Therapeutic compounds and methods

Abstract

The invention provides a compound of formula: (I), (II) and (III) or a salt thereof, wherein R1-R4, R4a, Rh and Ri have any of the values described in the specification, as well as compositions comprising a compound of formula (I), (II), and (III). The compounds are useful to treat viral infections, for example, when administered in combination with an antiviral nucleobase.

Description

[0001] U of M 2025-034 09531.606W01

[0002] THERAPEUTIC COMPOUNDS AND METHODS

[0003] CROSS-REFERENCE TO RELATED PPLICATION

[0004] This application claims priority to United States Provisional Application Number 63 / 723,866 that was filed on November 22, 2024. The entire content of the application referenced above is hereby incorporated by reference herein.

[0005] BACKGROUND

[0006] Dengue, Zika, influenza, SARS-CoV-2 and other emerging viruses infect hundreds of millions of people each year and represent a global health emergency requiring the development of potent antiviral treatments. Dengue virus (DENV) is a worldwide health threat, with hundreds of millions of people infected yearly in more than 100 countries (S. Bhatt et aL, (2013) Nature 496, 504-507). There are four known DENV serotypes. A first infection with one serotype followed by a second infection with another serotype may result in severe disease (S. B. Halstead, (2003) Adv Virus Res 60:421-467; C. P. Simmons, (2015) New Engl. Jour, of Med. 373 : 1263-1264). For these and other issues, vaccines designed for pan-serotype protection, including the commercial dengue vaccine approved and used in a few countries, have yielded mixed results (S. R. Hadinegoro et al. (2015) New Engl. Jour, of Med. 373: 1195-1206). Safety and partial efficacy concerns in addition to cost, storage and delivery issues may hinder implementation of vaccines in many countries.

[0007] Zika virus (ZIKV), like DENV, is a member of the Flaviviridae family of viruses and both are spread to humans by mosquitoes. ZIKV is likely spread by additional routes including intimate contact and mother-to-fetus during pregnancy (L. R. Petersen et al (2016) N Engl. Jour. Med 374: 1552-1563). Although isolated in the late 1940’s, ZIKV research has not been a high priority in the U.S. because infection was often believed to be asymptomatic or mild with shortlived symptoms. ZIKV has become a high priority due to the dramatic rise in the number of cases, geographic spread of the outbreak, and ZIKV infection during the first trimester of pregnancy increases the risk of fetal microcephaly and other central nervous system anomalies (M. A. Johansson et al (2016) N Engl. Jour. Med, 375(1): 1-4). There are serious concerns about ZIKV establishing itself in areas of high population density as DENV has done. The development of anti-ZIKV drugs is an effective way to control ZIKV outbreaks and spread. Effective ZIKV drugs could be used prophylactically to prevent infections and as treatment to U of M 2025-034 09531.606W01 reduce viral load, thereby reducing virus spread. There are currently no approved drugs to treat DENV or ZIKV infection. Thus far, classical antiviral approaches (e.g. NS5 polymerase inhibitors, entry inhibitors, protease inhibitors, etc.) have yet to provide treatments for DENV infection and therefore the investigation of new antiviral strategies is warranted (Y. L. Chen, et al (2015) Antiviral Res 122:12-19; S. P. Lim et al in Antiviral Res. (2013 Elsevier B.V, Netherlands, 2013), vol. 100, pp. 500-519; J. G. Low, et al (2017) J. Infect. Dis. 215:S96-S102).

[0008] Influenza A virus (IAV) is an orthomyxovirus with a segmented single-stranded RNA genome and lipid enveloped viral particles. IAV is a significant cause of morbidity and mortality worldwide despite vaccine and antiviral availability. The CDC estimates between 290,000- 640,000 deaths worldwide associated with IAV infections (luliano, et al, The Lancet, 391 : 1285- 1300. 2018). The currently used IAV vaccines suffer from several challenges including inefficient production, requirement for annual inoculation and the need for modification for use in the elderly population (House and Subbarao, Influenza Vaccines: Challenges and Solutions, Cell Host Microbe. 2015. 17(3):295-300). Currently, three classes of inhibitors are approved for treatment of IAV infections, neuraminidase inhibitors (NAIs), M2 ion channel inhibitors (M2Is) and PA mRNA cap cleavage inhibitors (CCIs). Rampant resistance to the M2Is amantadine and rimantadine in circulating IAV strains has rendered those drugs nearly useless (Hsu et al, Ann. Intern. Med. 2012, 156, 512-524). The NAIs, including zanamivir and oseltamivir approved in the U. S. as well as peramivir and laninamivir approved in other countries, must be used judiciously to avoid generating wide-spread resistance. Baloxavir marboxyl is a recently been approved CCI and with results as good or better than the NAIs but resistance to it is present in circulating IAV strains (NE vol 379(10):913-923. 2018). Baloxavir overuse could increase the frequency of resistant IAV and render the drug ineffective similarly to the M2Is.

[0009] Coronaviruses have large (26-32 kb) plus-sense single-strand RNA genomes and enveloped viral particles with distinctive lollipop spike proteins projecting from their surface. Disease causing human coronaviruses identified thus far are mainly from the Alphacoronavirus and Betacoronavirus genera. Human alphacoronaviruses NL-63 and 229E, as well as human betacoronaviruses HKU1 and OC43 (HCoV-OC43), cause cold-like symptoms and the conditions are usually non-life threatening. Betacoronaviruses that normally circulate in animals but sporadically infect humans can cause severe disease. In 2002 severe acute respiratory syndrome (SARS)-CoV was identified to cause more than 800 deaths and since 2012 Middle U of M 2025-034 09531.606W01

[0010] East respiratory syndrome (MERS)-CoV has caused more than 800 fatalities (WHO). In late 2019 a new human betacoronavirus emerged, SARS-CoV-2, that is related but genetically distinct from SARS-CoV and MERS-CoV. SARS-CoV-2 causes coronavirus disease 2019 (CO VID-19), an escalating pandemic infecting millions of people worldwide (Zhu, N. et al (2020) N. Engl. J. Med. 382:727 -733; Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. (2020) AW Microbiol. 5:536-544). Symptoms of COVID- 19 infection include respiratory illness, sometimes severe requiring hospitalization and breathing assistance (Wolfel, R., et al (2020) Nature 581 :465-469

[0011] Although nucleoside analogues represent a successful class of antiviral drugs, the discovery of new antiviral nucleosides has been impaired by several hurdles including the toxicity of the potential drugs as well as synthetic challenges. In addition, potentially antiviral nucleosides frequently suffer from poor metabolic conversion to the active triphosphate form required by the viral polymerase. The first phosphorylation of the nucleoside analogue is often the rate limiting step to obtain the active nucleoside triphosphate used by the viral polymerase (A. R. Van Rompay, et al (2000) Pharmacol. Ther. 87: 189-198; A. R. Van Rompay, et al (2003) Pharmacol. Ther. 100:119-139).

[0012] International Patent Application Publication Number WO 2021 / 007283 describes methods of treating RNA virus infections with a therapeutic combination of an antiviral nucleobase compound and a de novo nucleotide biosynthesis inhibitor. The compound (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-(methylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol, 6- methylmercaptopurine riboside (6-MMPR) is identified as a specific de novo nucleotide biosynthesis inhibitor. Currently there is a need for additional synergistic, broad-spectrum, antiviral nucleobases and de novo nucleotide biosynthesis inhibitors that can be used in the methods described in International Patent Application Publication Number WO 2021 / 007283. In particular, there is a need for antiviral nucleobases (e.g., broad-spectrum antiviral nucleobases) and de novo nucleotide biosynthesis inhibitors that possess one or more improved properties, such as, for example, greater efficacy, lower toxicity, oral availability and improved biodistribution.

[0013] SUMMARY

[0014] Additional de novo nucleotide biosynthesis inhibitors that can be used in the methods described in International Patent Application Publication Number WO 2021 / 007283 are U of M 2025-034 09531.606W01 provided as well as prodrugs of antiviral nucleobases (including favipiravir prodrugs). Certain de novo nucleotide biosynthesis inhibitors and nucleobase prodrugs provided herein have improved properties, such as, for example, lower toxicity.

[0015] Accordingly, a compound of formula (I): or a salt thereof, wherein:

[0016] R1is (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRaRb;

[0017] R2is H, (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRcRd;

[0018] R3is H, (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NReRf; each Raand Rbis independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RaandRbtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each Rcand Rdis independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and each Reand Rfis independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Reand Rftogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is provided.

[0019] A compound of formula (II) or formula (III): U of M 2025-034 09531.606W01 or a salt thereof, wherein:

[0020] R4is (Ci-Ci8)alkanoyl, (Ci-Ci8)alkoxycarbonyl or -C(=O)NRfRg;

[0021] R4ais halogen or H; each Rfand Rgis independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RfandRgtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and each Rhand R1is independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Rhand R1together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is also provided.

[0022] A pharmaceutical composition comprising a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is also provided.

[0023] A method for treating a viral infection in an animal (e.g., a mammal such as a human) comprising administering a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof to the animal is also provided.

[0024] A compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof for use in medical therapy is also provided.

[0025] A compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a viral infection is also provided.

[0026] Use of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a viral infection in an animal (e.g., a mammal such as a human) is also provided.

[0027] A method for the treatment of an RNA virus infection comprising administering a therapeutic combination as a combined formulation or by alternation to a patient (a mammal patient such as a human patient), wherein the therapeutic combination comprises therapeutically effective amounts of (i) an antiviral nucleobase or a pharmaceutically acceptable salt thereof; and (ii) a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof is also provided. U of M 2025-034 09531.606W01

[0028] Processes and intermediates disclosed herein that are useful for preparing a compound of formula (I), (II), or (III) or a salt thereof are also provided.

[0029] BRIEF DESCRIPTION OF DRAWINGS

[0030] Fig. 1 shows Favipiravir (Fav), T-l 105, and Ribavirin base (Rib) combined with 6MMPr prodrug (Pdrg2) effects on DENV replicon replication. DEN BHK replicon cells were treated with compounds indicated and three days later evaluated for luciferase activity (left graph) and cell viability (right graph). The results for compound plus vehicle (DMSO) were plotted with: FAV, T-l 105, or Rib with 1.5 pMPrdg2. Results were plotted in GraphPadPrism.

[0031] Figs. 2A-2D show favipiravir (Fav) and 6MMPR prodrug combinations and effects on DENV replicon replication. DENV BHK replicon cells were treated with compounds indicated and three days later evaluated for luciferase activity (left graph) and cell viability (right graph). The results for Fav plus vehicle (DMSO) were plotted with: Fig. 2A Fav with 0.065 pM 6MMPR, Fig. 2B Fav with 0.09 pM Prdg 1, Fig. 2C Fav with 1.5 pM Prdg 2, and Fig 2D Fav with 1.4 pM Prdg 3. Fav doses ranged from 500 to 2 pM. Results were plotted in GraphPad Prism.

[0032] Figs. 3A-3D show the effect of the combination of F AVI and 6-MMPr on Fig 3 A % weight change over time in uninfected animals, Fig. 3B survival, Fig 3C weight change between 4 and 7 dpi, and Fig. 3D viremia titers at 6 dpi (n = 15 / infected, n = 10 / uninfected, n = 5 / normal control groups) of infected hamsters treated with combination or monotherapy of F AVI and 6- MMPr administered beginning 4 h prior to challenge with YFV (** p < 0.01, * p < 0.05, when compared with vehicle), n = 10 / infected group, n = 5 / uninfected group. Pathogens 2025, 14(9), 925 (doi.org / 10.3390 / pathogens 14090925).

[0033] Fig. 4 shows the crystal structure of the compound of example 6.

[0034] Fig. 5 shows the crystal structure of the compound of example 7.

[0035] DETAILED DESCRIPTION

[0036] Alkyl, alkanoyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

[0037] The term “halo” or “halogen” as used herein refers to for example fluoro, chloro, bromo and iodo. U of M 2025-034 09531.606W01

[0038] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., Ci-8 means one to eight carbons). Examples include (Ci-C8)alkyl, (C2-C8)alkyl, Ci-Ce)alkyl, (C2-Ce)alkyl and (C3-Ce)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.

[0039] The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).

[0040] The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbomane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.

[0041] The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency U of M 2025-034 09531.606W01 requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0042] The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle U of M 2025-034 09531.606W01 includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1, 2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-l,l'- isoindolinyl]-3'-one, isoindolinyl-l-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-di oxane.

[0043] The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.

[0044] The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O-C(=O)-, wherein the term alkyl has the meaning defined herein. U of M 2025-034 09531.606W01

[0045] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0046] As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006.

[0047] As used herein a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

[0048] The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and / or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already U of M 2025-034 09531.606W01 with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention,

[0049] The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0050] The term “animal” includes mammals, fish, amphibians, reptiles, birds and invertebrates. The term “mammal” includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the animal is a mammal. In one embodiment, the animal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient.

[0051] The terms “synergistic” and “synergy” as used herein refer to a therapeutic combination which is more effective than the additive effects of the two or more single agents. A determination of a synergistic interaction between a compound of an antiviral nucleobase, or a pharmaceutically acceptable salt thereof, and one or more DNNBi potentiator agent may be based on the results obtained from the assays described herein. The results of these assays can be analyzed using the Chou and Talalay combination method and Dose-Effect Analysis with Calcusyn® software in order to obtain a Combination Index (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The combinations provided by this invention have been evaluated in several assay systems, and the data can be analyzed utilizing a standard program for quantifying synergism, additivism, and antagonism among anticancer agents described by Chou and Talalay, in “New Avenues in Developmental Cancer Chemotherapy,” Academic Press, 1987, Chapter 2. Combination Index values less than 0.8 indicates synergy, values greater than 1.2 indicate antagonism and values between 0.8 and 1.2 indicate additive effects. The combination therapy may provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage U of M 2025-034 09531.606W01 formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes or in separate pills or tablets. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Combination effects may also be evaluated using both the BLISS independence model and the highest single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3:80). BLISS scores quantify degree of potentiation from single agents and a BLISS score > 0 suggests greater than simple additivity. An HSA score > 0 suggests a combination effect greater than the maximum of the single agent responses at corresponding concentrations. Three dimensional synergistic analyses can also be processed using MacSynergy II software (Prichard, M. N. et al (1990) Antiviral Res 14:181-205; Smee, D.F. and Prichard, M.N. (2017) Antiviral Research 145: 1-5).

[0052] A “solid oral dosage form” refers to a formulation that is ready for administration to a subject via an oral route. Exemplary oral dosage forms include, but are not limited to, tablets, minitablets, capsules, caplets, powders, pellets, beads, granules, and pelletized tablets containing polymer-coated pellets. A dosage form can be a “unit dosage form,” which is intended to deliver one therapeutic dose per administration.

[0053] The term “excipient” refers to a substance formulated with an active pharmaceutical ingredient (API) of a therapeutic medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The selection of appropriate excipients also depends upon the route of administration and the dosage form, as well as the active ingredient and other factors. In some formulations, excipients can be a key determinant of dosage form performance, with effects on pharmacodynamics and pharmacokinetics. Types of excipients for oral dosage formulations include antiadherents, U of M 2025-034 09531.606W01 binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.

[0054] The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated.

[0055] It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3.

[0056] The pharmaceutical compositions can comprise one or more excipients. When used in combination with the pharmaceutical compositions the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I), (II), of (III) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

[0057] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often U of M 2025-034 09531.606W01 called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0058] It will be appreciated by those skilled in the art that compounds having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

[0059] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

[0060] Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.

[0061] Specifically, (Ci-Ce)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, secbutyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(Ci-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, U of M 2025-034 09531.606W01 cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl; (Ci-Ce)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (Ci-C6)alkanoyl can be acetyl, propanoyl or butanoyl; (Ci-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

[0062] A specific value for R1is (Ci-C6)alkanoyl.

[0063] A specific value for R1is 2-methylpropanoyl.

[0064] A specific value for R1is (Ci-C6)alkoxycarbonyl.

[0065] A specific value for R1is -C(=O)NRaRb.

[0066] A specific value for Rais H.

[0067] A specific value for Rais (Ci-C4)alkyl.

[0068] A specific value for Rais methyl.

[0069] A specific value for Rbis H.

[0070] A specific value for Rbis (Ci-C4)alkyl.

[0071] A specific value for Rbis methyl.

[0072] A specific value for R2is (Ci-C6)alkanoyl.

[0073] A specific value for R2is 2-methylpropanoyl.

[0074] A specific value for R2is (Ci-Ce)alkoxy carbonyl.

[0075] A specific value for R2is -C(=O)NRcRd.

[0076] A specific value for Rcis H.

[0077] A specific value for Rcis (Ci-C4)alkyl.

[0078] A specific value for Rcis methyl.

[0079] A specific value for Rdis H.

[0080] A specific value for Rdis (Ci-C4)alkyl.

[0081] A specific value for Rdis methyl.

[0082] A specific value for R3is (Ci-C6)alkanoyl.

[0083] A specific value for R3is 2-methylpropanoyl. U of M 2025-034 09531.606W01

[0084] A specific value for R3is (Ci-C6)alkoxycarbonyl.

[0085] A specific value for R3is -C(=0)NReRf.

[0086] A specific value for Reis H.

[0087] A specific value for Reis (Ci-C4)alkyl. A specific value for Reis methyl.

[0088] A specific value for Rfis H.

[0089] A specific value for Rfis (Ci-C4)alkyl.

[0090] A specific value for Rfis methyl.

[0091] A specific compound or salt is selected from the group consisting of and salts thereof.

[0092] The compounds (one or more) disclosed herein (e.g., compounds of formula (I), (II) or (III)) may display broad spectrum antiviral activity. Accordingly, in one embodiment one or more of the compounds disclosed herein (e.g., compounds of formula (I), (II) or (III)) display broad spectrum antiviral activity.

[0093] The compounds (one or more) disclosed herein (e.g., compounds of formula (I), (II) or (III)) when used in combination with each other or other compounds (e.g., other antiviral nucleobases), may display synergy. Accordingly, in one embodiment one or more of U of M 2025-034 09531.606W01 compounds disclosed herein (e.g., compounds of formula (I), (II) or (III) and other antiviral nucleobases) display synergy when used in combination.

[0094] A specific compound is a compound of formula (II): or a salt thereof.

[0095] A specific value for R4ais F.

[0096] A specific value for R4ais halogen.

[0097] A specific value for R4ais H.

[0098] A specific value for R4is (Ci-Ci6)alkanoyl.

[0099] A specific value for R4is (C2-Ci6)alkanoyl.

[0100] A specific value for R4is acetyl, propanoyl, 2-methylpropanoyl. butanoyl, pentanoyl, hexanoyl, dodecanoyl, or palmitoyl.

[0101] A specific value for R4is -C(=0)NRfRg.

[0102] A specific value for Rfis H.

[0103] A specific value for Rfis (Ci-C4)alkyl.

[0104] A specific value for Rfis methyl.

[0105] A specific value for Rgis H.

[0106] A specific value for Rgis (Ci-C4)alkyl.

[0107] A specific value for Rgis methyl.

[0108] A specific compound or salt is selected from the group consisting of: U of M 2025-034 09531.606W01 or a salt thereof.

[0109] A specific value compound or salt is a compound of formula (III): or a salt thereof.

[0110] A specific value for Rfis H.

[0111] A specific value for Rfis (Ci-C4)alkyl.

[0112] A specific value for Rfis methyl. A specific value for Rgis H.

[0113] A specific value for Rgis (Ci-C4)alkyl.

[0114] A specific value for Rgis methyl.

[0115] A compound or salt which is: or a salt thereof. U of M 2025-034 09531.606W01

[0116] ANTIVIRAL NUCLEOBASE COMPOUNDS

[0117] In order to overcome the potential first phosphorylation difficulty of nucleosides, nucleobases, the base of a nucleoside without its ribose moiety, are employed in the compositions of the invention. Enzyme mediated condensation of nucleobases with 5- phosphoribosyl-1 -pyrophosphate (PRPP) to give the corresponding nucleoside-5’- monophosphate provide an alternative pathway to the antiviral nucleotide triphosphate active form. Thus, for a nucleoside where the first phosphorylation is inefficient, using its corresponding nucleobase could allow metabolic conversion to the corresponding nucleoside triphosphates thereby providing a more efficient metabolic conversion to the triphosphate (K. Negishi, et al (1994) Mutat. Res. 318:227-238) as demonstrated for nucleobases 5 -fluorouracil and favipiravir (T-705) nucleobases (R. Agudo, et al (2009) Future Med Chem 1 :529-539; S. Sierra, M et al (2000) J. Virol. 74:8316-8323; T. Baranovich et al., et al (2013) J. Virol. 87:3741-3751; A. Arias, et al(2014) Elife 3, e03679). However, in the context of targeting viruses that affect developing countries, nucleobases present key advantages over nucleosides. In addition to their different metabolic activation pathways, nucleobase analogues are considerably cheaper, more diverse and commercially available in higher numbers compared to corresponding nucleoside analogues. The chemical synthesis of a nucleobase is faster and simpler than the synthesis of the corresponding nucleoside. Similar to nucleosides, nucleobases possess their own cellular transporters (H. de Koning, et al (2000) Nucleobase transporters (review). Mol Membr Biol 17:75-94; D. A. Griffith, et al (1996) Biochim Biophys Acta 1286: 153-181).

[0118] The nucleobase favipiravir, approved in Japan against influenza, possesses a broad antiviral activity. In late 2014, favipiravir was evaluated in the JIKI trial for Ebola virus infected patients and demonstrated moderate benefits by reducing the mortality rate for patients in the early infection stage of the disease (D. Sissoko et al (2016) PloSMed 13, el001967; T. H. Nguyen et al (2017) PloS Negl Prop Dis 11, e0005389). Additional studies revealed that the administered dose during the JIKI trial failed to achieve the expected plasma concentration necessary to obtain an optimal antiviral effect.

[0119] The antiviral nucleobases of the invention are ambiguous base-pairing nucleobases. An ambiguous base-pairing nucleobase and corresponding ambiguous base-pairing nucleoside U of M 2025-034 09531.606W01 resemble more than one natural nucleoside due to structural variability. The ambiguous basepairing nature of nucleobases and their structural variability may be due to (i) ionization (ii) tautomerism, (iii) bond rotation and / or (iv) ring opening which make ambiguous base-pairing compounds resemble more than one natural nucleotide. Ribavirin and T-705 nucleotide are embodiments of ambiguous base-pairing through bond rotation with the possible orientation of the amido group of the base in two different positions to either resemble adenosine or guanosine resulting in the antiviral effect.

[0120] Ambiguous base-pairing nucleobases may include electron-withdrawing groups such as halogen, cyano, nitro and amido, or electron-donating groups such as alkyl, alkene, and alkyne which alter the ionization state or tautomerism of pyrimidine or purine resulting in ambiguous base-pairing. Ambiguous base-pairing nucleobases may include rotatable amide groups that alter base-pairing, or modifications at position 5 of pyrimidines and position 7 of purines with groups such as alkyl, heterocycle, and heteroaryl which increase the stacking abilities of the nucleobase analogue during viral RNA synthesis yet decrease the specificity of the base-pairing. Ambiguous base-pairing nucleobases may include T-705 analogues, ribavirin nucleobase analogues, and sulfur containing nucleobases as depicted below. Desulfurization can occur, resulting in switching of base-pairing capacities.

[0121] Embodiments of antiviral nucleobases include purine analogs having the structures:

[0122] Embodiments of antiviral nucleobases include T-705 analogs having the structure:

[0123] Embodiments of antiviral nucleobases include ribavirin analogs having the structure: U of M 2025-034 09531.606W01

[0124] Embodiments of antiviral nucleobases include ribavirin analogs having the structure:

[0125] Substituents of the four above embodiments of antiviral nucleobases include wherein: R1is selected from the group consisting of H, Me, F, Cl, Br, I, OH, NH2, SH, OMe, NO2,

[0126] NHOH, NHOMe, NHNH2, C=ONH2, Ci-Cs alkyl, and 5- or 6-membered heteroaryl;

[0127] R2is selected from the group consisting of H, OH, OMe, NH2, NHMe, C=ONH2 , Ci-Cs alkyl, and 5- or 6-membered heteroaryl;

[0128] R3is selected from the group consisting of H, F, Cl, Br, I, OH, S, NH2, SH, OMe, NO2, NHOH, NHOMe, NHNH2, C=ONH2, Ci-Cs alkyl, and 5- or 6-membered heteroaryl;

[0129] R4is selected from the group consisting of H, NH2 and Ci-Cs alkyl; and

[0130] X is NR2, 0 or S.

[0131] Embodiments of antiviral nucleobases include purine analogs having the structures: Embodiments of antiviral nucleobases include T-705 analogs having the structure: U of M 2025-034 09531.606W01

[0132] Embodiments of antiviral nucleobases include ribavirin analogs having the structure:

[0133] Substituents of the three above embodiments of antiviral nucleobases include wherein:

[0134] R1is selected from the group consisting of H, Me, F, Cl, Br, I, OH, NH2, SH, OMe, NO2, NHOH, NHOMe, NHNH2, C=ONH2, (Ci-C8)alkyl, and 5- or 6-membered heteroaryl;

[0135] R2is selected from the group consisting of H, OH, OMe, NH2, NHMe, C=ONH2 , Ci-Cs alkyl, and 5- or 6-membered heteroaryl;

[0136] R3is selected from the group consisting of H, F, Cl, Br, I, OH, S, NH2, SH, OMe, NO2, NHOH, NHOMe, NHNH2, C=ONH2, (Ci-C8)alkyl, and 5- or 6-membered heteroaryl;

[0137] R4is selected from the group consisting of H, NH2 and (Ci-C8)alkyl;

[0138] R5is H, NH2, (Ci-C8)alkyl (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRalRbl;

[0139] R6is H, Ci-Cs alkyl (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRalRbl;

[0140] X’ is’N, O, or S (X’ can also be CR1);

[0141] X is NR2, O, or S; and each Raland Rblis independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RalandRb 1together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino.

[0142] COMBINATIONS

[0143] The combinations of the invention comprise: (i) a nucleobase with antiviral activity; and (ii) a potentiator compound that promotes the conversion of the antiviral nucleobase to their active forms or promotes the use of the active forms by reducing the pool of normal cellular triphosphates. Specifically, these combinations display synergistic anti-DENV, anti-ZIKV, antiinfluenza and anti-HCoV-OC43 surrogate for SARS-cov-2 properties. The invention relates to chemically stable combinations of structurally diverse antiviral agent nucleobases and potentiators; inhibitors of the de novo nucleotide biosynthesis.

[0144] The combinations of the invention display synergistic anti-DENV, anti-ZIKV Anti- U of M 2025-034 09531.606W01 influenza and anti-HCoV-OC43 surrogate for SARS-cov-2 properties. The combinations of the invention increase synergistically the antiviral effect of favipiravir and similar molecules against DENV, ZIKV, influenza, and HCoV-OC43 surrogate for SARS-cov-2. The combinations have the broad antiviral properties of favipiravir. Therapeutic combinations with favipiravir are applicable to target flaviviruses (such as DENV, ZIKV, influenza, and HCoV-OC43 surrogate for SARS-CoV-2), influenza viruses and other RNA viruses, including so-called “emerging viruses”. Other therapeutic combinations include antiviral nucleobases structurally similar or operating by a mechanism of action related to favipiravir. In an exemplary embodiment, the combination is synergistically active against DENV, ZIKV, influenza, and HCoV-OC43 surrogate for SARS-cov-2 and includes favipiravir, an antiviral nucleobase, and a de novo nucleotide biosynthesis inhibitor (DNNBi) such as 6-MMPR.

[0145] The use of the combinations of the invention may result in an equivalent or better antiviral effect than an antiviral compound alone and reduces the administrated dose and toxicity. Lower overall drug doses can decrease the rate of occurrence of drug-resistant variants of the targeted virus. Lower drug doses predict better patient compliance when pill burden is decreased or dosing schedule is simplified, particularly when synergy between compounds is obtained.

[0146] In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula (I), (II), of (III) can be useful as an intermediate for isolating or purifying a compound of formula (I), (II), of (III). Additionally, administration of a compound of formula (I), (II), of (III) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

[0147] Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. U of M 2025-034 09531.606W01

[0148] The compounds of formula (I), (II), of (III) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

[0149] Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0150] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. U of M 2025-034 09531.606W01

[0151] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0152] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0153] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0154] For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. U of M 2025-034 09531.606W01

[0155] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

[0156] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0157] Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I), (II), of (III) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

[0158] Useful dosages of the compounds of formula (I), (II), of (III) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

[0159] The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

[0160] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

[0161] A compound of formula (I) wherein R2and / or R3are -C(=O)NRR’ can be prepared using known techniques or can be prepared as illustrated in the following scheme: U of M 2025-034 09531.606W01

[0162] A compound of formula (I) wherein R2and / or R3are (Ci-C6)alkoxycarbonyl can be prepared using known techniques or can be prepared as illustrated in the following scheme:

[0163] The invention will now be illustrated by the following non-limiting Examples. U of M 2025-034 09531.606W01

[0164] All commercial reagents were used as provided unless otherwise indicated. An anhydrous solvent-dispensing system (J.C. Meyer) using two packed columns of neutral alumina was used for drying THF, Et2O, and CH2CI2, whereas two packed columns of molecular sieves were used to dry DMF. Solvents were dispensed under argon. Flash chromatography was performed with Ultra Pure silica gel (SiliCycle) or with RediSep Rf silica gel columns on a Teledyne ISCO CombiFlash Rf system using the solvents as indicated. All reactions were performed under a dry atmosphere of argon unless otherwise specified. Indicated reaction temperatures refer to the reaction bath, while room temperature (rt) is noted as 25°C. Commercial grade reagents and anhydrous solvents were used as received from vendors, and no attempts were made to purify or dry these components further. Removal of solvents under reduced pressure was accomplished with a Buchi rotary evaporator at approximately 28 mmHg pressure using a Teflon-linked KNF vacuum pump. Thin layer chromatography was performed using either 1 in. * 3 in. Anal Tech No. 02521 or Merck 60 F254 silica gel plates with fluorescent indicator using appropriate solvent mixtures. Visualization of TLC plates was made by observation with either short wave UV light (254 nm lamp) or 10% sulfuric acid in ethanol. Nuclear magnetic resonance spectra were recorded on a Varian 600 MHz or Bruker 400 spectrometer with Me4Si or signals from residual solvent as the internal standard for 1H. Chemical shifts are reported in ppm, and signals are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br s (broad singlet), and dd (double doublet). Values given for coupling constants are of first order. Mass spectroscopic analyses were performed either using positive mode electron spray ionization (ESI) on a Varian ProStar LC-MS with a 1200L quadrupole mass spectrometer or using positive mode atmospheric pressure chemical ionization (APCI) on a Shimadzu LC-MS system. High performance liquid chromatography (HPLC) purity analysis was conducted using a Varian Pro Star HPLC system with a binary solvent system A and B using a gradient elution [A, H2O with 0.1% trifluoroacetic acid (TFA); B, CH3CN with 0.1% TFA] and flow rate = 1 mL / min, with UV detection at 254 nm. All final compounds were purified to >95% purity, and these purity levels were measured by a Varian Pro Star HPLC system. Three different Varian Pro Star HPLC methods were used to establish compound purity. HPLC Method A: Phenomenex Luna C18(2) column (4.6 mm x 250 mm); mobile phase, A = H2O with 0.1% TFA and B = CH3CN with 0.1% TFA; gradient 10-95 % B (0.0-10 min; hold for 6 min); UV detection at 254 nm. HPLC Method B: SunFire C18 column (4.6 mm x 250 U of M 2025-034 09531.606W01 mm); mobile phase, A = H2O with 0.1% TFA and B = CH3CN with 0.1% TFA; gradient 10-100 % B (0.0-20 min; hold for 5 min); UV detection at 254 nm. HPLC Method C: SunFire Cl 8 column (4.6 mm x 250 mm); mobile phase, A = H2O with 0.1% TFA and B = CH3CN with 0.1% TFA; gradient 0-100 % B (0.0-15 min; hold for 5 min)); UV detection at 254 nm.

[0165] Example 1. Synthesis of Prdgl :

[0166] 6-Methylmercaptopurine riboside (6MMPR) (leq, 0.330g, l. lmmol) was suspended in acetone (6mL). A catalytic amount of dimethylaminopyridine (DMAP) and triethylamine (NEt ) (3.3eq, 0.369g, 3.65mmol) were added and the reaction mixture was cooled to 0 °C with an ice bath. Isobutyric anhydride (3.3eq, 0.577g, 3.65mmol) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was then dissolved in 200mL of di chloromethane and wash with water (3xl00mL). The organic phase was concentrated and purified on silica gel chromatography (DCM, MeOH 0 to 2 %), Rf= 0.4 (DCM, MeOH 2%), colorless thick oil, yield 86%. 'HNMR (400 MHz, CDCI3) 8 8.71 (s, 1H), 8.11 (s, 1H), 6.20 (d, J= 5.5 Hz, 1H), 5.89 (t, J= 5.5 Hz, 1H), 5.64 (dd, J= 5.6, 4.3 Hz, 1H), 4.55 - 4.29 (m, 3H), 2.71 (s, 3H), 2.67 - 2.42 (m, 3H), 1.36 - 0.87 (m, 18H).13C NMR (101 MHz, CDCI3) 6 176.91, 176.02, 175.77, 162.68, 152.57, 148.31, 141.25, 132.26, 86.86, 81.25, 73.63, 70.93, 63.47, 34.32, 34.20, 34.06, 19.41, 19.30, 19.27, 19.23, 19.16, 19.06, 12.26. HRMS (ESI+): m / z calculated for C23H33N4O7S+ [M+H]+5092064, found 509.2060.

[0167] Example 2. Synthesis of Prdg2: U of M 2025-034 09531.606W01

[0168] OH OH Acetronitrile OH OH 0 to rt

[0169] 6-Methylmercaptopurine riboside (6MMPR) (leq, 0.330g, l. lmmol) was suspended in acetonitrile (18mL). A catalytic amount of dimethylaminopyridine (DMAP) and triethylamine (NEti) (l.leq, 0.123g, 1.21mmol) were added and the reaction mixture was cooled to 0 °C with an ice bath. The acyl chloride (l. leq, 0.130g, 1.21mmol) was added dropwise over 10 minutes. The mixture was then stirred at room temperature for 72 hours. The mixture was then dissolved in 300mL of dichloromethane and wash with water (3xl00mL). The organic phase was concentrated and purified on silica gel chromatography (DCM, MeOH 0 to 5 %), Rf= 0.2 (DCM, MeOH 5%), white paste, yield 25%. ' H NMR (400 MHz, MeOD) 8 8.69 (s, 1H), 8.60 (s, 1H), 6.11 (d, J= 6.7 Hz, 1H), 5.29 (dd, J= 5.3, 2.5 Hz, 1H), 4.97 (dd, J= 6.8, 5.3 Hz, 1H), 4.30 (q, J= 2.7 Hz, 1H), 4.02 - 3.65 (m, 2H), 3.06 (s, 3H), 2.95 (s, 3H), 2.72 (s, 3H).13C NMR (101 MHz, MeOD) 6 163.33, 157.29, 152.60, 148.63, 144.06, 132.55, 90.36, 85.94, 75.75, 74.26, 62.84, 36.53, 36.17, 11.58. HRMS (ESI+): m / z calculated for C14H20N5O5S+ [M+H]+370.1180, found 370.1181

[0170] Example 3. Synthesis of Prdg3 : U of M 2025-034 09531.606W01

[0171] 6-methylmercaptopurine riboside (6MMPR) (leq, 0.330g, l.lmmol) was suspended in acetonitrile (18mL). A catalytic amount of dimethylaminopyridine (DMAP) and triethylamine (NEts) (l.leq, 0.123g, 1.21mmol) were added and the reaction mixture was cooled to 0 °C with an ice bath. The acyl chloride (l. leq, 0.130g, 1.21mmol) was added dropwise over 10 minutes. The mixture was then stirred at room temperature for 72 hours. The mixture was cooled to 0 °C with an ice bath and isobutyric anhydride was added. The mixture was then stirred at room temperature for 48 hours. The mixture was then dissolved in 300mL of dichloromethane and washed with water (3xl00mL). The organic phase was concentrated and purified on silica gel chromatography (Ethyl acetate, MeOH 0 to 5 %), Rf= 0.7 (EA, MeOH 5%), colorless thick oil, yield 35%. 'HNMR (400 MHz, CDC13) 8 8.73 (s, 1H), 8.15 (s, 1H), 6.26 (d, J= 5.6 Hz, 1H), 5.81 (t, J= 5.6 Hz, 1H), 5.64 (dd, J= 5.6, 4.3 Hz, 1H), 4.49 - 4.32 (m, 3H), 2.89 (s, 3H), 2.85 (s, 3H), 2.73 (s, 3H), 2.62 (dt, J= 11.5, 7.0 Hz, 2H), 1.29 - 1.13 (m, 12H).13C NMR (101 MHz, CDC13) 6 176.35, 175.33, 161.96, 154.13, 151.77, 147.90, 140.80, 131.61, 86.14, 80.72, 74.18, 70.65, 63.00, 36.48, 35.76, 33.75, 33.69, 18.83, 18.74, 18.69, 18.52, 11.85. HRMS (ESI+): m / z calculated for C22H32N5O7S+ [M+H]+510.2017, found 510.2010.

[0172] Example 4. Potentiation Studies

[0173] Cells.

[0174] BHK pD2-hRucPac-2ATG30 DENV replicon cells were a gift from M. Diamond (Washington University School of Medicine) and cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% FBS, 100 IU penicillin / streptomycin per mL, 5 pg / mL plasmocin, IX GlutaMAX, , and 3 pg / mL puromycin (InvivoGen).

[0175] DENV Replicon cell assay.

[0176] The DENV replicon assay was performed as described (Qiu, L., et al., PLoS neglected tropical diseases. 2018, 12, e0006421, doi: 10.1371 / journal.pntd.0006421; and Soto-Acosta, R., et al., Viruses. 2021, 13, 2508, doi: 10.3390 / vl3122508. Briefly, DENV replicon cells were plated at 1,500-2,000 cells per well 1.5-2 X 103 cells per well of a 96-well dish (Coming 3596) plate the day before use. The next day, compounds were added and cells incubated at 37°C, 5% CO2, in a humidified incubator for three days. The cells were the washed with PBS and Complete U of M 2025-034 09531.606W01

[0177] Promega Renilla reagent was added (Promega E2720, 1 pL Renilla-Glo Substrate + 99 pL Renilla-Glo Buffer + 100 pL phenol-red-free DMEM supplemented with 10% FBS per well). Cells were lysed for 10 minutes at room temp and 160 pL of lysate per well transferred to wells of a 96-well opaque white plate (Falcon 353296) and luminescence measured using a BioTek Neo2 plate reader with the Gen5 Basic Luminescence program.

[0178] The compound 6MMPR and the compounds of Examples 1-3 were evaluated for their ability to potentiate the anti-replicon activity of FAV, its defluorinated analogue T-l 105, and the ribavirin nucleobase. Dose-response analysis of FAV with a single non-toxic dose of potentiator resulted in a shift in the ECso curve and a reduction in the ECso value compared to FAV dose- response with vehicle DMSO (Figures 1 A-1D, Figure 2A-2D and Table 1). T-l 105 was also strongly potentiated by 6MMPR and prodrugs (Figures 1 A-1D, Figure 2A-2D and Table 1)), demonstrating a broader applicability to two different purine nucleobase analogues.

[0179] Table 1 U of M 2025-034 09531.606W01

[0180] Exampl e 5. Cy totoxi city

[0181] Cell viability assay (MTS).

[0182] Cell viability assays were performed as described (Qiu, L., et al., PLoS neglected tropical diseases. 2018, 12, e0006421, doi: 10.1371 / journal.pntd.0006421; Soto-Acosta, R., et al., Viruses. 2021, 13, 2508, doi: 10.3390 / vl3122508; and Soto-Acosta, R., et al., Molecules 2021, 26, doi: 10.3390 / molecules26133779). Briefly, DENV replicon cells were plated at 1,500- 2,000 cells per well of a 96-well dish plate (Coming 3596) the day before use. The next day, compounds were added and cells incubated at 37°C, 5% CO2, in a humidified incubator for three days. The cells were washed with phosphate buffered saline (PBS) and incubated with the MTS reagent (Promega G5430) as per manufacturer’s instructions. The plates were read at 490nm wavelength at 30-minute intervals in a BioTek Neo2 plate reader using Gen5 software. Results for 6MMPR and the compounds of Examples 1-3 are shown in the following Table 2.

[0183] Table 2

[0184] Broad-spectrum antivirals are urgently needed to develop countermeasures against emerging and re-emerging viruses. Broad-spectrum antiviral drugs are of major interest because of their high potential to treat different viral infections. Developing broad-spectrum antivirals allows accelerated drug approval compared to the classical virus-specific drug development which is too slow and costly to provide solutions in possible pandemic emergencies. Only a few broad-spectrum antiviral drugs are currently approved and have limitations. FAV is a broadspectrum antiviral drug active against many viruses but displayed limited efficacy in clinical trials against Ebola and SARS-CoV-2 viruses. One limitation of FAV is it can be a poor U of M 2025-034 09531.606W01 substrate for HGPRT, the enzyme responsible for its conversion to its corresponding nucleoside monophosphate. The drug combination strategy described herein significantly increases the formation of FAV’s active form, leading to a synergistic and broad-spectrum antiviral effect via two distinct yet complementary mechanisms.

[0185] Example 6. Synthesis of:

[0186] 2H-1, 2, 4-triazole-3 -carboxamide (CAS# 3641-08-5) (MW= 112.09, leq, 3g, 26.76mmol) and K2CO3 (138.20, l.leq, 4.07g, 29.43mmol) were suspended in dioxane 4ml / mmol HOmL and stirred at rt for 1 hour. The mixture was then cooled to 0 Celsius with ice bath and dimethylcarbamyl chloride (CAS# 79-44-7) (MW= 107.54, l. leq, 3.16g, 29.43mmol, d- 1.17, 2.7mL) was added dropwise, then warmed back to rt. The mixture was then stirred at 45 Celsius for 72 hours. The mixture was allowed to return to rt, 40mL of silica gel was added and the mixture concentrated for solid deposit flash chromatography EA gradient 0 to 15% methanol. Or combiflash column 80g. Ethyl Acetate MeOH 0 to 15%. Rf= 0.4 (EA, MeOH 10%), 3.2g (65%) white solid obtained. Recrystallization of 1.5g in 80mL of boiling ethanol, overnight. 'H NMR. (400 MHz, DMSO) 8 9.10 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 3.10 (s, 6H).13C NMR (101 MHz, DMSO) 6 159.9, 156.8, 149.2, 147.2, 37.6, 37.4. HRMS (ESI+) (M+H)+ 184.0826

[0187] Example 7. Synthesis of:

[0188] Favipiravir (MW= 157.1, leq, 5.5g, 35mmol) is suspended in isobutyric anhydride as solvent (Iml / mmol) 35mL and stirred at rt for 10 minutes, then pyridine (MW= 79.1, l.leq, 3.045g, 38.5 mmol, d= 0982, 3.1mL) is added dropwise (1 minute) and the mixture is stirred at U of M 2025-034 09531.606W01 rt for 3-4 hours. Crystallization occurs after 3-4 hours, the solid (pure product) is filtered off on a frit and washed with hexane. The filtrate is left under house vacuum overnight to evaporate all the anhydride, pyridine and hexane.

[0189] The solid obtained from the filtrate, about 7 g of crude, is then recrystallized in boiling hexane (200mL) and a minimum of acetone (30-40mL total) is added in small amounts in the boiling hexane until complete solubility is observed. The clear solution is removed from the heat and left to crystallize at rt overnight. Once crystals have been obtained, the crystals are filtered off and washed whit hexane, crystallization in the filtrate occurs almost immediately and can be filtered again as well. Too many consecutive recrystallizations do bring impurities. Total 6.32g (79%) of pure off-white crystal needles are obtained.

[0190] 'HNMR (400 MHz, DMSO) 8 8.73 (d, J= 8.3 Hz, 1H), 8.2 (s, 1H), 7.9 (s, 1H), 2.88 (m, 1H), 1.25 (m, 6H).19F NMR (376 MHz, DMSO) 6 -85.06.13C NMR (101 MHz, DMSO) 6 174.1, 162.9, 157.4, 154.9, 149.9, 134.7, 134.3, 33.3, 18.3. HRMS (ESI+) (M+H)+ 228.0780.

[0191] Examples 8-15

[0192] The compounds of examples 8-15 were prepared by the following general synthetic procedure.

[0193] Favipiravir (MW= 157.1, leq) was suspended in the appropriate acid anhydride as solvent (Iml / mmol) 35mL and stirred at rt for 10 minutes, then pyridine (MW= 79.1, l.leq) was added dropwise (1 minute) and the mixture was stirred at rt for 3-4 hours. Crystallization generally occured after 3-4 hours, the solid (pure product) was filtered off on a frit and washed with hexane. The filtrate was left under house vacuum overnight to evaporate all the anhydride, pyridine and hexane. The solid obtained from the filtrate was either recrystallized in boiling hexane and a minimum of acetone or just washed with hexane to obtain the pure product.

[0194] Example 8. Synthesis of:

[0195] XH NMR (400 MHz, DMSO) 6 8.74 (d, J= 8.3 Hz, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 2.32 (s, 3H). U of M 2025-034 09531.606W01

[0196] 19F NMR (376 MHz, DMSO) 6 -84.92.13C NMR (101 MHz, DMSO) 6 168.7, 162.91, 157.4, 154.9, d 149.8, m 134.4, 20.7. HRMS (ESI+) (M+H)+ 200.0463.

[0197] Example 9. Synthesis of:

[0198] 'HNMR (400 MHz, DMSO) 6 8.73 (d, J= 8.3 Hz, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H).19F NMR (376 MHz, DMSO) 6 -85.02.13C NMR (101 MHz, DMSO) 6 172.0, 162.9, 157.4, 154.9, d 150.0, m 134.8, 26.9, 8.4. HRMS (ESI+) (M+H)+ 214.0622.

[0199] Example 10. Synthesis of:

[0200] 'H NMR (400 MHz, DMSO) 6 8.73 (d, J= 8.3 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H), 2.63 (t, J = 7.2 Hz, 2H), 1.67 (q, J= 7.3 Hz, 2H), 0.98 (t, J= 7.4 Hz, 3H).19F NMR (376 MHz, DMSO) 6 - 85.03.13C NMR (101 MHZ, DMSO) 6 171.1, 162.3, 157.4, 154.9, d 149.9, m 134.8, 35.1, 17.41, 13.3. HRMS (ESI+) (M+H)+ 228.0773

[0201] Example 11. Synthesis of:

[0202] 'H NMR (400 MHz, DMSO) 6 8.73 (d, J= 8.3 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H), 2.64 (t, J = 7.4 Hz, 2H), 1.78 - 1.54 (m, 2H), 1.53 - 1.25 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H).19F NMR (376 MHz, DMSO) 6 -85.03.13C NMR (101 MHz, DMSO) 6 171.2, 162.9, 157.4, 154.9, d 149.9, m U of M 2025-034 09531.606W01

[0203] 134.8, 33.0, 25.9, 21.5, 13.6. HRMS (ESI+) (M+H)+ 242.0936

[0204] Example 12. Synthesis of:

[0205] 'H NMR (400 MHz, DMSO) 6 8.73 (d, J= 8.3 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H), 2.63 (t, J = 7.4 Hz, 2H), 1.77 - 1.56 (m, 2H), 1.35 (ddt, J= 11.3, 8.4, 4.1 Hz, 4H), 0.99 - 0.79 (m, 3H).19F NMR (376 MHz, DMSO) 6 -85.02.13C NMR (101 MHz, DMSO) 6 171.2, 162.9, 157.4, 154.9, d 149.9, m 134.8, 33.2, 30.4, 23.5, 21.7, 13.8. HRMS (ESI+) (M+H)+ 256.1092.

[0206] Example 13. Synthesis of:

[0207] 'H NMR (400 MHz, DMSO) 6 8.73 (d, J= 8.3 Hz, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 2.63 (t, J = 7.4 Hz, 2H), 1.74 - 1.50 (m, 2H), 1.48 - 1.13 (m, 16H), 0.99 - 0.74 (m, 3H).19F NMR (376 MHz, DMSO) 6 -85.02. HRMS (ESI+) (M+H)+ 340.2028.

[0208] Example 14. Synthesis of:

[0209] XH NMR (400 MHz, CDC13) 6 8.41 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 5.83 (s, 1H), 2.72 (t, J = 7.6 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.69 - 1.12 (m, 24H), 0.94 - 0.73 (m, 3H). ).19F NMR (376 MHz, DMSO) 6 -84.40. HRMS (ESI+) (M+H)+ 396.2651.

[0210] Example 15. Synthesis of: U of M 2025-034 09531.606W01

[0211] 'H NMR (400 MHz, DMSO) 6 8.67 (d, J= 8.3 Hz, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 3.07 (s, 3H), 2.90 (s, 3H).19F NMR (376 MHz, DMSO) 6 -85.0 HRMS (ESI+) (M+H)+ 229.0737. Example 16.

[0212] The compounds of examples 6-15 were tested in DENV BHK Replicon cells. The results of this test are shown in Table 3

[0213] Table 3 U of M 2025-034 09531.606W01

[0214] All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The publications L. F. Bonnac et al., Molecules 2025, 30(2), 210 (PMID: 39860080 PMCID: PMC11767801 DOI: 10.3390 / molecules30020210) and A. E. Weight et al., Pathogens 2025, 14(9), 925 (doi.org / 10.3390 / pathogensl4090925) are incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

U of M 2025-034 09531.606W01ClaimsWhat is claimed is:

1. A compound of formula (I):or a salt thereof, wherein:R1is (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRaRb;R2is H, (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRcRd;R3is H, (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NReRf; each Raand Rbis independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RaandRbtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each Rcand Rdis independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and each Reand Rfis independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Reand Rftogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino,2. The compound or salt of claim 1, wherein R1is (Ci-C6)alkanoyl.

3. The compound or salt of claim 1, wherein R1is 2-methylpropanoyl.U of M 2025-034 09531.606W014. The compound or salt of claim 1, wherein R1is (Ci-C6)alkoxycarbonyl.

5. The compound or salt of claim 1, wherein R1is -C(=O)NRaRb.

6. The compound or salt of claim 5, wherein Rais H.

7. The compound or salt of claim 5, wherein Rais (Ci-C4)alkyl.

8. The compound or salt of claim 5, wherein Rais methyl.

9. The compound or salt of any one of claims 5-8, wherein Rbis H.

10. The compound or salt of any one of claims 5-8, wherein Rbis (Ci-C4)alkyl.

11. The compound or salt of any one of claims 5-8, wherein Rbis methyl.

12. The compound or salt of any one of claims 1-11, wherein R2is (Ci-C6)alkanoyl.

13. The compound or salt of any one of claims 1-11, wherein R2is 2-methylpropanoyl.

14. The compound or salt of any one of claims 1-11, wherein R2is (Ci-C6)alkoxycarbonyl.

15. The compound or salt of any one of claims 1-11, wherein R2is -C(=O)NRcRd.

16. The compound or salt of claim 15, wherein Rcis H.

17. The compound or salt of claim 15, wherein Rcis (Ci-C4)alkyl.

18. The compound or salt of claim 15, wherein Rcis methyl.

19. The compound or salt of any one of claims 15-18, wherein Rdis H.U of M 2025-034 09531.606W0120. The compound or salt of any one of claims 15-18, wherein Rdis (Ci-C4)alkyl.

21. The compound or salt of any one of claims 15-18, wherein Rdis methyl.

22. The compound or salt of any one of claims 1-21, wherein R3is (Ci-C6)alkanoyl.

23. The compound or salt of any one of claims 1-21, wherein R3is 2-methylpropanoyl.

24. The compound or salt of any one of claims 1-21, wherein R3is (Ci-C6)alkoxycarbonyl.

25. The compound or salt of any one of claims 1-21, wherein R3is -C(=O)NReRf.

26. The compound or salt of claim 25, wherein Reis H.

27. The compound or salt of claim 25, wherein Reis (Ci-C4)alkyl.

28. The compound or salt of claim 25, wherein Reis methyl.

29. The compound or salt of any one of claims 25-28, wherein Rfis H.

30. The compound or salt of any one of claims 25-28, wherein Rfis (Ci-C4)alkyl.

31. The compound or salt of any one of claims 25-28, wherein Rfis methyl.

32. The compound or salt of claim 1, which is selected from the group consisting of:U of M 2025-034 09531.606W01and salts thereof.

33. A compound of formula (II) or formula (III):or a salt thereof, wherein:R4is (Ci-Ci8)alkanoyl, (Ci-Ci8)alkoxycarbonyl or -C(=O)NRfRg;R4ais halogen or H; each Rfand Rgis independently selected from the group consisting of H, (Ci-Ci8)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RfandRgtogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and each Rhand R1is independently selected from the group consisting of H, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or Rhand R1together with the nitrogen to which they are attached form aU of M 2025-034 09531.606W01 aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino.

34. The compound or salt of claim 33 that is a compound of formula (II):or a salt thereof.

35. The compound or salt of claim 33 or 34, wherein R4ais F.

36. The compound or salt of any one of claims 33-35, wherein R4is (Ci-Ci6)alkanoyl.

37. The compound or salt of any one of claims 33-35, wherein R4is acetyl, propanoyl, 2- methylpropanoyl. butanoyl, pentanoyl, hexanoyl, dodecanoyl, or palmitoyl.

38. The compound or salt of any one of claims 33-35, wherein R4is -C(=O)NRfRg.

39. The compound or salt of any one of claims 33-35 or 38, wherein Rfis H.

40. The compound or salt of any one of claims 33-35 or 38, wherein Rfis (Ci-C4)alkyl.

41. The compound or salt of any one of claims 33-35 or 38, wherein Rfis methyl.

42. The compound or salt of any one of claims 33-35 or 38-41, wherein Rgis H.

43. The compound or salt of any one of claims 33-35 or 38-41, wherein Rgis (Ci-C4)alkyl.

44. The compound or salt of any one of claims 33-35 or 38-41 wherein Rgis methyl.

45. The compound or salt of claim 33 or 34 which is selected from the group consisting of:U of M 2025-034 09531.606W01and salts thereof.

46. The compound or salt of claim 33 that is a compound of formula (III):or a salt thereof.

47. The compound or salt of claim 33 or 46, wherein Rfis H.

48. The compound or salt of claim 33 or 46, wherein Rfis (Ci-C4)alkyl.

49. The compound or salt of claim 33 or 46, wherein Rfis methyl.

50. The compound or salt of any one of claims 33 or 46-49, wherein Rgis H.U of M 2025-034 09531.606W0151. The compound or salt of any one of claims 33 or 46-49, wherein Rgis (Ci-C4)alkyl.

52. The compound or salt of any one of claims 33 or 46-49, wherein Rgis methyl.

53. The compound or salt of claim 33 or 46 which is:or a salt thereof.

54. A pharmaceutical composition comprising a compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

55. A method for treating a viral infection in an animal comprising administering a compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof to the animal.

56. A compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof for use in medical therapy.

57. A compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a viral infection.

58. Use of a compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a viral infection in an animal.

59. A method for the treatment of an RNA virus infection comprising administering a therapeutic combination as a combined formulation or by alternation to a patient, wherein the therapeutic combination comprises therapeutically effective amounts of (i) an antiviralU of M 2025-034 09531.606W01 nucleobase or a pharmaceutically acceptable salt thereof; and (ii) a compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof.

60. The method of claim 59 wherein the RNA virus infection is selected from dengue virus (DENV), Zika virus (ZIKV), Ebola virus, West Nile virus, severe acute respiratory syndrome (SARS) virus, Middle East Respiratory syndrome (MERS) coronavirus, rabies virus, common cold viruses, influenza, hepatitis C, West Nile fever, polio, measles, respiratory syncytial virus, Nipah virus, Lassa fever virus, and SARS-CoV-2.

61. The method of claim 59 wherein the viral infection is dengue virus (DENV).

62. The method of claim 59 wherein the viral infection is Zika virus (ZIKV).

63. The method of claim 59 wherein the viral infection is influenza A.

64. The method of claim 59 wherein the viral infection is SARS-CoV-2.

65. The method of any one of claims 59-64 wherein the antiviral nucleobase is selected from the structures:U of M 2025-034 09531.606W01or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, Me, F, Cl, Br, I, OH, NH2, SH, OMe, NO2, NHOH, NHOMe, NHNH2, C=ONH2, (Ci-C8)alkyl, and 5- or 6-membered heteroaryl;R2is selected from the group consisting of H, OH, OMe, NH2, NHMe, C=ONH2 , Ci-Cs alkyl, and 5- or 6-membered heteroaryl;R3is selected from the group consisting of H, F, Cl, Br, I, OH, S, NH2, SH, OMe, NO2, NHOH, NHOMe, NHNH2, C=ONH2, (Ci-C8)alkyl, and 5- or 6-membered heteroaryl;R4is selected from the group consisting of H, NH2 and (Ci-C8)alkyl;R5is H, NH2, (Ci-C8)alkyl (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRalRbl;R6is H, (Ci-Cs )alkyl (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl or -C(=O)NRalRbl;X’ is’N, O, or SX is NR2, O, or S; and each Raland Rblis independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C4)alkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl and heteroaryl(Ci-C4)alkyl; or RalandRbltogether with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino.U of M 2025-034 09531.606W0166. The method of any one of claims 59-64 wherein the antiviral nucleobase is selected from a compound or pharmaceutically salt thereof as described in any one of claims 33-53.

67. The method of any one of claims 59-64 wherein the antiviral nucleobase is selected from lH-l,2,4-triazole-3-carboxamide, 5 -hydroxy- lH-imidazole-4-carboxamide, 3-hydroxypyrazine- 2-carboxamide, 9H-purine-2,6-diamine; and 6-fluoro-3-hydroxypyrazine-2-carboxamide (favipiravir).

68. The method of any one of claims 59-67 wherein the therapeutic combination is administered to the patient as a combined formulation.

69. The method of claim 68 wherein the therapeutic combination is a solid, oral dosage form.

70. The method of claim 69 wherein the solid, oral dosage form is a tablet or capsule.

71. The method of any one of claims 49-70 wherein the therapeutic combination is administered to the patient by alternation during a dosing regimen.

72. A method of inhibiting replication of a virus comprising treating a virus-infected cell with an antiviral nucleobase and a compound as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising therapeutically effective amounts of: (i) an antiviral nucleobase, (ii) compound a as described in any one of claims 1-53 or a pharmaceutically acceptable salt thereof, and (iii) an excipient.

74. The pharmaceutical composition of claim 73 in solid, oral dosage form.

75. The pharmaceutical composition of claim 74 wherein the solid, oral dosage form is aU of M 2025-034 09531.606W01 tablet or capsule.

76. The pharmaceutical composition of claim 75 wherein the antiviral nucleobase and the compound a as described in any one of claims 1-53 or the pharmaceutically acceptable salt thereof are in synergistic amounts.

77. The pharmaceutical composition of claim 76 wherein the antiviral nucleobase is favipiravir, T-1105 or Ribavirin nucleobase.

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