences a primary infection (or reactivation) during pregnancy. In some embodiments, this disclosure relates to methods of treating pregnant subjects diagnosed with cytomegalovirus or preventing cytomegalovirus infection in subjects at risk of becoming or currently pregnant by administering compounds disclosed herein.

[1682] Subjects infected with CMV typically develop antibodies against the virus. Numerous laboratory tests have been developed to detect these antibodies against CMV. Active infection can be detected by culturing the virus from specimens obtained from urine, throat swabs, bronchoalveolar lavage fluid, and tissue samples. Viral load in CMV-infected subjects can be monitored using PCR. The CMV pp65 antigenemia test is an immunoaffinity-based assay used to identify the pp65 protein of cytomegalovirus in peripheral blood leukocytes. CMV should be suspected if a patient presents with symptoms of infectious mononucleosis but tests negative for mononucleosis and Epstein-Barr virus, or if they show signs of hepatitis but tests negative for hepatitis A, B, and C. Viral cultures can be performed at any time when a subject is symptomatic. Laboratory tests for antibodies against CMV can be performed to determine whether a subject has a CMV infection.

[1683] Enzyme-linked immunosorbent assay (or ELISA) is the most common available serum test for measuring antibodies against CMV. This result can be used to determine if there is an acute infection, a previous infection, or passively acquired maternal antibodies in the infant. Other tests include various fluorescent assays, indirect hemagglutination, (PCR), and latex agglutination. ELISA techniques are available for CMV-specific IgM.

[1684] The hepatitis B virus is a hepatotropic virus. The virion (virus body) consists of an outer lipid envelope and an icosahedral nucleocapsid core consisting of proteins. The genome of HBV consists of circular DNA, but the DNA is not completely double-stranded. One end of the strand is linked to a viral DNA polymerase. The virus replicates via an RNA intermediate form by means of reverse transcription. Replication usually occurs in the liver, which causes inflammation (hepatitis). The virus is transmitted to the blood of the infected population, in which viral-specific proteins and their corresponding antibodies are found. Blood tests for these proteins and antibodies are used to diagnose infection.

[1685] The hepatitis B virus enters the cell by endocytosis. Since the virus propagates through RNA produced by host enzymes, the viral genomic DNA must be transferred to the nucleus by a host chaperone. The partially double-stranded viral DNA is then made completely double-stranded and converted into a covalently closed circular DNA (cccDNA), which serves as a template for viral mRNA transcription. The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on the antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to total nucleotide sequence variation of the genome.

[1686] The hepatitis B surface antigen (HBsAg) is commonly used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, this antigen can not be present in the early stages of infection, and if it is cleared by the host, it can not be detected in the later stages of infection. The infectious virion contains an internal "core particle" that encloses the viral genome. The icosahedral core particle is made of core proteins, or known as hepatitis B core antigen or HBcAg. IgM antibodies against the hepatitis B core antigen (anti-HBc IgM) can be used as a serological marker. The hepatitis B e antigen (HBeAg) can appear. The presence of HBeAg in the host serum is associated with a high rate of viral replication. Certain variants of the hepatitis B virus do not produce the 'e' antigen,

[1687] If the host clears the infection, the HBsAg will typically become undetectable, and subsequently IgG antibodies to hepatitis B surface antigen and core antigen (anti-HBs and anti-HBc IgG) will appear. The time between HBsAg clearance and the appearance of anti-HBs is called the window period. A person who is negative for HBsAg but positive for anti-HBs either has cleared the infection or has been previously vaccinated. Individuals who remain positive for HBsAg for at least six months are considered to be hepatitis B carriers. Carriers of the virus can have chronic hepatitis B, which will be reflected by serum alanine aminotransferase levels and liver inflammation that can be identified by biopsy. Nucleic acid (PCR) tests have been developed to detect and measure the amount of HBV DNA in clinical specimens.

[1688] Acute infection with hepatitis B virus is associated with acute viral hepatitis. Acute viral hepatitis typically begins with symptoms of poor general health, loss of appetite, nausea, vomiting, body aches, mild fever, and dark urine, followed by jaundice. Chronic infection with hepatitis B virus can be asymptomatic or associated with chronic inflammation of the liver (chronic hepatitis), which can lead to cirrhosis. Having a chronic hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer).

[1689] During HBV infection, the host immune response causes liver cell damage and viral clearance. The adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), causes most of the liver damage associated with HBV infection. CTLs eliminate the virus by killing infected cells and by producing antiviral cytokines that are capable of clearing HBV from living liver cells. While liver damage is initiated and mediated by CTLs, antigen nonspecific inflammatory cells can exacerbate CTL-induced immunopathology, and activated platelets at the site of infection can promote accumulation of CTLs in the liver.

[1690] Therapeutic agents can prevent viral replication, thereby minimizing liver damage. In certain embodiments, the present disclosure relates to methods of treating a subject diagnosed with HBV by administering a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In certain embodiments, the compound is used in combination with another antiviral agent such as lamivudine, adefovir, tenofovir, telbivudine, and entecavir and / or an immune system modulator, interferon alpha-2a and pegylated interferon alpha-2a (Pegasys). In certain embodiments, the present disclosure relates to methods of preventing HBV infection in an immunocompromised subject at risk of infection by administering a pharmaceutical composition disclosed herein, and optionally one or more antiviral agents. In certain embodiments, the subject is at risk of infection because the subject’s sexual partner is diagnosed with HBV.

[1691] Zika virus (ZIKV) is an emerging arthropod-borne human pathogen in the Flaviviridae family (Flavivirus genus) that was first isolated in 1947 from febrile sentinel macaques in the Zika forest in Uganda. Although primarily transmitted by Aedes aegypti, current reports strongly suggest that the virus is transmitted perinatally, sexually, and through transfusion. ZIKV infection is usually self-limiting, with 80% of infected individuals being clinically asymptomatic. Symptoms in affected patients are usually mild and not life-threatening. Symptoms include fever, maculopapular rash, arthralgia and / or conjunctivitis, myalgia, headache, and retro-orbital pain. Recently, the most common cause of non-polio virus-associated acute flaccid myelitis is Guillain-Barre syndrome (GBS) has a higher incidence than normal, and cases of congenital microcephaly have been linked to ZIKV outbreaks in French Polynesia and Brazil. GBS is a serious disease believed to be triggered by an immune-mediated response to antigenic exposure from certain viral or bacterial infections. About 20% of patients suffer severe disability, and about 5% of patients die. Also of concern is the apparent correlation between ZIKV infection reported in Brazil in 2015 and a 20-fold increase in the incidence of microcephaly cases. Among these symptoms, the most common are seizures, mental retardation, developmental delays, cerebral palsy, hearing and vision loss. Currently, there are no vaccines or treatment options for the prevention or treatment of ZIKV infection.

[1692] The mechanism of infection by ZIKV has not been well studied, but the viral replication cycle can be similar to other flaviviruses such as DFV. Infection of human skin with saliva from ZIKV infected mosquitoes results in infection of epidermal keratinocytes, dermal fibroblasts, and Langerhans cells. ZIKV continues to spread in the human host through lymph nodes and the bloodstream. ZIKV genome replication occurs in intracellular compartments in the endoplasmic reticulum through a membrane-bound viral replication complex composed of viral nonstructural proteins, viral RNA, and host proteins, the nature of which is largely unknown. The genome of ZIKV is a single-stranded (+)-RNA molecule of approximately 10.7 kb in length with two noncoding flanking regions (NCRs) known as the 5'-NCR and 3'-NCR. The ZIKV RNA genome contains a single open reading frame (ORF) encoding a 3,419 amino acid polypeptide that is cleaved into three structural proteins (C, prM, and E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). This complex first transcribes the genomic positive-strand RNA into a complementary negative-strand RNA intermediate, resulting in the formation of a duplex RNA. The negative strand of this duplex serves as a template for multiple rounds of positive-strand RNA synthesis. Viral RNA synthesis occurs through an asymmetric replication cycle in which ten times more positive-strand RNA is synthesized than negative-strand RNA.

[1693] In certain embodiments, the 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, phosphacyl, ganciclovir, ibacitabine, iminosine, 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, stavudine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, tenofovir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, valaciclovir, valganciclovir, vicriviroc, vidarabine, virox, zalcitabine, zanamivir, or zidovudine, and combinations thereof.

[1694] Also provided are methods of treating an HCV infection in a subject. The method includes administering a compound of the application to provide at least two direct acting antivirals (DAA) with or without ribavirin for a duration of no more than twelve weeks, or another duration as described herein. In one embodiment, the duration of treatment is no more than twelve weeks. In another embodiment, the duration of treatment is no more than eight weeks. Preferably, the two or more direct acting antivirals (DAA) with or without ribavirin are administered in an amount effective to provide a sustained virologic response (SVR) or another measure of effectiveness in the subject. The subject is not administered interferon during the treatment regimen. In other words, in one embodiment, the method does not include administering interferon to the subject, thereby avoiding side effects associated with interferon. In some embodiments, the method further includes administering to the subject an inhibitor of cytochrome P-450 (such as ritonavir) to improve the pharmacokinetics or bioavailability of one or more of the DAAs.

[1695] As another aspect, provided are methods of treating an HCV infection in a subject. The method includes administering to the subject (a) a protease inhibitor, (b) at least one polymerase inhibitor, wherein at least one is a polymerase of the application, and combinations thereof, with or without (c) ribavirin and / or (d) an inhibitor of cytochrome P-450, for a duration of no more than twelve weeks, or another duration as described herein (e.g., the treatment regimen can be for a duration of no more than 8 weeks). Preferably, the compounds are administered in an amount effective to provide a high rate of SVR or another measure of effectiveness in the subject. As a non-limiting example, the compounds can be co-formulated and administered once daily, and the treatment regimen preferably lasts for eight weeks or six weeks.

[1696] As another aspect, provided are methods for treating a population of subjects having an HCV infection. The method includes administering to the subjects at least two DAAs, wherein one DAA is a compound of the application, with or without ribavirin, for a duration of no more than 12 or 8 or 6 weeks. Preferably, the at least two DAAs are administered to the subjects in an amount effective to produce an SVR or another measure of effectiveness in at least about 70% of the population, preferably, at least 90% of the population.

[1697] In the foregoing methods, as well as the methods described below, the DAAs can be selected from protease inhibitors, nucleoside or nucleotide polymerase inhibitors (one of which is provided herein), non-nucleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS5A inhibitors, NS5B inhibitors, cyclophilin inhibitors, and combinations of any of the foregoing. For example, in some embodiments, the DAAs used in the present methods comprise or consist of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor provided herein.

[1698] At least one of the HCV polymerase inhibitors is one of the compounds of the application (as described herein). By way of example, the compounds of the application can be administered in a total daily dose of about 100 mg to about 250 mg, or about 150 mg to about 250 mg once daily.

[1699] In some embodiments, the at least two DAAs comprise at least one HCV polymerase inhibitor of the application and at least one NS5A inhibitor. By way of example, the polymerase inhibitor of the application can be administered in a total daily dose of about 100 mg to about 250 mg, and the NS5A inhibitor can be administered in a total daily dose of about 25 mg to about 200 mg. Ritonavir (or another cytochrome P450 3A4 inhibitor) can be co-administered therewith to improve the pharmacokinetics and bioavailability of the compounds.

[1700] In the foregoing methods, as well as the methods described herein, the DAAs, with or without ribavirin, can be administered in any effective dosing regimen and / or frequency, e.g., they can be administered daily. Each DAA can be administered separately or in combination, and each DAA can be administered at least once per day, at least twice a day, or at least three times a day. Likewise, ribavirin can be administered alone or in combination with one or more DAAs, at least once per day, at least twice a day, or at least three times a day. In some preferred embodiments, the compounds are administered once per day.

[1701] In some aspects, the present technology provides methods of treating an HCV infection comprising administering to a subject in need thereof at least two DAAs, with or without ribavirin, for a duration of no more than 12 or 8 or 6 weeks, wherein the subject is not administered interferon for the duration. In some aspects, the at least two DAAs, with or without ribavirin, are administered in an amount effective to produce an SVR. Some methods further comprise administering to the subject an inhibitor of cytochrome P450. In some aspects, the duration is no more than eight weeks.

[1702] In another aspect, the at least two directly acting antiviral agents comprise a combination of drugs selected from the group consisting of: a compound of the present application, one or more of ABT-450 and / or ABT-267 and / or ABT-333 and / or ABT-493 and / or ABT-530; a novel compound of the present application and a compound disclosed in any one of the following patents: US 2010 / 0144608; US 61 / 339,964; US 2011 / 0312973; WO 2009 / 039127; US 2010 / 0317568; 2012 / 151158; US 2012 / 0172290; WO 2012 / 092411; WO 2012 / 087833; WO 2012 / 083170; WO 2009 / 039135; US 2012 / 0115918; WO 2012 / 051361; WO 2012 / 009699; WO 2011 / 156337; US 2011 / 0207699; WO 2010 / 075376; US 7,9105,95; WO 2010 / 120935; WO 2010 / 111437; WO 2010 / 111436; US 2010 / 0168384 or US 2004 / 0167123; a compound of the present application and one or more of simeprevir and / or gsk805; a compound of the present application and one or more of asunaprevir and / or daclatasvir and / or BMS 325; a compound of the present application and one or more of GS-9451 and / or asunaprevir and / or ledipasvir and / or GS-9669; a compound of the present application and one or more of ACH-2684 and / or ACH-3102 and / or ACH-3422; a compound of the present application and one or more of Bocprevir and / or MK-8742; a compound of the present application and one or more of faricenvir and / or Deleobuvir; a compound of the present application and PPI 668; a compound of the present application and one or more of telaprevir and / or VX-135; a compound of the present application and one or more of Samatasvir and / or IDX-437; a compound of the present application and PSI-7977 and / or PSI-938, a compound of the present application and BMS-790052 and / or BMS-650032; a compound of the present application and GS-5885 and / or GS-9451; a compound of the present application and GS-5885, GS-9190 and / or GS-9451; a compound of the present application and BI-201335 and / or BI-27127; a compound of the present application and telaprevir and / or VX-222; a compound of the present application and PSI-7977 and / or TMC-435; and a compound of the present application and danoprevir and / or R7128.

[1703] In yet another aspect, the at least two directly acting antiviral agents include a compound of the application in combination with PSI-7977 and / or BMS-790052 (Daclatasvir). In yet another aspect, the at least two directly acting antiviral agents include a compound of the application in combination with PSI-7977 and / or BMS-650032 (Asunaprevir). In another aspect, the at least directly acting antiviral agents include a compound of the application in combination with PSI-7977, BMS-650032 (Asunaprevir), and / or BMS-790052 (Daclatasvir). The compound of the application can be added to these combinations or used to replace the listed polymerase.

[1704] In another aspect, the technology features a combination of at least two DAAs for treating a HCV infection, wherein the duration of the treatment regimen is no more than twelve weeks (e.g., the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5.4, or 3 weeks). The treatment comprises administering to a subject infected with HCV the at least two DAAs. The duration of the treatment can be 12 weeks and further comprises, for example, no more than 8 weeks (e.g., the duration is 8 weeks; or the duration is 7, 6, 5, 4, or 3 weeks). The treatment can comprise administering ribavirin but does not comprise administering an interferon. If one of the DAAs requires pharmacokinetic boosting, the treatment can further comprise administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. In another example, both DAAs are administered once a day. In another example, both DAAs are co-formulated in a single composition and administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, e.g., genotype la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As another non-limiting example, the patient can be a naive patient, a treated patient, an interferon null-responder (e.g., a non-responder, partial-responder, or relapser), or a non-candidate for interferon treatment.

[1705] In another aspect, the technology features a combination of at least two DAAs for treating a HCV infection, wherein the combination comprises a compound of the application in combination with a compound selected from the group consisting of:

[1706] a combination of PSI-7977 and / or PSI-938;

[1707] a combination of BMS-790052 and / or BMS-650032;

[1708] GS-5885 and / or GS-9451 in combination with

[1711] GS-5885, GS-9190 and / or GS-9451 in combination with

[1712] BI-201335 and / or BI-27127 in combination with

[1713] Telaprevir and / or VX-222 in combination with

[1714] PSI-7977 and / or TMC-435 in combination with

[1715] Danoprevir and / or R7128 in combination with

[1716] ABT-450 and / or ABT-267 and / or ABT-333 and / or ABT-493 and / or ABT-530 in combination with

[1717] one or more of the following protease inhibitors: ABT450, ABT-493, simeprevir, asunaprevir, GS-9451, ACH-2684, boceprevir, MK-5172, faleravir, and telaprevir;

[1718] one or more of the following NS5A inhibitors: ABT-267, ABT-530, GSK805, daclatasvir, Dedipasvir, GS-5816, ACH-3102, MK-8742, PPI-668, and Samatasvir; one or more of the following non-nucleoside NS5B inhibitors: ABT-333, TMC055, BMS-325, GS-9669, and Deleobuvir.

[1719] In one embodiment, the compound of the application used in the above combination therapy is 1911, 2023 or 2024. In a presently preferred embodiment, the novel compound of the application used in the above combination therapy is 2023. One or more of 1911, 2033 and 2024 can be used in combination with one or more of ABT-450, ABT-267 and / or ABT-333 and / or ABT-493 and / or ABT-530 and / or a compound disclosed in US 2010 / 0144608, US 61 / 339,964, US 2011 / 0312973, WO 2009 / 039127, US 2010 / 0317568, 2012 / 151158, US 2012 / 0172290, WO 2012 / 092411, WO 2012 / 087833, WO 2012 / 083170, WO 2009 / 039135, US 2012 / 0115918, WO 2012 / 051361, WO 2012 / 009699, WO 2011 / 156337, US 2011 / 0207699, WO 2010 / 075376, US 7,9105,95, WO 2010 / 120935, WO 2010 / 111437, WO 2010 / 111436, US 2010 / 0168384 or US 2004 / 0167123.

[1718] In yet another aspect, the present features concern the use of a combination of at least two DAAs for the treatment of HCV infection, wherein said combination comprises a compound of the application in combination with a compound selected from the group consisting of:

[1719] ABT-450 and / or ABT-267 and / or ABT-333 and / or a compound disclosed in US 2010 / 0144608, US 61 / 339,964, US 2011 / 0312973, WO 2009 / 039127, US 2010 / 0317568, 2012 / 151158, US 2012 / 0172290, WO 2012 / 092411, WO 2012 / 087833, WO 2012 / 083170, WO 2009 / 039135, US 2012 / 0115918, WO 2012 / 051361, WO 2012 / 009699, WO 2011 / 156337, US 2011 / 0207699, WO 2010 / 075376, US 7,9105,95, WO 2010 / 120935, WO 2010 / 111437, WO 2010 / 111436, US 2010 / 0168384, or US 2004 / 0167123;

[1720] a combination of PSI-7977 and / or BMS-790052;

[1721] a combination of PSI-7977 and / or BMS-650032;

[1722] a combination of PSI-7977, BMS-790052 and / or BMS-650032;

[1723] a combination of INX-189 and / or BMS-790052;

[1724] a combination of INX-189 and / or BMS-650032; or

[1725] a combination of INX-189, BMS-790052 and / or BMS-650032.

[1726] In yet another aspect, the present features are directed to the use of PSI-7977 or a combination of at least two DAAs for the treatment of an HCV infection, wherein the combination comprises a compound of the present application in combination with a compound selected from:

[1727] a combination of Mericitabine and / or Danoprevir;

[1728] a combination of Daclatasvir and / or BMS-791325; and

[1729] a combination of PSI-7977 and / or GS-5885;

[1730] The treatment comprises administering to a subject infected with HCV PSI-7977 or a combination of DAAs.

[1731] In yet another aspect, the technology features a combination of at least two DAAs for use in the treatment of an HCV infection, wherein the combination comprises a combination selected from the group consisting of:

[1732] Mericitabine and / or Danoprevir;

[1733] INX-189, Daclatasvir and / or BMS-791325; and

[1734] PSI-7977 and / or GS-5885;

[1735] The treatment comprises administering to a subject infected with HCV PSI-7977 or a combination of DAAs.

[1736] In yet another aspect, the technology features a combination of at least two DAAs for use in the treatment of an HCV infection, wherein the combination comprises a combination selected from the group consisting of a compound of the application in combination with:

[1737] Tegobuvir and / or GS-9256;

[1738] BMS-791325, Anidulafvir and / or Daclatasvir; and

[1739] TMC-435 and / or Daclatasvir.

[1740] The treatment comprises administering to a subject infected with HCV a combination of DAAs.

[1741] In yet another aspect, the technology features a compound of the application in combination with PSI-7977 and / or BMS-790052 for use in the treatment of an HCV infection. The treatment comprises administering to a subject infected with HCV a combination of DAAs.

[1742] In yet another aspect, the technology features a compound of the application in combination with PSI-7977 and / or TMC-435 for use in the treatment of an HCV infection.

[1743] In yet another aspect, the technology features a compound of the application in combination with Danoprevir and / or Mericitabine for use in the treatment of an HCV infection.

[1744] In yet another aspect, the technology features a compound of the application in combination with Danoprevir and / or BMS-791325 for use in the treatment of an HCV infection. The treatment comprises administering to a subject infected with HCV a combination of DAAs.

[1745] In yet another aspect, the technical feature resides in a compound of the application in combination with PSI-7977 and / or GS-5885 for use in the treatment of an HCV infection. The treatment comprises administering the combination of DAAs to a subject infected with HCV.

[1746] The treatment regimen lasts no more than sixteen weeks (e.g., the duration is 16 weeks; or the duration is 14 weeks, 12 weeks, or 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week). The treatment includes administration of ribavirin but does not include administration of interferon. If pharmacokinetic boosting is required for one of the DAAs, the treatment can include administration of ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once daily and the other DAA can be administered twice daily. In another example, both DAAs are administered once daily. In yet another example, both DAAs are co-formulated in a single composition and administered simultaneously (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As another non-limiting example, the patient can be a naive patient, a treatment- experienced patient, an interferon non-responder (e.g., a non-responder), or a non-candidate for interferon treatment.

[1747] In yet another embodiment of this aspect of the application, the at least two DAAs include an HCV protease inhibitor of the application and an HCV polymerase inhibitor. The treatment can last, for example, but not limited to, no more than 12 weeks, such as 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. Preferably, the treatment lasts 12 weeks. The treatment can also last 8 weeks. The subject being treated can be, for example, a naive patient. The subject can also be a treatment-experienced patient or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1, for example, HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

[1748] In still another embodiment of this aspect of the application, the at least two DAAs include a compound of the application with an HCV protease inhibitor and a non-nucleos(t)ide HCV polymerase inhibitor. The treatment can last, for example, but not by way of limitation, no more than 12 weeks, such as 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. Preferably, the treatment lasts 12 weeks. The treatment can also last 8 weeks. The subject being treated can be, for example, a treatment naive patient. The subject can also be a treatment experienced patient or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1 (e.g., HCV genotype la). As another non-limiting example, the subject being treated is infected with HCV genotype 3.

[1749] In still another embodiment of this aspect of the application, the DAA includes a compound of the application with an HCV protease inhibitor and an HCV NS5A inhibitor.

[1750] In still another embodiment of this aspect of the application, the at least two DAAs include an HCV protease inhibitor and an HCV NS5A inhibitor of the application.

[1751] In still another embodiment of this aspect of the application, the DAA includes a compound of the application and an HCV non-nucleos(t)ide polymerase inhibitor and an HCV NS5A inhibitor.

[1752] In still another embodiment of this aspect of the application, the DAA can include an HCV nucleos(t)ide polymerase inhibitor and an HCV NS5A inhibitor of the application.

[1753] In still another embodiment of this aspect of the application, the at least two DAAs include a compound of the application with PSI-7977 and / or TMC-435.

[1754] In still another embodiment of this aspect of the application, the DAA includes a compound of the application with PSI-7977 and / or daclatasvir.

[1755] In still another embodiment of this aspect of the application, the DAA includes a compound of the application with PSI-7977 and / or GS-5885.

[1756] In still another embodiment of this aspect of the application, the DAA includes a compound of the application with Mericitabine and / or Danoprevir.

[1757] In still another embodiment of this aspect of the application, the DAA includes a compound of the application with BMS-790052 and / or BMS-650032.

[1758] In yet another embodiment of this aspect of the application, the DAAs include a compound of the present application and INX-189, daclatasvir, and / or BMS-791325.

[1759] The treatment regimen of the present technology generally constitutes a complete treatment regimen, i.e., no subsequent interferon-containing regimen is planned. Thus, the treatment or use described herein generally does not include any subsequent interferon-containing treatment.

[1760] In one aspect of the disclosure, "infection" or "bacterial infection" refers to an infection caused by Acinetobacter, Bacteroides, Burkholderia, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Enterobacter, Enterococcus, Escherichia, Fusobacterium, Gardnerella, Haemophilus, Helicobacter, Klebsiella, Legionella, Moraxella, Morganella, Mycoplasma, Neisseria, Peptococcus, Peptostreptococcus, Proteus, Pseudomonas, Salmonella, Serratia, Staphylococcus, Streptococcus, Stenotrophomonas, or Ureaplasma.

[1761] In one aspect of the disclosure, "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter lwoffi, Bacteroides fragilis, Bacteroides vulgatus, Burkholderia cepacia, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia urealyticum, Chlamydophila pneumoniae, Clostridium difficile, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecium, Enterococcus faecalis, Escherichia coli, Gardnerella vaginalis, Haemophilus parainfluenzae, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Methicillin-resistant Staphylococcus aureus, Methicillin-sensitive Staphylococcus aureus, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Penicillin-resistant Streptococcus pneumoniae, Penicillin-sensitive Streptococcus pneumoniae, Peptostreptococcus asaccharolyticus, Peptostreptococcus micros, Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis, Proteus mirabilis, Pseudomonas aeruginosa, Quinolone-resistant Staphylococcus aureus, Quinolone-resistant Staphylococcus epidermidis, Salmonella typhi, Salmonella paratyphi A, Salmonella enteritidis, Salmonella typhimurium, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Stenotrophomonas maltophilia, Ureaplasma urealyticum, Vancomycin-resistant Enterococcus faecium, Vancomycin-resistant Enterococcus faecalis, Vancomycin-resistant Staphylococcus aureus, Vancomycin-resistant Staphylococcus epidermidis, Mycobacterium tuberculosis, Clostridium perfringens, Klebsiella oxytoca, Neisseria meningitidis, Proteus vulgaris, or Coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophyticus).

[1762] In one aspect of the disclosure, “infection” or “bacterial infection” refers to an aerobic bacteria, obligate anaerobic bacteria, facultative anaerobic bacteria, gram-positive bacteria, gram-negative bacteria, gram-indeterminate bacteria, or atypical respiratory pathogen.

[1763] In some embodiments, the disclosure relates to treating a bacterial infection, such as a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, or a urinary tract infection.

[1764] In some embodiments, the disclosure relates to treating a bacterial infection, such as an infection caused by a drug-resistant bacteria.

[1765] In some embodiments, the disclosure relates to treating a bacterial infection, such as a community-acquired pneumonia, a hospital-acquired pneumonia, a skin and skin structure infection, a gonococcal cervicitis, a gonococcal urethritis, a febrile neutropenia, an osteomyelitis, an endocarditis, a urinary tract infection, and an infection caused by a drug-resistant bacteria, such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant Enterococcus, syphilis, ventilator-associated pneumonia, intra-abdominal infection, gonococcus, meningitis, tetanus, or tuberculosis.

[1766] In some embodiments, the disclosure relates to treating a fungal infection, such as an infection caused by ringworm, Microsporum, Trichophyton, Epidermophyton, Candida, Cryptococcus, or Aspergillus.

[1767] In some embodiments, the disclosure relates to treating an infection caused by a protozoan, including but not limited to malaria, amebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery.

[1768] Certain compounds disclosed herein can be used to prevent or treat an infection of a Plasmodium in a subject and / or to prevent, treat, and / or alleviate complications and / or symptoms associated therewith, and can then be used to prepare a medicament for the treatment and / or prevention of such diseases. Malaria can be caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae.

[1769] In one embodiment, the compound is administered to a subject after the subject has been exposed to a Plasmodium. In another embodiment, the compound disclosed herein is administered to a subject prior to the subject traveling to a country where malaria is endemic.

[1770] The compound or the above pharmaceutical composition can also be used in combination with one or more other therapeutically useful substances selected from anti-malarial drugs such as quinolines (e.g., quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine); peroxide anti-malarials (e.g., artemisinin, artesunate, artemether, lumefantrine); sulfadoxine-pyrimethamine anti-malarials (e.g., Fansidar®); hydro naphthoquinolines (e.g., atovaquone); acroline-type anti-malarials (e.g., pyronaridine); and anti-protozoal agents such as ethyl-stibamine, oxyclozanide, pentamidine, tribendimidine, quinapyramine, puromycin, propamidine, nifursol, melarsoprol, nimorazole, nifuramide, and the like.

[1771] In one embodiment, the compounds disclosed herein can be used in combination with one additional drug selected from chloroquine, a hortisan, artemisinin, 8-aminoquinoline, amodiaquine, artemether, artesunate, artemisinin extract, artemotil, lumefantrine, atovaquone, azithromycin, biguanides, chloroquine phosphate, chlorproguanil, cycloguanil, dapsone, dibutyl lafium, desipramine, doxycycline, dihydrofolate reductase inhibitors, dipyridamole, halofantrine, haloperidol, hydroxychloroquine sulfate, imipramine, mefloquine, penfluridol, phospholipid inhibitors, primaquine, proguanil, pyrimethamine, pyronaridine, quinine, quinidine, quinacrine artemisinin, sulfonamides, sulfones, sulfadoxine, sulfamethoxypyrazine, tafenoquine, tetracyclines, tetrandrine, triazines, salts, or mixtures thereof.

[1772] cancer

[1773] In a typical embodiment, the disclosure relates to a method of treating cancer comprising administering to a patient a compound disclosed herein. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[1774] In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioalveolar cancer), and prostate cancer.

[1775] In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of biliary tract cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, endometrial cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, leukemia (including ALL and CML), multiple myeloma, and lymphoma.

[1776] In some embodiments, this disclosure relates to a compound disclosed herein or a pharmaceutically acceptable salt thereof, as defined herein, for the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastatic tumors, and also for the treatment of glioblastoma.

[1777] In some embodiments, the compounds disclosed herein may be used clinically, either alone as a single agent or in combination with other clinically relevant agents. These compounds may also prevent potential cancer resistance mechanisms that may arise from a group of gene mutations.

[1778] The anticancer therapeutic agents defined herein may be administered as a single treatment, or, in addition to the compounds disclosed herein, may include conventional surgery, radiation therapy, or chemotherapy. Such chemotherapy may include one or more antitumor agents from the following classes:

[1779] (i) Antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosourea); antimetabolites (e.g., antifolate agents, such as fluoropyrimidines (e.g., 5-fluorouracil and gemcitabine), sulfadiazine, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); and antitumor antibiotics (e.g., anthracycline antibiotics, such as doxorubicin, bleomycin, and dextrin). Anthracycline antibiotics such as rhubarb, donomycin, epirubicin, idarubicin, mitomycin C, dextrin, and scintillans; antimitotic agents (such as vinblastine alkaloids (such as vincristine, vinblastine, vinorelbine, and vinorelbine) and taxanes (such as paclitaxel and tesolete)); topoisomerase inhibitors (such as epipodophyllotoxin (such as etoposide and teniposide), acridine, topotecan, and camptothecin); and proteasome inhibitors (such as bortezomib). ); and the drug Anagrel And the drug alpha-interferon;

[1780] (ii) Cell inhibitors such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), anti-androgens (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors (e.g., finasteride);

[1781] (iii) agents that inhibit cancer cell invasion (for example metalloproteinase inhibitors (such as marimastat) and inhibitors of urokinase plasminogen activator receptor function);

[1782] (iv) inhibitors of growth factor function, for example such inhibitors including growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin TM ] and the anti-erbb l antibody cetuximab), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family, for example EGFR family tyrosine kinase inhibitors (such as: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib) and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family, for example inhibitors of the hepatocyte growth factor family, for example inhibitors of phosphatidylinositol 3-kinase (PI3K), for example inhibitors of mitogen-activated protein kinase (MEK1 / 2), for example inhibitors of protein kinase B (PKB / Akt), for example inhibitors of the Src tyrosine kinase family and / or the Abelson (AbI) tyrosine kinase family (such as dasatinib (BMS-354825) and imatinib mesylate (Gleevec TM )); and agents that modify STAT signalling;

[1783] (v) antiangiogenic agents, such as those which inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin TM ]) and compounds which work by other mechanisms (for example linomide, inhibitors of integrin ocvβ3 function and angiostatin);

[1784] (vi) vascular damaging agents such as combretastatin;

[1785] (vii) antisense therapy, for example antisense therapy directed to the above targets, for example anti-ras antisense;

[1786] (viii) gene therapy approaches, including for example approaches in which abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT) are replaced by normal versions of those genes (gene-directed enzyme prodrug therapy), such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and approaches in which patient tolerance to chemotherapy or radiotherapy is increased (for example multiple drug resistance gene therapy); and

[1787] (ix) immunotherapy methods, including, for example, in vitro and in vivo methods for increasing the immunogenicity of tumor cells in a patient, such as transfection with cytokines (such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor), methods to decrease T-cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies, as well as methods using the immunomodulatory drugs thalidomide and lenalidomide

[1788] Such combination therapies can be achieved by way of separate, sequential or alternating dosing regimens of the individual components of the therapeutic agents. Such combination products utilize the compounds of the present disclosure or a pharmaceutically acceptable salt thereof at doses and other

[1789] Formulations

[1790] The pharmaceutical compositions disclosed herein can be in the form of pharmaceutically acceptable salts, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are hydrochloric, hydrobromic, sulfuric, nitric, acetic, and citric acid, as well as pharmaceutically acceptable acids known per se (cf. references mentioned below).

[1791] When a compound of the present disclosure comprises an acidic group and a basic group, the compound of the present disclosure can also form internal salts, and such compounds are within the scope of the present disclosure. When a compound of the present disclosure comprises a hydrogen- donating heteroatom (e.g., NH), the present disclosure also encompasses salts and / or isomers formed by the transfer of a hydrogen atom to a basic group or atom within the molecule.

[1792] Pharmaceutically acceptable salts of the compounds include the acid addition and base salts. Suitable acid addition salts are formed from acids which form nontoxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, heptanoate, hexanoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / diphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate salts. Suitable base salts are formed from bases which form nontoxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Acid and base half salts, such as hemisulfate and hemicalcium salts, can also be formed. For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002), which is incorporated herein by reference.

[1793] The compounds described herein can be administered in the form of a prodrug. A prodrug can include a covalently bound carrier that releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present on the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds in which a hydroxyl group is bonded to any group, which, when used in a mammalian subject, cleaves to form a free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups in the compounds. Methods of constructing compounds as prodrugs are known, for example, in Testa and Mayer, “Hydrolysis in Drug and Prodrug Metabolism” (Wiley, 2006). Typical prodrugs form active metabolites by hydrolysis or cleavage of amides, lactams, peptides, carboxylate esters, epoxides, or inorganic acid esters by hydrolytic enzymes. Ester prodrugs have been found to be susceptible to in vivo degradation to release the corresponding alcohol. See, for example, Imai, Drug Metab Pharmacokinet, 2006, vol. 21, no. 3, pp. 173-85, “Human carboxylesterase isozymes: catalytic properties and rational drug design.”

[1794] Pharmaceutical compositions for use in the present disclosure typically include an effective amount of a compound and a suitable pharmaceutically acceptable carrier. Formulations can be prepared according to known methods, which generally include mixing at least one compound according to the present disclosure with one or more pharmaceutically acceptable carriers, and if desired, other pharmaceutically active compounds, if necessary under aseptic conditions. Reference is made to U.S. Patent No. 6,372,778, U.S. Patent No. 6,369,086, U.S. Patent No. 6,369,087, U.S. Patent No. 6,372,733, the above other references, and to standard manuals, such as the latest edition of “Remington’s Pharmaceutical Sciences.”

[1795] In general, for pharmaceutical use, the compounds can be formulated into pharmaceutical formulations including at least one compound and at least one pharmaceutically acceptable carrier, diluent, or excipient, and optionally one or more other pharmaceutically active compounds.

[1796] The pharmaceutical formulations of the present disclosure are preferably in unit dosage form and can be suitably packaged, e.g., in a box, blister, vial, bottle, pouch, ampoule, or any other suitable single-dose or multi-dose holder or container (suitably labeled); optionally, one or more leaflets containing product information and / or instructions for use. Generally, such unit doses will contain between 1 and 1000 mg (typically between 5 and 500 mg) of at least one compound of the present disclosure, e.g., about 10, 25, 50, 100, 200, 300, or 400 mg per unit dose.

[1797] The compounds can be administered by a variety of routes, including oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, depending primarily on the particular formulation used. The compounds are generally administered in an "effective amount," by which is meant any amount of the compound that, upon proper administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Typically, such effective amounts are generally 0.01 to 1000 mg, more typically 0.1 to 500 mg, such as 1 to 250 mg, per kilogram of patient body weight per day, depending on the condition to be prevented or treated and the route of administration. For example, about 5, 10, 20, 50, 100, 150, 200, or 250 mg per kilogram of patient body weight per day can be administered, either as a single daily dose or divided into one or more doses per day. The amount to be administered, route of administration, and further treatment regimen can be determined by the treating clinician, taking into account factors such as the age, sex, and general condition of the patient, as well as the nature and severity of the disease / symptoms to be treated. Reference is made to U.S. Patent No. 6,372,778, U.S. Patent No. 6,369,086, U.S. Patent No. 6,369,087, U.S. Patent No. 6,372,733, the other references cited above, and to standard manuals, such as the most recent edition of "Remington's Pharmaceutical Sciences."

[1798] For oral administration forms, the compounds can be mixed with suitable additives such as excipients, stabilizers or inert diluents and processed by conventional methods into suitable administration forms such as tablets, coated tablets, hard capsules and aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the preparation process can be carried out both in dry granules and in wet granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycols and polypropylene glycols can also be used as further auxiliaries for other administration forms. As immediate release tablets, these compositions can comprise microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

[1799] When administered by nasal aerosol or inhalation, the compositions can be prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions, emulsions or physiologically tolerable salts of the compounds of the present disclosure in physiologically tolerable solvents such as ethanol or water or mixtures of such solvents. If desired, the formulations can additionally comprise other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as propellants.

[1800] For subcutaneous or intravenous administration, the compounds are, if desired, introduced into solutions, suspensions or emulsions together with conventional substances such as solubilizers, emulsifiers or other auxiliaries. The compounds can also be lyophilized and the lyophilizates obtained used for the production of, for example, injection or infusion preparations. Suitable solvents are, for example, water, aqueous saline solutions, alcohols such as ethanol, propanol, glycerol, sugar solutions such as glucose, mannitol solutions or mixtures of the various solvents mentioned. The injectable solutions or suspensions can be formulated according to known art using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland fixed oils, including synthetic mono- or diglycerides and fatty acids, including oleic acid.

[1801] When administered rectally in the form of suppositories, the formulations can be prepared by mixing the compounds of the formula I with suitable non-irritating excipients such as cocoa butter, synthetic glyceride or polyethylene glycols, which are solid at ordinary temperatures but liquidify and / or dissolve in the rectal cavity to release the drug.

[1802] In certain embodiments, it is contemplated that these compositions can be sustained release formulations. Typical sustained release forms utilize an enteric coating. Typically, a barrier is applied to an oral drug that controls where in the digestive system the oral drug is absorbed. Enteric coatings can prevent the drug from being released before it reaches the small intestine. Enteric coatings can include polymers of polysaccharides such as maltodextrin, xanthan gum, sclerotium gum, starch, alginate, pullulan, hyaluronic acid, chitin, chitosan, and the like; other natural polymers such as proteins (albumin, gelatin, and the like), poly-L-lysine; poly(sodium acrylate); poly(hydroxyalkyl methacrylate) (e.g., poly(hydroxyethyl methacrylate)); polyvinyl alcohol; polyvinyl acetate; polyvinylpyrrolidone; gums such as guar gum, gum arabic, karaya gum, gum ghatti, locust bean gum, tamarind gum, gellan gum, tragacanth gum, agar, pectin, gluten, and the like; poly(vinyl alcohol); ethylene-vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), and sodium carboxymethylcellulose (Na-CMC); and copolymers and / or (simple) mixtures of any of the above polymers. Certain of the above polymers can be further cross-linked by standard techniques. TM ) carboxyvinyl polymers; polyvinyl alcohol; polyvinyl acetate; polyvinylpyrrolidone; gums such as guar gum, gum arabic, karaya gum, gum ghatti, locust bean gum, tamarind gum, gellan gum, tragacanth gum, agar, pectin, gluten, and the like; poly(vinyl alcohol); ethylene-vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), and sodium carboxymethylcellulose (Na-CMC); and copolymers and / or (simple) mixtures of any of the above polymers. Certain of the above polymers can be further cross-linked by standard techniques.

[1803] The choice of polymer will be determined by the nature of the active ingredient / drug employed in the compositions of the present disclosure, as well as the desired release rate. In particular, it will be appreciated by those skilled in the art that, for example, in the case of HPMC, generally speaking, higher molecular weight drugs will release from the composition at a slower rate. Furthermore, in the case of HPMC, different degrees of substitution of the methoxyl and hydroxypropoxyl groups will result in variations in the rate of drug release from the composition. In this regard, and as noted above, it can be desirable to provide the compositions of the present application in the form of a coating, wherein the polymeric carrier is provided by a mixture of two or more polymers (e.g., polymers of different molecular weight) to produce a particular desired or expected release profile.

[1804] Microspheres of polylactide, polyglycolide, and their copolymer poly(lactide-co-glycolide) can be used to form sustained release protein delivery systems. Proteins can be entrapped in poly(lactide-co-glycolide) microspheres reservoirs by a variety of methods including forming a water-in-oil emulsion with an aqueous protein and an organic solvent-borne polymer (emulsion method), forming a solid protein suspension with solid protein dispersed in a solvent-borne polymer solution (suspension method), or by dissolving the protein in a solvent-borne polymer solution (dissolution method). Poly(ethylene glycol) can be attached to the protein (PEGylation) to increase the in vivo half-life of circulating therapeutic proteins and to reduce the chance of an immune response.

[1805] Liposome suspensions, including liposomes targeted to viral antigens, can also be prepared in a conventional manner, to prepare a pharmaceutically acceptable carrier. This can be suitable for delivery of free nucleosides, acyl nucleosides, or phosphate prodrug forms of the nucleoside compounds according to the present application.

[1806] It will be appreciated that the nucleosides of the present application have multiple chiral centers and can exist in and be isolated as optically active and racemic forms. Some compounds can exhibit polymorphism. It should be understood that the present application encompasses any racemic, optically active, diastereomeric, polymorphic, stereoisomeric form, or mixtures thereof, of a compound of the present application that has useful properties as described herein. Methods of preparing optically active forms (e.g., by resolution of racemic forms, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) are well known in the art.

[1807] The carbons of the nucleosides are chiral, and their non-hydrogen substituents (the base and CHOR groups, respectively) can be cis (on the same side) or trans (on opposite sides) with respect to the sugar ring system. Thus, four optical isomers are represented by the following configurations (when the sugar moiety is oriented in the horizontal plane such that the oxygen atom is behind): cis (in which both groups are "up", corresponding to the configuration of the naturally occurring β-D nucleoside), cis (in which both groups are "down", which is a non-naturally occurring β-L configuration), trans (in which the C2' substituent is "up" and the C4' substituent is "down"), and trans (in which the C2' substituent is "down" and the C4' substituent is "up"). A "D-nucleoside" is a cis nucleoside of the natural configuration, and an "L-nucleoside" is a cis nucleoside of the non-naturally occurring configuration.

[1808] Likewise, most amino acids are chiral (designated L or D, with the L enantiomer being the naturally occurring configuration) and can exist as individual enantiomers.

[1809] Examples of methods to obtain optically active materials are known in the art and include at least the following: i) physical separation of crystals - a technique to manually separate macroscopic crystals of individual enantiomers. This technique can be used if crystals of individual enantiomers exist, i.e. the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique to individually crystallize each enantiomer from a solution of the racemate (only possible if the latter is a conglomerate of solid states); iii) enzymatic resolution - a technique to partially or completely separate a racemate by different reaction rates of the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a technique of synthesis of enantiomerically pure or enriched precursors for synthesis where at least one synthesis step uses an enzymatic reaction to obtain the desired enantiomer; v) chemical asymmetric synthesis - a technique of synthesis where the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e. chirality) in the product. This can be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomeric separation - a technique where a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts each enantiomer into a diastereomer. The resulting diastereomers are then separated by chromatography or crystallization (as their structural differences are now more pronounced) and the chiral auxiliary is subsequently removed to obtain the desired enantiomer; vii) primary and secondary asymmetric transformations - a technique where a diastereomer from a racemate is equilibrated to produce a preponderance in the solution of the diastereomer of the desired enantiomer, or the diastereomer preferentially crystallizes from the desired enantiomer to perturb the equilibrium so that eventually in principle all the material is converted from the desired enantiomer to the crystallized diastereomer. The desired enantiomer is then liberated from the diastereomer; viii) kinetic resolution - this technique refers to the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by different reaction rates of the enantiomers with a chiral non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthesis technique where the desired enantiomer is obtained from an achiral starting material and where the stereochemical integrity is not compromised or only minimally compromised during the synthesis; x) chiral liquid chromatography - a technique where the enantiomers of a racemate are separated in a liquid mobile phase due to their different interactions with a stationary phase. The stationary phase can be made of chiral material, or the mobile phase can contain additional chiral material to cause the different interactions; xi) chiral gas chromatography - a technique where a racemate is volatilized and the enantiomers are separated due to their different interactions with a chromatographic column containing a stationary non-racemic chiral adsorbent in a gaseous mobile phase; xii) extraction with chiral solvents - a technique to separate enantiomers by preferentially dissolving one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique where a racemate is contacted with a thin film barrier.The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration difference or pressure difference causes preferential transport through the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane allowing only one enantiomer of the racemate to pass through. In one embodiment chiral chromatography, including simulated moving bed chromatography, is used. Various chiral stationary phases are commercially available.

[1810] Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are meant to include E and Z geometric isomers.

[1811] In addition, some of the nucleosides described herein can exist in tautomeric forms, such as keto-enol tautomers. Each tautomer and mixtures thereof are intended to be included in the compounds of the application.

[1812] Examples

[1813] Example 1.

[1814] Preparation of conjugates

[1815] Several sets of monophosphate and diphosphate prodrugs have been prepared. See Jessen et al., "Bioreversible Protection of Nucleoside Diphosphates", Angewandte Chemie- International Edition English, 2008, Vol. 47, No. 45, pp. 8719-8722, which is incorporated herein by reference. To prevent cleavage of the P-O-P anhydride linkage, a rapidly cleaving pendant group (e.g., bis-(4-acyloxybenzyl)-nucleoside diphosphates (BAB-NDP) is deacylated by endogenous esterases) is used to generate a negative charge on the second phosphate. See also Routledge et al., "Synthesis, Bioactivation and Anti-HIV Activity of 4-Acyloxybenzyl-bis(nucleosid-5'-yl) Phosphates", Nucleosides & Nucleotides, 1995, Vol. 14, No. 7, pp. 1545-1558, and Meier et al., "Comparative study of bis(benzyl)phosphate triesters of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and cycloSal-d4TMP-hydrolysis, mechanistic insights and anti-HIV activity", Antiviral Chemistry and Chemotherapy, 2002, Vol. 13, pp. 101-114, both of which are incorporated herein by reference. Once this occurs, the P-O-P anhydride linkage is less susceptible to cleavage, and the remaining protecting group can then be subjected to final deprotection to yield the nucleoside diphosphate.

[1816] Other methods for preparing diphosphate and monothiophosphate prodrugs are shown in Figure 5. Standard coupling conditions are used to prepare the sphingolipid-nucleoside monophosphate prodrugs. The corresponding diphosphate prodrugs can be prepared according to the protocols shown in Figure 5 and as provided in Smith et al., "Substituted Nucleotide Analogs," U.S. Patent Application 2012 / 0071434; Skowronska et al., "Reaction of Oxophosphorane-Sulfenyl and Oxophosphorane-Selenenyl Chlorides with Dialkyl Trimethylsilyl Phosphites - Novel Synthesis of Compounds Containing a Sulfur or Selenium Bridge Between 2 Phosphoryl Centers," Journal of the Chemical Society-Perkin Transactions 1, 1988, Issue 8, pp. 2197-2201; Dembinski et al., "An Expedient Synthesis of Symmetrical Tetra-Alkyl Mono-thiopyrophosphates," Tetrahedron Letters, 1994, Vol. 35, No. 34, pp. 6331-6334; Skowronska et al., "Novel Synthesis of Symmetrical Tetra-Alkyl Monothiophosphates," Tetrahedron Letters, 1987, Vol. 28, No. 36, pp. 4209-4210; and Chojnowski et al., "Methods of Synthesis of O, O-Bis Trimethyl Silyl Phosphorothiolates," Synthesis-Stuttgart, 1977, No. 10, pp. 683-686, all of which are incorporated herein by reference in their entirety.

[1817] Example 2.

[1818] Activity of 2-fluoro nucleosides

[1819] When activated to the corresponding triphosphates, the ribonucleoside analogs inhibit RNA-dependent RNA viral replication by acting as competitive substrate inhibitors of the virus-encoded RdRp. Compounds in this therapeutic class are useful for treating viruses found in, but not limited to, the Arenaviridae, Bunyaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Togaviridae families. Certain compounds disclosed herein are expected to have advantages such as high genetic barrier to antiviral resistance; broad activity within a viral family; and high oral bioavailability, with targeted delivery to the site of infection.

[1820] Nucleoside analogs are designed with a 2'-alpha-fluoro substituent to mimic natural ribonucleosides. The C-F bond length Similar to the C-O bond length Fluorine is a heteroatom that makes the fluoro substituent heteropolar and a hydrogen bond acceptor in place of the hydroxyl group. Unlike the ribonucleoside analogs currently in clinical trials for the treatment of HCV infection, the 2',3'-dideoxy-2'-fluoro nucleoside analogs encompassed by the present disclosure lack the 3'-hydroxyl group in certain embodiments, and are therefore obligate chain terminators of viral replication. Once the nucleosides are converted to their triphosphates, they act as competitive substrate inhibitors of the virus-encoded RdRp. Upon incorporation of the chain terminator into nascent RNA, viral replication ceases. One advantage of obligate chain terminators is that they have no mutagenic effect on the host when treating chronic disease.

[1821] Example 3.

[1822] Results of ZIKV NS5 RNA-dependent RNA polymerase assays

[1823] The following table shows the activity of selected mimic triphosphates against ZIKV NS5 RdRp.

[1824]

[1825] Example 4. Results of ZIKV infectivity assays

[1826]

[1827]

[1828] Example 5.

[1829] General procedure for base coupling

[1830] Prepare the per-silylated nucleobase in a round bottom flask under nitrogen with the dry nucleobase (15.5 mmol), trimethylsilyl chloride (12.21 mmol), and bis(trimethylsilyl)amine (22.2 mmol). Stir the mixture under reflux overnight (16 hours) until all the solids are dissolved. Cool the mixture to room temperature, remove the volatiles by rotary evaporation, then high vacuum to yield the per-silylated nucleobase. Immediately use this compound in the next step.

[1831] Prepare the per-silylated nucleobase in a round bottom flask under nitrogen with the dry nucleobase (15.5 mmol), trimethylsilyl chloride (12.21 mmol), and bis(trimethylsilyl)amine (22.2 mmol). Stir the mixture under reflux overnight (16 hours) until all the solids are dissolved. Cool the mixture to room temperature, remove the volatiles by rotary evaporation, then high vacuum to yield the per-silylated nucleobase. Immediately use this compound in the next step.

[1832] Add SnCl4(11.63 mmol) dropwise to the mixture by syringe and stir the mixture at room temperature for 6 hours until all the starting material is consumed. Cool the mixture to 0 °C and add saturated aqueous NaHCO3(125 mL). Warm the mixture to room temperature and stir for 30 minutes. Extract the mixture with EtOAc (2 x 200 mL) and wash the combined organic layers with brine (1 x 100 mL), dry over Na2SO4, filter, and concentrate by rotary evaporation to yield 5.5 g of crude product. Dissolve the crude material in dichloromethane, load onto celite, and perform flash chromatography to yield the desired acetate-protected product. Use the general deprotection conditions to deprotect the ribonucleoside.

[1833] Example 6.

[1834] General coupling of cytosine analogs

[1835] Prepare the per-silylated nucleobase in a round bottom flask under nitrogen with the dry nucleobase (15.5 mmol), trimethylsilyl chloride (12.21 mmol), and bis(trimethylsilyl)amine (22.2 mmol). Stir the mixture under reflux overnight (16 hours) until all the solids are dissolved. Cool the mixture to room temperature, remove the volatiles by rotary evaporation, then high vacuum to yield the per-silylated nucleobase. Immediately use this compound in the next step. 4A flask of benzoyl protected cytosine analogue (0.793 mmol) was charged with bis(trimethylsilyl)amine (8.45 mmol) and ammonium sulfate (0.02 mmol) under N2. This was heated at reflux for 2 h, after cooling to room temperature the solvent was removed in vacuo and further dried under high vacuum for 1 h. The residue was dissolved in anhydrous chlorobenzene (10 ml) and β-D-ribofuranosyl 1,2,3,5-tetraacetate (0.53 mmol) was added. SnCl4(0.27 ml, 2.3 mmol) was then added dropwise. After stirring at room temperature for 1 h, this was then heated to 60 °C overnight. After cooling to 0 °C, solid sodium bicarbonate (0.85 g) was added followed by EtOAc (5 mL). This was stirred for 15 min, then water (0.5 mL) was added slowly. The insoluble material was filtered off and washed with more EtOAc (2.5 mL). The filtrate was washed once with water, once with brine, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by SiO2column chromatography.

[1836] Example 7.

[1837] General deamination conditions

[1838] An 80% aqueous solution of AcOH (30 mL) of benzoyl protected cytidine ribonucleoside (1.02 mmol) was heated at reflux for 16 h. The solvent was then removed under vacuum and dried under high vacuum. The white solid was triturated with diethyl ether, filtered off and washed with more diethyl ether to give the desired product.

[1839] Example 8.

[1840] General benzoyl deprotection conditions

[1841] A benzoyl protected ribonucleoside analogue (0.25 mmol) was stirred with 7 N ammonia in MeOH at room temperature for 15.5 h. The solvent was then removed and the crude material was purified by SiO2column chromatography to give the desired ribonucleoside.

[1842] Example 9.

[1843] Synthesis of methyl-β-D-2'-spirooxirane riboside

[1844]

[1845] Procedure for the preparation of 1. A solution of methyl β-D- riboside (40.9 mmol, 1.0 equiv) was added dropwise via syringe to a solution of 1,3-dichloro-1,1,3,3-tetraisopropyl disiloxane (45.0 mmol, 1.1 equiv) over 15 min at 0 °C under an argon atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for a further 3 h. The reaction was quenched with MeOH (10 mL) and the solvent evaporated. The viscous residue was dissolved in DCM (400 mL) and washed with saturated NaCO3H solution, brine and dried over MgSO4. The solvent was evaporated and co-evaporated with toluene to remove traces of pyridine. The product was purified by column chromatography on silica gel eluting with hexanes:ethyl acetate (3:2) to give the desired product.

[1846]

[1847] Procedure for the preparation of 2. A solution of protected riboside 1 (32.9 mmol, 1 equiv) in DCM (150 mL) was added to Dess-Martin periodinane (18.1 g, 42.7 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred at 25-30 °C for 24 h. After this time, about 75 mL of DCM was evaporated, diethyl ether (400 mL) was added to the reaction mixture and the precipitate was removed by filtration through celite. The resulting filtrate was washed with 300 mL of saturated NaHCO3solution containing 18.5 g of Na2S2O3and brine, respectively. The organic layer was dried over anhydrous Na2SO4and the organic layer was evaporated to give 2 which was used in the next step without further purification.

[1848]

[1849] Procedure for the preparation of 3. A solution of ketone 2 (8.87 mmol, 1 equiv) and DCM (2.28 mL, 35.5 mmol, 4.0 equiv) in THF (50 mL) was added to a solution of LDA (31.1 mL, 1.0 M, 3.5 equiv) over 20 min at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 3 h and then at room temperature overnight. The reaction was quenched with saturated NH4Cl solution. The solution was extracted with diethyl ether (150 mL x 2). The combined organic layers were washed with brine, dried over MgSO4, evaporated and then purified by column chromatography on silica gel eluting with hexanes:ethyl acetate (3:1) to give 3. The epoxide can then be opened using sodium chloride, sodium azide, followed by reduction with TBAF. After converting the resulting aldehyde to an alkyne, the riboside can be alkylated using a general alkylation of a riboside.

[1850] Example 10.

[1851] General conversion of aldehyde to alkyne

[1852] The 2'-aldehyde obtained from the ring opening of the epoxide above can be converted to the aldehyde using the following protocol. A solution of the 2'-aldehyde in anhydrous DCM (10 mL / mmol riboside) is treated with carbon tetrabromide (2.0 equivalents) followed by triphenylphosphine (2.0 equivalents) in anhydrous DCM (10 mL / mmol riboside) over 10 minutes at 0 °C under argon. The reaction is stirred overnight while warming to room temperature. The reaction mixture is then diluted with petroleum ether, filtered, and concentrated under reduced pressure. The purified product is obtained after silica gel chromatography. The purified intermediate is then dissolved in anhydrous THF (10 mL / mmol) under argon and the reaction mixture is cooled to -78 °C. Butyllithium (2 equivalents) is added to the solution. The reaction is allowed to proceed with stirring for 1 hour and quenched with ammonium chloride or an appropriate electrophile. The reaction mixture is warmed to room temperature and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. If the product is a carbohydrate, the product can be subjected to the general base coupling procedure followed by appropriate deprotection conditions, but if the product is a protected ribonucleoside, the product can be subjected to appropriate deprotection conditions.

[1853] Example 11.

[1854] General synthesis of 2'-chloro substituted spiro epiribonucleoside analogs

[1855]

[1856] Procedure for the preparation of 11. A solution of the ribonucleoside (40.9 mmol, 1.0 equivalent) is added dropwise by syringe to 1,3-dichloro-1,1,3,3-tetraisopropyl disiloxane (45.0 mmol, 1.1 equivalent) over 15 minutes at 0 °C under argon. The reaction mixture is warmed to room temperature and stirred for a further 3 hours. The reaction is quenched with MeOH (10 mL) and the solvent evaporated. The viscous residue is dissolved in DCM (400 mL) and washed with saturated NaCO3H solution, brine, and dried over MgSO4. The solvent is evaporated and co-evaporated with toluene to remove traces of pyridine. The product is purified by silica gel column chromatography eluting with hexanes:ethyl acetate (3:2) to give the desired product.

[1857] Procedure for the preparation of 12. To a solution of protected ribonucleoside 11 (32.9 mmol, 1 equiv) in DCM (150 mL) was added Dess-Martin periodinane (18.1 g, 42.7 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred at 25-30 °C for 24 h. After this time, about 75 mL of DCM was evaporated, diethyl ether (400 mL) was added to the reaction mixture and the precipitate was removed by filtration through celite. The resulting filtrate was washed with 300 mL of saturated NaHCO3solution containing 18.5 g of Na2S2O3and brine, respectively. The organic layer was dried over anhydrous Na2SO4and the organic layer was evaporated to give 12, which was used in the next step without further purification.

[1858] Procedure for the preparation of 13. To a solution of ketone 12 (8.87 mmol, 1 equiv) and DCM (2.28 mL, 35.5 mmol, 4.0 equiv) in THF (50 mL) was added a solution of LDA (31.1 mL, 1.0 M, 3.5 equiv) at -78 °C under argon atmosphere over a period of 20 min. The reaction mixture was stirred at -78 °C for 3 h and then at room temperature overnight. The reaction was quenched with saturated NH4Cl solution. The solution was extracted with diethyl ether (150 mL x 2). The combined organic layers were washed with brine, dried over MgSO4, evaporated and then purified by silica gel column chromatography eluting with hexane: ethyl acetate (3: 1) to give 13. The uridine ribonucleoside analogs were further protected with PMB group at the N3 position of the nucleobase.

[1859] Example 12.

[1860] General procedure for PMB protection

[1861] To a solution of uridine ribonucleoside analog in DMF was added PMBCl (1.2 equiv) and K2CO3(1.5 equiv) at 0 °C under argon atmosphere. The mixture was then stirred at room temperature for 12-16 h. The mixture was quenched with water and extracted with ethyl acetate three times. The organic extracts were combined, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel eluting with hexane / ethyl acetate or used without further purification.

[1862] Example 13.

[1863] General conditions for opening of epoxide with sodium chloride

[1864]

[1865] Synthetic procedure for 14. To a solution of 13 (7.50 mmol, 1.0 equiv) and 15-crown-5 (1.48 mL, 7.50 mmol, 1.0 equiv) in DMF (10 mL) was added sodium chloride (4.38 g, 75.0 mmol, 10.0 equiv) at room temperature. The mixture was stirred at 45 °C for 16 h. It was then cooled to room temperature and diluted with DCM (150 mL). The solution was washed with water (2x), brine, dried over MgS04, evaporated, and purified by silica gel column chromatography eluting with hexanes: ethyl acetate to give the desired product. The product can then be subjected to the general conditions for formation of alkyne.

[1866] Example 14.

[1867] General conditions for opening of epoxide with sodium azide

[1868]

[1869] Preparation of 15. To a solution of 13 (3.75 mmol, 1.0 equiv) and 15-crown-5 (0.74 mL, 3.75 mmol, 1.0 equiv) in DMF (10 mL) was added sodium azide (1.2 g, 18.7 mmol, 5 equiv) at room temperature. The mixture was stirred at 30 °C for 2 h. It was then cooled to room temperature and diluted with DCM (100 mL). The solution was washed with water (2x), brine, dried over MgS04, evaporated, and purified by silica gel column chromatography eluting with hexanes: ethyl acetate (3:1) to give the desired product. The product can then be subjected to the general conditions for formation of alkyne.

[1870] Example 15.

[1871] General conditions for opening of epoxide with TBAF

[1872]

[1873] Preparation of 16. A solution of 13 (3.75 mmol, 1.0 equiv) and TBAF (6.0 equiv) in DMF (10 mL) was stirred at room temperature. The mixture was stirred at 30 °C for 2 h. It was then cooled to room temperature and diluted with DCM (100 mL). The solution was washed with water (2x), brine, dried over MgS04, evaporated, and purified by silica gel column chromatography eluting with hexanes: ethyl acetate (3:1) to give the desired product. The desired product was then re-protected with TBSC1. The product can then be subjected to the general conditions for formation of alkyne.

[1874] Example 16.

[1875] General conditions for reduction of azide

[1876] The 2'-azidoribonucleoside analog is reduced to a 2'-aminoribonucleoside analog by the following procedure. The 2'-azidoribonucleoside analog is dissolved in methanol and then palladium hydroxide is added to the carbon. The reaction mixture is then stirred under an atmosphere of hydrogen at room temperature for 30 minutes. The reaction mixture is filtered through a pad of celite and washed with methanol. The solvent is removed under reduced pressure and the product is purified by silica gel chromatography eluted with DCM and methanol.

[1877] Example 17.

[1878] General de-silylation conditions

[1879] The silyl-protected ribonucleoside analog is dissolved in THF and then 1M TBAF (2.1 equivalents) is added at room temperature. The reaction solution is stirred at room temperature for 20 minutes. The solvent is then removed under reduced pressure and the resulting residue is dissolved in DCM and loaded onto a silica gel column. The desired ribonucleoside analog is eluted with DCM and methanol.

[1880] Example 18.

[1881] General de-benzylation conditions

[1882] The benzyl-protected ribonucleoside analog is dissolved in anhydrous DCM and treated with a 1M solution of BCl3(3 equivalents) in DCM at -78°C under an argon atmosphere. The reaction solution is stirred at -78°C for 2-4 hours. The mixture is quenched by the slow addition of methanol at -78°C and the solvent is removed under reduced pressure. The desired ribonucleoside analog is purified by silica gel chromatography eluted with DCM and methanol.

[1883] Alternatively, 20% palladium (II) hydroxide is added to a MeOH solution of the nucleoside on carbon. The reaction vessel is purged with a balloon and held under an atmosphere of hydrogen for 24 hours. Once the reaction is complete, the catalyst is filtered off and the solvent is removed under reduced pressure to yield the desired product.

[1884] Example 19.

[1885] General conditions for removal of PMB groups

[1886] To a solution of the PMB-protected ribonucleoside analog in MeCN:H2O (3:1) is added CAN (3 equivalents). The reaction solution is stirred at room temperature for 12-16 hours. The reaction solution is then extracted with ethyl acetate. The organic extract is dried over MgS04, filtered, and concentrated under reduced pressure. The desired product is purified by silica gel chromatography.

[1887] Example 20.

[1888] Uridine protection

[1889]

[1890] A solution of the protected sugar 17 (16.0 g, 32.9 mmol, 1 equiv) in DCM (150 mL) was added to Dess-Martin periodinane (18.1 g, 42.7 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred at 25-30 °C for 24 h. After that, about 75 mL of DCM was evaporated, diethyl ether (400 mL) was added to the reaction mixture, and the precipitate was removed by celite filtration. The resulting filtrate was washed with 300 mL of saturated NaHC03solution containing 18.5 g of Na2S203and brine, respectively. The organic layer was dried over anhydrous Na2S04and evaporated to give 18 (15.1 g, 95% yield) as a white foam, which was used in the next step without further purification.

[1891] Example 21.

[1892] Oxidation of protected uridine

[1893]

[1894] A solution of the protected sugar 17 (16.0 g, 32.9 mmol, 1 equiv) in DCM (150 mL) was added to Dess-Martin periodinane (18.1 g, 42.7 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred at 25-30 °C for 24 h. After that, about 75 mL of DCM was evaporated, diethyl ether (400 mL) was added to the reaction mixture, and the precipitate was removed by celite filtration. The resulting filtrate was washed with 300 mL of saturated NaHC03solution containing 18.5 g of Na2S203and brine, respectively. The organic layer was dried over anhydrous Na2S04and evaporated to give 18 (15.1 g, 95% yield) as a white foam, which was used in the next step without further purification.

[1895] Example 22.

[1896] Formation of epoxide

[1897]

[1898] A solution of ketone 18 (4.30 g, 8.87 mmol, 1 equiv) and DCM (2.28 mL, 35.5 mmol, 4.0 equiv) in THF (50 mL) was added to a solution of LDA (31.1 mL, 1.0 M, 3.5 equiv) at -78 °C under argon atmosphere over a period of 20 min. The reaction mixture was stirred at -78 °C for 3 h and then at room temperature overnight. The reaction was quenched with saturated NH4Cl solution. The solution was extracted with diethyl ether (150 mL x 2). The combined organic layers were washed with brine, dried over MgS04, evaporated and purified by silica gel column chromatography eluting with hexane: ethyl acetate (3:1) to give 19 (1.90 g, 40% yield).

[1899] Example 23.

[1900] Opening of the epoxide with sodium azide

[1901]

[1902] To a solution of 19 (2.0 g, 3.75 mmol, 1.0 equiv) and 15-crown-5 (0.74 mL, 3.75 mmol, 1.0 equiv) in DMF (10 mL) was added sodium azide (1.2 g, 18.7 mmol, 5 equiv) at room temperature. The mixture was stirred at 30 °C for 2 h. It was then cooled to room temperature and diluted with DCM (100 mL). The solution was washed with water (2x), brine, dried over MgS04, evaporated and purified by silica gel column chromatography eluting with hexane: ethyl acetate (3:1) to give 20 as a light brown foam (1.71 g, 84% yield).

[1903] Example 24.

[1904] Opening of the epoxide with sodium chloride

[1905]

[1906] To a solution of 19 (4.0 g, 7.50 mmol, 1.0 equiv) and 15-crown-5 (1.48 mL, 7.50 mmol, 1.0 equiv) in DMF (10 mL) was added sodium chloride (4.38 g, 75.0 mmol, 10.0 equiv) at room temperature. The mixture was stirred at 45 °C for 16 h. It was then cooled to room temperature and diluted with DCM (150 mL). The solution was washed with water (2x), brine, dried over MgS04, evaporated and purified by silica gel column chromatography eluting with hexane: ethyl acetate (3:1) to give 21 as a light yellow foam (2.60 g, 65% yield).

[1907] Example 25.

[1908]

[1909] Acetylene trimethylsilane (37 mmol, 3 eq) was dissolved in anhydrous THF (40 mL) under argon and the reaction flask was cooled to -78°C. n-Butyllithium (37 mmol, 3 eq, 2.5 M in hexanes) was added dropwise. The resulting mixture was stirred for 30 minutes. A solution of the ketone (12.4 mmol, 1 eq) in THF (15 ml) was added dropwise. The reaction was stirred at -78°C for 3 hours. After warming to room temperature, the reaction was quenched with saturated aqueous NH4C1 and extracted with diethyl ether. The organic layers were combined, dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with hexanes: ethyl acetate (3: 1) to give the pure product.

[1910] To a stirred solution of the resulting alcohol (1 g, 1.72 mmol) in toluene (8.6 mL, 0.2 M) at -78°C was added DAST (1.13 mL, 8.58 mmol) dropwise. After stirring for 3 hours, the reaction was quenched with saturated aqueous NaHC03(100 mL) and extracted with 3 x 100 mL ethyl acetate. The extracts were dried over sodium sulfate, filtered, and concentrated to a paste under reduced pressure and purified by silica gel chromatography eluting with 25% to 75% ethyl acetate in hexanes to give the desired product.

[1911] Example 26.

[1912]

[1913] A stirred solution of DMP (27.5 g, 64.9 mmol) in DCM (162 mL, 0.2 M) was cooled to 0°C and 23 (15 g, 32.4 mmol) was added. The reaction was stirred at 0°C and allowed to warm to room temperature. After stirring for 18 hours, the reaction mixture was concentrated to a paste under reduced pressure and then slurried in 100 mL of diethyl ether and then filtered through a pad of 50 g of silica / magnesium sulfate in a 1 : 1 mass ratio and washed with a total of 400 mL of diethyl ether. The ether layer was washed with 15 mL of an aqueous solution containing 2.5 g of sodium thiosulfate, then with 2 x 30 mL of cooled sodium bicarbonate, and finally with 30 mL of brine. The filtrate was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a foam which was used without further purification. A solution of the ketone (32.6 mmol) in DCM (200 mL) was prepared and stirred with 5 g of magnesium sulfate at room temperature overnight. After stirring for 18 hours, the solution was filtered and concentrated under reduced pressure.

[1914] To a stirred solution of the above product (32.4 mmol) in anhydrous DCM (163 mL, 0.2 M) at 0 °C under argon was added triethylamine (18 mL, 130 mmol), DMAP (3.98 g, 32.4 mmol) and benzoyl chloride (9.46 mL, 82 mmol) sequentially. After stirring for 16 h, the reaction mixture was concentrated under reduced pressure, then slurried in 200 mL of diethyl ether and filtered. The organic was concentrated under reduced pressure to give a paste which was purified by silica gel chromatography eluting with 10% to 25% ethyl acetate in hexanes to give 25 as a mixture of anomers. Compound 25 can then be subjected to the general base coupling conditions followed by the appropriate deprotection conditions.

[1915] To a stirred solution of the above product (32.4 mmol) in anhydrous DCM (163 mL, 0.2 M) at 0 °C under argon was added triethylamine (18 mL, 130 mmol), DMAP (3.98 g, 32.4 mmol) and benzoyl chloride (9.46 mL, 82 mmol) sequentially. After stirring for 16 h, the reaction mixture was concentrated under reduced pressure, then slurried in 200 mL of diethyl ether and filtered. The organic was concentrated under reduced pressure to give a paste which was purified by silica gel chromatography eluting with 10% to 25% ethyl acetate in hexanes to give 25 as a mixture of anomers. Compound 25 can then be subjected to the general base coupling conditions followed by the appropriate deprotection conditions.

[1916] Example 27.

[1917] 2'-ethynyluridine (27)

[1918]

[1919] A suspension of uracil (5.19 g, 2.1 eq) in 11 mL of acetonitrile and 3 mL of BSA (4 eq) was heated for 30 minutes to bring the temperature to 90 °C, then allowed to cool to room temperature. Compound 25 (14.6 g, 1 eq) was azeotroped to a paste in 12 mL of acetonitrile, then redissolved in 6 mL of acetonitrile. The compound 25 solution was added to the base via cannula, with 2 x 3 mL rinses during. SnCl4(1.5 mL, 4.25 eq) was then added dropwise over a 5 minute period. The reaction was then heated for 2 hours, with the temperature brought to 90 °C. The reaction was monitored by TLC (5% methanol in DCM). The reaction was stirred for 30 minutes, then allowed to cool to 0 °C. To the reaction was then added 5 g of NaCO3and 5 g of celite. The reaction was then diluted with 20 mL of ethyl acetate, and to this was added 10 mL of saturated aqueous NaCO3(gas evolution was considerable). After stirring for 15 minutes, the reaction was filtered through a celite pad. The celite pad was washed with ethyl acetate in 2 x 50 mL portions. The combined organics were washed with 75 mL of saturated aqueous NaCO3and 75 mL of brine. The aqueous layer was back extracted with ethyl acetate in 2 x 100 mL portions. The combined organics were dried over sodium sulfate, filtered, and concentrated to a foam under reduced pressure. Silica gel chromatography (eluted with 0% to 2.5% to 5% methanol in DCM) provided 1.74 g of compound 26.

[1920] A solution of compound 26 was prepared in 234 mL of 7 M ammonia in methanol. The reaction was stirred for 18 hours. The reaction was concentrated on 20 g of celite and purified by silica gel chromatography, eluting with 1% to 10% methanol in DCM, to provide 1 g of compound 27.

[1921] Example 28.

[1922] 2'-ethynyluridine-5'-monophosphate

[1923] To a solution of compound 27 (0.186 mmol, 1 equiv) in POMe3 (1.86 mL) stirred at 0 °C was added POCl3(0.317 mmol, 1.7 equiv) dropwise over a 5 min period. The reaction was allowed to warm from 0 °C to room temperature (rt) over a 3 h period. The reaction was monitored by TLC (7:2:2 IPA, NH4OH, H2O). The reaction was quenched with water (50 mL) and extracted with chloroform (2 x 100 mL). The pH of the aqueous layer was then adjusted to basic using concentrated ammonium hydroxide (500 uL). The aqueous layer was re-extracted with chloroform (2 x 100 mL). The aqueous layer was then concentrated under reduced pressure. The product was then purified several times using silica gel chromatography (eluting with 16:1 :1 IPA, NH4OH, H2O to 8:1 :1 IPA, NH4OH, H2O to 7:2:2 IPA, NH4OH, H2O) to give a 8% yield of the pure monophosphate salt after lyophilization.

[1924] Example 29.

[1925] 2'-ethynyl-5-fluorouridine (29)

[1926]

[1927] Compound 25 (5 g, 7.55 mmol) in MeCN (100 mL) was added to the residue followed by SnCl4(1 M in DCM, 26.5 mL, 26.5 mmol) and heated to 40 °C overnight. The reaction was monitored by TLC (33% EtOAc in hexanes). Upon completion, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3solution and brine, successively. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was loaded onto a silica gel column from a minimal amount of DCM. The product was eluted with 20% (increasing to 33%) EtOAc in hexanes. The product was isolated as a white foamy solid 3.34 g, 4.98 mmol, 66% yield.

[1928] The protected nucleoside 28 (3.3 g, 4.92 mmol) was dissolved in 7 N ammonium methanol (50 mL) in a sealed tube and stirred overnight. The reaction mixture was concentrated on a silica gel column and the product was eluted with 5% (increasing to 20%) methanol in DCM. The main spot was collected and purified again on silica gel eluting with 13% MeOH in DCM. Finally, the product was purified by a C18 ultra column eluting with 4% MeOH in water. The product was collected and lyophilized to yield a white solid 1.21 g, 4.23 mmol, 86% yield.

[1929] Example 30.

[1930] 2'-ethynyl-2-aminopurine furanoside (32)

[1931]

[1932] A stirred suspension of 2-aminopurine (0.459 g, 1.5 eq) and 25 (1.5 g, 1 eq) was prepared in acetonitrile (15 mL). Next, BSA (2.49 mL, 4.5 eq) and TMSOTf (1.227 mL, 3 eq) were added. The reaction solution was then heated to 130 °C in the microwave for 1 hour. The reaction was quenched with 1.2 mL of 1 M triethanolamine and stirred for 30 minutes. The reaction was concentrated under reduced pressure on celite and applied to a Sephadex column. The resulting desired product was a mixture.

[1933] The above mixture was dissolved in 7 N ammonium methanol (40 mL) and stirred for 16 hours. The reaction was concentrated under reduced pressure on celite. The product was purified by gel chromatography eluting with 0% to 15% methanol in DCM. Two products were obtained, the desired N9-32 (171 mg) and N7-33 (265 mg).

[1934] Example 31.

[1935] 2'-ethynyluridine-5'-monophosphate bis-POM (34)

[1936] To a 25 mL pear-shaped flask containing ((hydroxyphosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropane) (313 mg, 0.960 mmol) was added anhydrous THF (4 mL) to give a colorless solution. This was vacuumed and charged with argon. Then triethylamine (147 μl, 1.056 mmol) was added dropwise. After stirring at room temperature for 30 minutes, compound 27 (148 mg, 0.480 mmol) was added. This was cooled to 0 °C, then N-ethyl-N-isopropylpropan-2-amine (334 μl, 1.920 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (306 mg, 1.200 mmol), and 3-nitro-lH-l,2,4-triazole (137 mg, 1.200 mmol) were added. The reaction was stirred overnight while gradually warming to room temperature. The reaction was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by ISCO silica gel column chromatography (12 g column) eluting with 100% DCM to 5% MeOH in DCM to give the desired product.

[1937] Example 32.

[1938] 2'-ethynyluridine-5'-monophosphate mono-POM (35)

[1939] A solution of NaCl was prepared by dissolving 240 mg of sodium chloride in 24 mL of water. The pH was adjusted to 7.3 with 2 M aqueous disodium hydrogen phosphate. A suspension of compound 34 was prepared and the reaction was heated to 37 °C. After 4 days, the reaction was stopped. Another 240 mg of NaCl was added and the reaction was stirred for another 16 hours. The reaction appeared to have reacted further. The reaction was concentrated under reduced pressure to 5 mL at 25 °C. The resulting residue was loaded onto a 100 g C18 column eluting with 0% to 100% acetonitrile in water. Fractions containing product were combined, concentrated, and then purified again using a 50 g C18 column. Fractions were combined, concentrated, and lyophilized to give 36 mg of the desired product.

[1940] Example 33.

[1941] 2'-ethynyl-5-fluorouridine-5'-monophosphate bis-POM (36)

[1942] To a stirred solution of ((hydroxyphosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanamide) (230 mg, 2 eq) and compound 29 (101 mg, 1 eq) in THF (7 mL) was added triethylamine (0.1 mL, 2.2 eq). After 10 h, the reaction was cooled to 0 °C and N,N-diisopropylethylamine (0.25 mL, 4 eq), BOPC1 (225 mg, 2.5 eq) and 3-nitro-1H-1,2,4-triazole (101 mg, 2.5 eq) were added sequentially. The reaction was stirred for 14 h. The reaction mixture was then concentrated under reduced pressure on celite. The celite pad was placed on a silica gel column and the product was eluted with 1-7% methanol in DCM. The product obtained (31 mg) was a white solid.

[1943] Example 34.

[1944] Alternative method for base coupling

[1945] A mixture of nucleobase (9.05 mmol) and 25 (4.53 mmol) was co-evaporated with anhydrous toluene (x3) and then dried on a high vacuum line for two hours. The residue was dissolved in anhydrous MeCN (50 mL), BSA (4.4 mL, 18.11 mmol) was added and the mixture was heated at 70 °C for one hour to allow the nucleobase to fully dissolve. The mixture was cooled to room temperature for the addition of SnCl4 (1M in DCM, 18.1 mL, 18.1 mmol) via syringe and then heated at 70 °C overnight. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in DCM and pyridine to precipitate the Sn salt. After filtration through celite, the organics were concentrated and then dissolved in ethyl acetate and washed with NaHCO3 and brine. The organic layer was then dried, filtered and concentrated to give a solid. Purification by column chromatography (SNAP 50g, 0-100% EA in DCM) gave the recovered sugar donor and the desired nucleoside. The resulting white solid desired nucleoside was triturated with ether.

[1946] Example 35.

[1947] Cytidine nucleosides prepared using the alternative method for base coupling and general benzoyl deprotection conditions

[1948]

[1949] Example 36.

[1950] N-tert-butoxycarbonyl-sphingosine (124)

[1951]

[1952] Prepared according to Boumendjel, Ahcene and Miller, Stephen, Journal of Lipid Research 1994, 35, 2305.

[1953] A mixture of sphingosine (450 mg, 1.50 mmol) and di-tert-butyl ester (0.656 g, 3.01 mmol) in dichloromethane (100 mL) at 4 °C was treated dropwise with diisopropylethylamine (0.53 mL, 3.01 mmol). After warming to room temperature, the mixture was stirred for an additional 12 h, then diluted with dichloromethane (100 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (19 mm x 175 mm) using 50% ethyl acetate in hexanes to give N-tert-butoxycarbonyl-sphingosine as a white solid (540 mg, 90%).

[1954] 1 H NMR (300 MHz, Chloroform-d) δ 5.77 (dt, J = 15.4, 8.4 Hz, 1H), 5.52 (dd, J = 15.4, 8.4 Hz, 1H), 3.93 (dd, J = 11.4, 3.7 Hz, 1H), 3.70 (dd, J = 11.4, 3.7 Hz, 1H), 3.59 (s, 3H), 2.05 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.25 (s, 22H), 0.87 (t, J = 6.5 Hz, 3H).

[1955] Example 37.

[1956] N-tert-butoxycarbonyl-sphingosine-1-O-dimethylphosphate (125)

[1957]

[1958] N-tert-butoxycarbonyl-sphingosine 124 (540 mg, 1.35 mmol) was rendered anhydrous by co-evaporation with anhydrous pyridine (2 x 12 mL). The residue was then dissolved in anhydrous pyridine and treated with carbonic bromide (622 mg, 1.88 mmol). The mixture was cooled to 0 °C and treated dropwise with a solution of trimethyl phosphite (0.25 mL, 2.10 mmol) in anhydrous pyridine (3 mL) over 30 min. After standing at room temperature for a further 12 h, LCMS and tlc (5% methanol in dichloromethane) analysis indicated complete conversion. The mixture was quenched with water (2 mL) and then concentrated to dryness. The resulting dark oil was dissolved in ethyl acetate (150 mL), washed with 3% HCI solution (2 x 20 mL) and then saturated sodium bicarbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (19 mm x 175 mm) using 2% methanol in dichloromethane to give N-tert-butoxycarbonyl-sphingosine-1-0-dimethylphosphate 125 (350 mg, 51%) as a gum.

[1959] 1 H NMR (400 MHz, Chloroform-d) δ 5.82 (dt, J = 15.4, 7.1 Hz, 1H), 5.48 (dd, J = 15.4, 7.1 Hz, 1H), 4.99 (d, J = 8.9 Hz, 1H), 4.32 (ddd, J = 10.7, 8.0, 4.6 Hz, 1H), 4.11 (ddt, J = 10.7, 7.4, 3.1 Hz, 2H), 3.77 (dd, J = 11.1, 2.1 Hz, 6H), 2.01 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.34 (m, 2H), 1.23 (m, 20H), 0.86 (t, J = 6.4 Hz, 3H).

[1960] 31 P NMR (162 MHz, Chloroform-d) δ 2.00.

[1961] MS C17H25NO4 [M+Na+]; calc: 330.2, found: 330.2.

[1962] Example 38.

[1963] Sphingosine-1-phosphate (126).

[1964]

[1965] A solution of N-tert-butoxycarbonyl-sphingosine-1-0-dimethylphosphonate 125 (350 mg, 0.689 mmol) in dry dichloromethane (8 mL) was treated dropwise with trimethylsilyl bromide (0.45 mL, 3.45 mmol) at 0 °C. After warming to room temperature, the mixture was stirred at room temperature for 6 hours, then concentrated to dryness. The resulting residue was co-evaporated with dichloromethane to remove excess trimethylsilyl bromide, then treated with 66% aqueous THF (6 mL). The resulting precipitate was collected by filtration to give sphingosine-1 -phosphate 126 as a white solid (218 mg, 83%).

[1966] 1 H NMR (400 MHz, Methanol-d4 + CD3CO2D) δ 5.84 (dt, J = 15.5, 6.7 Hz, 1H), 5.46 (dd, J = 15.5, 6.7 Hz, 1H), 4.33 (t, J = 6.0 Hz, 1H), 4.13 (ddd, J = 11.8, 7.7, 3.6 Hz, 1H), 4.03 (dt, J = 11.8, 8.4 Hz, 1H), 3.47 (ddd, J = 8.3, 4.8, 3.2 Hz, 1H), 2.10 - 1.99 (m, 2H), 1.37 (m, 2H), 1.24 (m, 20H), 0.83 (t, J = 6.4 Hz, 3H).

[1967] 31 P NMR (162 MHz, Chloroform-d) δ 0.69.

[1968] MS C 18 H 38 NO5P [M-H + ]; calc: 378.2, found: 378.2.

[1969] Example 39.

[1970] N-trifluoroacetyl-phytosphingosine (131).

[1971]

[1972] To a slurry of phytosph...

Claims

1. A compound of the formula: Formula XXXIX or a pharmaceutically acceptable salt thereof, wherein: R 1 X is R 1 -OCH2; W is CR 7 ; R 1 selected from H or one of the following formulae: 、 、 ； aryl is phenyl; R 2 is hydrogen; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, or benzyl; and R 7 is fluorine.

2. The compound of claim 1, wherein R 4 is methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, or benzyl.

3. The compound of claim 1, wherein R 1 is selected from one of the following formulae: or ; and R 4 is methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, or benzyl.

4. The compound of claim 1, wherein R 1 is selected from one of the following formulae: or ; and R 4 is isopropyl.

5. A compound having the structure: 。 6. A compound having the structure: 。 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A liposomal composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The composition of claim 7 or 8, comprising at least one second antiviral agent selected from 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, phosphonoformic acid, ganciclovir, ibacitabine, iminosine, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oblimersen, oseltamivir, ombitasvir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, valaciclovir, valganciclovir, vicriviroc, vidarabine, virox, zalcitabine, zanamivir, or zidovudine, and combinations thereof.

10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of infections caused by Zika virus, dengue virus, human rhinovirus, and respiratory syncytial virus.

11. The use of claim 10, comprising administering at least one second antiviral agent selected from 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, phosphonoformic acid, ganciclovir, ibacitabine, iminosine, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oblimersen, oseltamivir, ombitasvir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, virox, zalcitabine, zanamivir, or zidovudine, and combinations thereof.

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