Synthesis and antiviral activity of dioxolane-derived 7-deazapurine nucleoside analogs and methods of treating epstein BARR virus (EBV) and human immunodeficiency virus (HIV) infections

Abstract

The present invention is directed to novel dioxolane-derived 7-deazapurine nucleoside analogs, the antiviral activity of these compounds, pharmaceutical compositions thereof and methods of treating Epstein Barr Virus (EBV), Human Immunodeficiency Virus (HIV) infections and Multiple Sclerosis or reducing the likelihood of these disease states occurring in patients or subjects at risk for same, and inhibiting, resolving or ameliorating symptoms associated therewith.

Description

[0001] SYNTHESIS AND ANTIVIRAL ACTIVITY OF DIOXOLANE-DERIVED 7-DEAZAPURINE NUCLEOSIDE ANALOGS

[0002] AND METHODS OF TREATING EPSTEIN BARR VIRUS (EBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTIONS Field of the Invention

[0003] The present invention is directed to novel dioxolane-derived 7-deazapurine nucleoside analogs, the antiviral activity of these compounds, pharmaceutical compositions thereof and methods of treating Epstein Barr Virus (EBV) and Human Immunodeficiency Virus (HIV) infections and resolving symptoms associated therewith.

[0004] Related Applications

[0005] This application claims the benefit of priority of United States provisional application s.n. 63 / 762,131, filed 24 February 2025, the entire contents of which is incorporated by reference in its entirety herein.

[0006] Background and Overview of the Invention

[0007] Herpesviruses pose a significant threat to humans due to their ability to establish lifelong latent infections.1These viruses may cause life-threatening diseases during both primary infections and reactivations. Epstein-Barr virus (EBV), a member of the herpesvirus family, is a major cause of infectious mononucleosis and contributes significantly to morbidity in adolescents and young adults. It is speculated that most people become infected with EBV during their lifetime. As a ubiquitous virus, EBV was first discovered in the tumor cells of pediatric Burkitt Lymphoma.4Later, researchers have revealed that EBV stimulates a variety of lymphoproliferative disorders. ' Its latent infections are linked to the development of cancer and autoimmune diseases. ’ Recent studies have also shown that EBV infection can logically and mechanistically enhance the progress of multiple sclerosis (MS).10MS is a prevalent chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), and it is triggered by the infection of the EBV. Globally, approximately 2.8 million people have MS , and recent findings of a longitudinal analysis on United States (US) troops (active adults on duty) have revealed a high prevalence of EBV associated with MS.14Rather than infectious mononucleosis, the risk of MS increases 32-fold after EBV infection.14Notably, worldwide, -90% of adults have been infected with EBV, and it isconstantly detected in numerous cancers, including nasopharyngeal carcinoma, subtypes of Hodgkin and non-Hodgkin lymphomas,15EBV-associated gastric carcinoma, leiomyosarcoma, and natural Killer (NT) / T cell carcinomas.16’17In EBV-driven cancers, MS, and fatal lymphoproliferative disorders, reactivation of the virus plays a critical role. Additionally, organ transplant patients on immune suppressant therapy also face a severe life-threatening condition after latent EBV infection. In the case of organ transplant patients, EBV causes post-transplant lymphoproliferative disease (PTLD).19PTLD conditions create a life-challenging situation for organ transplant patients and generate a critical concern for treatment and safe organ transplantations.19There is no approved antiviral specifically to treat EBV or its associated MS conditions.10Therefore, a large population with the underlying EBV infection, immunocompromised patients, and cancer-treating parties are on the edges of a major threat of this virus. However, broad-spectrum antiviral such as acyclovir, valacyclovir, penci cl ovir (PCV), famciclovir (FCV), and ganciclovir (GCV) are being used

[0008]

[0009] for the treatment of EBV infections. ’ These FDA-approved antivirals have less potency against EBV, and often, large doses of prescribed drugs promote severe side effects as well as 21

[0010] viral stress mutations. Furthermore, especially against MS conditions, approved antivirals have not demonstrated any clear benefits.10

[0011] Consequently, there is a void for potent antivirals, and a new directing acting antiviral (DAA) agent is urgently needed to overcome EBV-associated complications. The discovery of new antivirals will also assist in the future preparedness to deal with this life-threatening DNA virus, which establishes lifelong infection. Elaborating on our past two-decade efforts, in this communication, an extended structure-activity relationship of unexplored D-dioxolane-7-deazapurine analogs (12-19) has been reported, which demonstrated selective inhibition of EBV and expressed moderated activity against HIV. Out of these synthesized modified analogs, compounds 15 & 16 exhibited potential antiviral activity and will be proceeded for further preclinical development against EBV and other herpesviruses infections. The timely finding of this report is essential to accelerate the space of altered dioxolane-derived nucleos(t)ide against EBV as well as other emerging viruses.

[0012] Brief Description of the Invention

[0013] In an embodiment, the present invention is directed to compounds according to the chemical structure I:

[0014]

[0015] Where X and Z are each independently C or N;

[0016] Q and T are each C or N, with the proviso that

[0017] When Q is C, T is N,

[0018]

[0019] is a double bond between Q and the adjacent carbon atom and a double bond between X and the carbon atom between X and T, and

[0020] When Q is N, T is C, X is C, R2 is H, Z is N, R3 is absent,

[0021]

[0022] is a single bond between Q and the adjacent carbon atom, a double bond between T and the adjacent carbon atom and a double bond between X and the adjacent carbon atom;

[0023] Y is H, NRYRY, ORYor SRY, often NHRY, ORYor SRY;

[0024] Each RYis independently H, C1-C12 alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CEtji-Aryl or -(CEEji-Heterocycle;

[0025] Ri is H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo (F, Cl, Br or I), C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;

[0026] R2 is absent (when X is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, Ci-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i-Heterocycle;

[0027] R3 is absent (when Z is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;

[0028] R4 is H when T is N, or H, OH, CN, CH3, vinyl, alkyne when T is C; and

[0029] R is H, Ci-Ce alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CH2)i-Aryl or -(CH2)i-Heterocycle;

[0030] R1is H or a RPROgroup;

[0031] RPROis an acyl group according to the chemical structure:

[0032]

[0033] , where R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups; or RPROis a group according to the chemical structure:

[0034]

[0035] R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups;

[0036] RN1and RN2are each independently H or a Ci-Ce alkyl or acyl group optionally substituted with 1-3 hydroxy or halo groups; and

[0037] R is H, a Ci-Ce alkyl group optionally substituted with 1-3 hydroxy or halo groups, an O-R group where R3is the same as above or a NRN1RN2group where RN1and RN2are the same as above; or

[0038]

[0039] group;

[0040] Where x is 0 or 1; and

[0041] RN1and RN2are the same as above; or

[0042] RPROis a

[0043]

[0044] group;

[0045] Where RAAis H, a Ci-Ce alkyl group which is optionally substituted with from 1-3 hydroxyl groups or 1-3 halogroups or an amino acid side chain selected from the group consisting of is a side chain derived from an amino acid, said amino acid side chain being preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethylcarboxyamide (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl(phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyl eneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0046] R4a is H or a C1-C20 (often a Ci-Ce) alkyl group which is optionally substituted with from 1-3 hydroxyl groups and 1-3 halo groups; or

[0047] RPROis a phosphate ester, phosphodiester, phosphoramidate or phosphordiamidate group according to the chemical structure:

[0048]

[0049] Where R5 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryl oxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionallyl substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups, or the two R5groups link together to form a five- or six-membered heterocyclic group, with the proviso that no more than one R5 or R6group is H;

[0050] Each Re is independently H (with the proviso that not more than one Re or R5 group is H), a group according to the chemical structure:

[0051]

[0052] , or an amide group derived from an amino acid (a natural or unnatural amino acid such as, for example, alanine, P-alanine, arginine, asparagine, asparticacid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine, among

[0053] others) according to the structure:

[0054]

[0055] Where i is 0, 1, 2 or 3 (preferably 0 or 1);

[0056] R7 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryloxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionallyl substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups;

[0057] R7is H or C1-C3 alkyl, preferably H;

[0058] Rs is a side-chain of an amino acid, preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethyl carb oxy ami de (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyeneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0059] R” is H, a Ci to C20 alkyl (linear, branched or cyclic alkyl) or a phenyl or heteroaryl group, each of which groups is optionally substituted, or

[0060] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0061] In embodiments according to the invention, the compounds are according to chemical structure IA:

[0062]

[0063] IA

[0064] Where X, Y, Z, R R2, R3 and R1are the same as for the generic chemical structure I set forth herein above.

[0065] In embodiments of compounds according to the present invention, in compound structure IA, X is C, R2is H or halo, Y is NH2or NHMe, Z is N (R3 is absent in all cases when Z is N) and Ri is H or halo.

[0066] In embodiments of compounds according to the present invention, in compound structure IA, X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0067] X is C, R2is F, Y is NH2, Z is N and Ri is H;

[0068] X is C, R2is Cl, Y is NH2, Z is N and Ri is H;

[0069] X is C, R2is Br, Y is NH2, Z is N and Ri is H;

[0070] X is C, R2is I, Y is NH2, Z is N and Ri is H;

[0071] X is C, R2is H, Y is NH2, Z is N and Ri is NH2;

[0072] X is C, R2is H, Y is NH2, Z is N and Ri is F; or

[0073] X is C, R2is H, Y is NHMe, Z is N and Ri is NH2; or

[0074] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0075] In preferred embodiments of compounds according to the present invention, in compound structure IA,

[0076] X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0077] X is C, R2is F, Y is NH2, is Z is N and Ri is H;

[0078] X is C, R2is Br, Y is NH2, Z is N and Ri is H; or

[0079] X is C, R2is I, Y is NH2, Z is N and Ri is H.In embodiments according to the invention the compounds are according to chemical structure IB when X is C, Q is N and T is C:

[0080]

[0081] Where Y, Ri, R4 and R1are the same as for the generic chemical structure I set forth herein above.

[0082] In an embodiment, the present invention is directed to compounds according to the

[0083]

[0084] Where R2 is H or halo (F, Cl, Br or I);

[0085] Y is Cl;

[0086] Ri is H, NHR or halo (F, Cl, Br or I); and

[0087] R is H or CH3; ora pharmaceutically acceptable salt, solvate or polymorph thereof.

[0088] In specific embodiments of compounds according to the present invention, in compound structure II,

[0089] R2 is H, Y is Cl and Ri is H;

[0090] R2 is F, Y is Cl and Ri is H;

[0091] R2 is Cl, Y is Cl and Ri is H;

[0092] R2 is Br, Y is Cl and Ri is H;

[0093] R2 is I, Y is Cl and Ri is H;

[0094] R2 is H, Y is Cl and Ri is NH2;

[0095] R2 is H, Y is Cl and Ri is F; or

[0096] R2 is H, Y is Cl and Ri is NHMe; or

[0097] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0098] In preferred embodiments of compounds according to the present invention, in compound structure II,

[0099] R2 is H, Y is Cl and Ri is H;

[0100] R2 is F, Y is Cl and Ri is H;

[0101] R2 is Br, Y is Cl and Ri is H; or

[0102] R2 is I, Y is Cl and Ri is H.

[0103] In embodiments, the present invention is directed to pharmaceutical compositions useful in the treatment of viral infections, more particularly Epstein-Barr Virus (EB V) or human immunodefiency virus (HIV) infections such as mononucleosis (EBV) or autoimmune deficiency syndrome (HIV), comprising an effective amount of a compound according to the chemical structure I:

[0104]

[0105] Where X and Z are each independently C or N;

[0106] Q and T are each C or N, with the proviso that

[0107] when Q is C, T is N,

[0108]

[0109] is a double bond between Q and the carbon atom between Q and X and a double bond between X and the carbon atom between X and T, and

[0110] when Q is N, T is C, X is C, R2 is H, Z is N, R3 is absent and

[0111]

[0112] is a single bond between Q and the carbon atom between Q and X, a double bond between T and the carbon atom between T and X and a double bond between X and the carbon atom between X and Q;

[0113] Y is H, NRYRY, ORYor SRY, often NHRY, ORYor SRY;

[0114] Each RYis independently H, C1-C12 alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CH2)i-Aryl or -(CH2)i-Heterocycle;

[0115] Ri is H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo (F, Cl, Br or I), C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;

[0116] R2 is absent (when X is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, Ci-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i-Heterocycle;

[0117] R3 is absent (when Z is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;

[0118] R4 is H when T is N, or H, OH, CN, CH3, vinyl, alkyne when T is C; and

[0119] R is H, Ci-Ce alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CH2)i-Aryl or -(CH2)i-Heterocycle;

[0120] R1is H or a RPROgroup;

[0121] RPROis an acyl group according to the chemical structure:

[0122]

[0123] , where R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups; or RPROis a group according to the chemical structure:

[0124]

[0125] R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups;

[0126] RN1and RN2are each independently H or a Ci-Ce alkyl or acyl group optionally substituted with 1-3 hydroxy or halo groups; and

[0127] R is H, a Ci-Ce alkyl group optionally substituted with 1-3 hydroxy or halo groups, an O-R group where R3is the same as above or a NRN1RN2group where RN1and RN2are the same as above; or

[0128]

[0129] group;

[0130] Where x is 0 or 1; and

[0131] RN1and RN2are the same as above; or

[0132] RPROis a

[0133]

[0134] group;

[0135] Where RAAis H, a Ci-Ce alkyl group which is optionally substituted with from 1-3 hydroxyl groups or 1-3 halogroups or an amino acid side chain selected from the group consisting of is a side chain derived from an amino acid, said amino acid side chain being preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethylcarboxyamide (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl(phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyl eneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0136] R4a is H or a C1-C20 (often a Ci-Ce) alkyl group which is optionally substituted with from 1-3 hydroxyl groups and 1-3 halo groups; or

[0137] RPROis a phosphate ester, phosphodiester, phosphoramidate or phosphordiamidate group according to the chemical structure:

[0138]

[0139] Where R5 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryl oxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionallyl substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups, or the two R5 groups link together to form a five- or six-membered heterocyclic group, with the proviso that no more than one R5 or R6group is H;

[0140] Each Re is independently H (with the proviso that not more than one Re or R5 group is H), a group according to the chemical structure:

[0141]

[0142] , or an amide group derived from an amino acid (a natural or unnatural amino acid such as, for example, alanine, P-alanine, arginine, asparagine, asparticacid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine, among

[0143] others) according to the structure:

[0144]

[0145] Where i is 0, 1, 2 or 3 (preferably 0 or 1);

[0146] R7 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryloxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionally substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups;

[0147] R7is H or C1-C3 alkyl, preferably H;

[0148] Rs is a side-chain of an amino acid, preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethyl carb oxy ami de (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyeneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0149] R” is H, a Ci to C20 alkyl (linear, branched or cyclic alkyl) or a phenyl or heteroaryl group, each of which groups is optionally substituted, or

[0150] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0151] In embodiments of compositions according to the present invention, compositions comprise an effective amount of a compound according to chemical structure IA,Where X, Y, Z, Ri, R2, R3 and R1are the same as for the generic chemical structure I set forth herein above.

[0152] In embodiments of compositions according to the present invention, compositions comprise an effective amount of a compound according to chemical structure IA (R1is the same as for generic chemical structure I),

[0153] Where X is C, R2 is H or halo, Y is NH2 or NHMe, Z is N and Ri is H or halo.

[0154] In embodiments of compositions according to the present invention, compositions comprise an effective amount of a compound according to chemical structure IA (R1is the same as for general chemical structure I),

[0155] Where X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0156] X is C, R2 is F, Y is NH2, Z is N and Ri is H;

[0157] X is C, R2is Cl, Y is NH2, Z is N and Ri is H;

[0158] X is C, R2is Br, Y is NH2, Z is N and Ri is H;

[0159] X is C, R2 is I, Y is NH2, Z is N and Ri is H;

[0160] X is C, R2 is H, Y is NH2, Z is N and Ri is NH2;

[0161] X is C, R2 is H, Y is NH2, Z is N and Ri is F; or

[0162] X is C, R2 is H, Y is NHMe, Z is N and Ri is NH2; or

[0163] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0164] In embodiments of compositions according to the present invention, compositions comprise an effective amount of a compound according to chemical structure IA (R1is the same as for general chemical structure I),

[0165] Where X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0166] X is C, R2 is F, Y is NH2, is N and Ri is H;

[0167] X is C, R2 is Br, Y is NH2, Z is N and Ri is H; or

[0168] X is C, R2 is I, Y is NH2, Z is N and Ri is H.

[0169] In embodiments of compositions according to the present invention, compositions comprise an effective amount of a compound according to chemical structure IB, where Y, Ri and R1are the same as for the generic chemical structure I set forth herein above.In embodiments, pharmaceutical compositions according to the present invention may include an additional bioactive agent, including an anti-viral agent, such as a traditional anti-EBV agent or anti-HIV agent as otherwise described herein in effective amounts.

[0170] In embodiments, the present invention is directed to the treatment of an Epstein-Barr virus infection or its symptoms (mononucleoisis) or a human immunodeficiency virus (HIV) infection or its symptoms (including AIDS) in a patient or subject in need comprising administering to said patient or subject an effective amount of a compound according to chemical structure I or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure I:

[0171]

[0172] Where X and Z are each independently C or N;

[0173] Q and T are each C or N, with the proviso that

[0174] when Q is C, T is N,

[0175]

[0176] is a double bond between Q and the carbon atom between Q and X and a double bond between X and the carbon atom between X and T, and

[0177] when Q is N, T is C, X is C, R2 is H, Z is N, R3 is absent and

[0178]

[0179] is a single bond between Q and the carbon atom between Q and X, a double bond between T and the carbon atom between T and X and a double bond between X and the carbon atom between X and Q;

[0180] Y is H, NRYRY, ORYor SRY, often NHRY, ORYor SRY;

[0181] Each RYis independently H, C1-C12 alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl),

[0182] -(CH2)i-Aryl or -(CH2)i-Heterocycle;Ri is H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo (F, Cl, Br or I), C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CF^); -Heterocycle;

[0183] R2 is absent (when X is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, Ci-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i-Heterocycle;

[0184] R3 is absent (when Z is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;

[0185] R4 is H when T is N, or H, OH, CN, CH3, vinyl, alkyne when T is C; and

[0186] R is H, Ci-Ce alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CH2)i-Aryl or -(CH2)i-Heterocycle;

[0187] R1is H or a RPROgroup;

[0188] RPROis an acyl group according to the chemical structure:

[0189]

[0190] , where R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups; or RPROis a group according to the chemical structure:

[0191]

[0192] R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups;

[0193] RN1and RN2are each independently H or a Ci-Ce alkyl or acyl group optionally substituted with 1-3 hydroxy or halo groups; and

[0194] R is H, a Ci-Ce alkyl group optionally substituted with 1-3 hydroxy or halo groups, an O-R group where R3is the same as above or a NRN1RN2group where RN1and RN2are the same as above; or

[0195]

[0196] group;

[0197] Where x is 0 or 1; and

[0198] RN1and RN2are the same as above; or

[0199] RPROis a

[0200]

[0201] group;

[0202] Where RAAis H, a Ci-Ce alkyl group which is optionally substituted with from 1-3 hydroxyl groups or 1-3 halogroups or an amino acid side chain selected from the group consisting of a side chain derived from an amino acid, said amino acid side chain being preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethylcarboxyamide (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyl eneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0203] R4a is H or a C1-C20 (often a Ci-Ce) alkyl group which is optionally substituted with from 1-3 hydroxyl groups and 1-3 halo groups; or

[0204] RPROis a phosphate ester, phosphodiester, phosphoramidate or phosphordiamidate group according to the chemical structure:

[0205]

[0206] Where R5 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryloxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionally substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (oftenacetyl), ester or carboxyester groups, or the two R5 groups link together to form a five- or sixmembered heterocyclic group, with the proviso that no more than one R5 or 5 group is H; Each R6is independently H (with the proviso that not more than one Re or R5group is H), a group according to the chemical structure:

[0207]

[0208] , or an amide group derived from an amino acid (a natural or unnatural amino acid such as, for example, alanine, P-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine, among

[0209] others) according to the structure:

[0210]

[0211] Where i is 0, 1, 2 or 3 (preferably 0 or 1);

[0212] R7 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryloxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionally substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups;

[0213] R7is H or C1-C3 alkyl, preferably H;

[0214] Rs is a side-chain of an amino acid, preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethyl carb oxy ami de (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogengroup), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyeneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; and

[0215] R” is H, a Ci to C20 alkyl (linear, branched or cyclic alkyl) or a phenyl or heteroaryl group, each of which groups is optionally substituted, or

[0216] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0217] In specific method embodiments, the compound administered to the patient or subject is a compound according to chemical structure IA or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure IA,

[0218]

[0219] IA

[0220] Where X, Y, Z, Ri, R2, R3 and R1are the same as for the generic chemical structure I set forth herein above.

[0221] In specific method embodiments, the compound administered to the patient or subject is a compound according to chemical structure IA or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure IA (R1is the same as for generic chemical structure I),

[0222] Where X is C;

[0223] R2 is H or halo (F, Cl, Br or I);

[0224] Y isNHR;

[0225] Z is N (R3 is absent in all instances when Z is N),

[0226] Ri is H, NHR or halo (F, Cl, Br or I);

[0227] R is H or CH3; andR1is the same as for generic structure I or

[0228] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0229] In specific method embodiments, the compound administered to the patient or subject is a compound according to chemical structure IA or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure IA (R1is the same as for generic chemical structure I),

[0230] Where X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0231] X is C, R2is F, Y is NH2, Z is N and Ri is H;

[0232] X is C, R2is Cl, Y is NH2. Z is N and Ri is H;

[0233] X is C, R2is Br, Y is NH2, Z is N and Ri is H;

[0234] X is C, R2is I, Y is NH2, Z is N and Ri H;

[0235] X is C, R2is H, Y is NH2, Z is N and Ri is NH2;

[0236] X is C, R2is H, Y is NH2, Z is N and Ri is F; or

[0237] X is C, R2is H, Y is NHMe, Z is N and Ri is NH2; or

[0238] a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0239] In specific method embodiments, the compound administered to the patient or subject is a compound according to chemical structure I or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure IA (R1is the same as for generic chemical structure I),

[0240] Where X is C, R2is H, Y is NH2, Z is N and Ri is H;

[0241] X is C, R2is F, Y is NH2, Z is N and Ri is H;

[0242] X is C, R2is Br, Y is NH2, Z is N and Ri is H; or

[0243] X is C, R2is I, Y is NH2, Z is N and Ri is H.

[0244] In method embodiments, the compound administered to the patient or subject is a compound according to chemical structure IB or a pharmaceutical composition comprising an effective amount of a compound according to chemical structure IB,

[0245] Where Y, Ri, R4 and R1in chemical structure IB are the same as for the generic chemical structure I set forth herein above.

[0246] In embodiments, the method of treatment administering compounds or compositions described above to a patient or subject in need may also be used to inhibit, ameliorate,alleviate or reduce the likelihood of one or more of the symptoms of an Epstein-Barr virus (EBV) infection or a human immunodeficiency syndrome virus (HIV) infection wherein the symptom of EBV infection includes fatigue, including severe fatigue, lack of appetite, rash, sore throat, swollen glands in the neck, weak and sore muscles and enlarged spleen and liver and the symptoms of HIV infection include symptoms associated with acute HIV infection such as fever and muscle pain, headache, sore throat, night sweats, mouth sores, yeast infections (thrush), swollen lymph glands, diarrhea, or symptoms associated with autoimmune deficiency syndrome (AIDS) including various bacterial, viral, fungal and protozoal infections, as well as lung infections, intestinal infections, cancer, including Kaposi sarcoma and related symptoms including severe weight loss, fever, sweats, rashes and swollen lymph glands, among others as described herein.

[0247] In embodiments, the present invention is directed to a method for treating one or more symptoms of Multiple Sclerosis (MS) or reducing the likelihood that MS will occur in a patient or subject in need comprising administering an effective amount of a compound or pharmaceutical composition as otherwise described herein above to said patient or subject. MS symptoms include muscle weakness, vision problems, coordination issues, fatigue, pain, numbness, tingling or other unusual sensations, dizziness, difficulty with balance and coordination, problems with memory and cognition, spasticity and difficulty walking and bladder problems.

[0248] These and / or additional embodiments of the present invention also may be readily gleaned from a review of the detailed description of the invention which follows.

[0249] Brief Description of the Figures

[0250] FIGURE 1 shows chemical structures of currently used drugs for the treatment of EBV infection.

[0251] FIGURE 2 shows the chemical structures of certain di oxolane-derived potent antiviral nucleosides.

[0252] FIGURE 3 shows Scheme 1 which is directed to the chemical synthesis of targeted compounds 12-19 via D-dioxolane (1). The reagents and conditions utilized in Scheme I are as follows: (a) IM LTBA, THF; (b) DMAP, Ac2O, THF; (c) TMSI, CHC13; (d) Appropriatesubstituted 7-deazapurines, KOH, ACN, TDA-1; (pNELjOH, 1,4-dioxane; (k) methylamine, EtOH.

[0253] FIGURE 4, Table 1 shows the antiviral activity of 7-deazanucleosides (12-19) against EBV in P3HR cell lines and HIV-FL in TZM-GFP cells.

[0254] Detailed Description of the Invention

[0255] The following terms are used to describe the present invention. In instances where a term is left undefined, the term is given its art recognized meaning. In accordance with the present invention there may be employed conventional chemical synthetic methods and other biological and pharmaceutical techniques within the skill of the art. Such techniques are well-known and are otherwise explained fully in the literature.

[0256] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0257] 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.It is to be noted that as used herein and in the appended claims, the singular forms "a," "and" and "the" include plural references unless the context clearly dictates otherwise. The term “about” when used, signifies an amount within +5% of the amount or number specifically set forth.

[0258] The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein, and often refers to / >-D nucleoside analogs, but may include, within context, tautomers, regioisomers, geometric isomers, anomers, and where applicable, optical isomers (enantiomers) or diastereomers (two chiral centers) thereof of these compounds, as well as pharmaceutically acceptable salts thereof, solvates and / or polymorphs thereof. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures and / or diastereomers as described herein) as well as specific enantiomers, enantiomerically enriched or individual diastereomers or mixtures of disclosed compounds. It is noted that in the event that a carbon range is provided for a compound, that range signifies that each and every carbon individually is considered part of the range.

[0259] The symbol

[0260]

[0261] used between two atoms in a chemical structure is used to designate that the bond between atoms is either a single bond or a double bond depending on the context of the chemical structure in order to maintain integrity of the valences of the atoms in the chemical structure.

[0262] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a domesticated animal especially including a mammal or a human, more preferably a human to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal. In general, in the present invention, the term patient refers to a human patient unless otherwise stated. In the present invention, in addition to humans, domesticated animals (e.g., horses, cows, pigs, sheep, goats, dogs, cats, etc.) also may be commonly treated.The term “Epstein-Barr virus” or “EBV”, also called Human herpesvirus 4 (HHV-4), is a virus of the herpes family and is one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic, but infection commonly causes infectious mononucleosis (also known as glandular fever). EBV occurs worldwide. Most people become infected with EBV sometime during their lives, and therefore gain adaptive immunity, preventing repeated sickness from re-infection through EBV antibodies. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) disappears. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 69% of the time. Symptoms of an EBV infection include fatigue, including severe fatigue, lack of appetite, rash, sore throat, swollen glands in the neck, weak and sore muscles and enlarged spleen and liver. EBV infections also refer to acute EBV infections, chronic active EBV infections and PostTransplant Lymphoproliferative Disease (PTLD).

[0263] The term “human immunodeficiency virus” or “HIV” shall be used to describe human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) which are responsible for HIV infections in humans. Typical symptoms of an HIV infection include symptoms associated with acute HIV infection such as fever and muscle pain, headache, sore throat, night sweats, mouth sores, yeast infections (thrush), swollen lymph glands, diarrhea, or symptoms associated with autoimmune deficiency syndrome (AIDS) including various bacterial, viral, fungal and protozoal infections, as well as lung infections, intestinal infections, cancer, including Kaposi sarcoma and related symptoms including severe weight loss, fever, sweats, rashes and swollen lymph glands, among others as described further in detail herein below.

[0264] The terms “ARC” and “AIDS” refer to syndromes of the immune system caused by the human immunodeficiency virus (HIV), which are characterized by susceptibility to certain diseases and T cell counts which are depressed compared to normal counts. HIV progresses from Category 1 acute HIV disease followed by asymptomatic HIV Disease to Category 2 (ARC), to Category 3 (AIDS), with the severity of the disease.

[0265] A Category 1 HIV infection is characterized by the patient or subject being HIV positive, acute at an early stage asymptomatic (no symptoms) at a later stage and having never had fewer than 500 CD4 cells. If the patient has had any of the AIDS-defining diseaseslisted for categories 2 (ARC) or 3 (AIDS), then the patient is not in this category. If the patient’s t-cell count has ever dropped below 500, that patient is considered either Category 2 (ARC) or Category 3 (AIDS).

[0266] A Category 2 (ARC) infection is characterized by the following criteria: The patient’s T-cells have dropped below 500 but never below 200, and that patient has never had any Category 3 diseases (as set forth below) but have had at least one of the following defining illnesses —

[0267] o Bacillary angiomatosis

[0268] o Candidiasis, oropharyngeal (thrush)

[0269] o Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy o Cervical dysplasia (moderate or severe) / cervical carcinoma in situ o Constitutional symptoms, such as fever (38.5 C) or diarrhea lasting longer than 1 month

[0270] o Hairy leukoplakia, oral

[0271] o Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome

[0272] o Idiopathic thrombocytopenic purpura

[0273] o Listeriosis

[0274] o Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

[0275] o Peripheral neuropathy

[0276] According to the U.S. government, in Category 2 ARC, the immune system shows some signs of damage but it isn't life-threatening.

[0277] A Category 3 (AIDS) infection is characterized by the following criteria:

[0278] your T-cells have dropped below 200 or

[0279] you have had at least one of the following defining illnesses —

[0280] o Candidiasis of bronchi, trachea, or lungs

[0281] o Candidiasis, esophageal

[0282] o Cervical cancer, invasive**

[0283] o Coccidioidomycosis, disseminated or extrapulmonaryo Cryptococcosis, extrapulmonary

[0284] o Cryptosporidiosis, chronic intestinal (greater than 1 month's duration) o Cytomegalovirus disease (other than liver, spleen, or nodes)

[0285] o Cytomegalovirus retinitis (with loss of vision)

[0286] o Encephalopathy, HIV-related

[0287] o Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis

[0288] o Histoplasmosis, disseminated or extrapulmonary

[0289] o Isosporiasis, chronic intestinal (greater than 1 month's duration)

[0290] o Kaposi's sarcoma

[0291] o Lymphoma, Burkitt's (or equivalent term)

[0292] o Lymphoma, immunoblastic (or equivalent term)

[0293] o Lymphoma, primary, of brain

[0294] o Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary

[0295] o Mycobacterium tuberculosis, any site (pulmonary** or extrapulmonary) o Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

[0296] o Pneumocystis carinii pneumonia

[0297] o Pneumonia, recurrent**

[0298] o Progressive multifocal leukoencephalopathy

[0299] o Salmonella septicemia, recurrent

[0300] o Toxoplasmosis of brain

[0301] o Wasting syndrome due to HIV

[0302] The term “Multiple Sclerosis” is used to describe an autoimmune disease that affects the central nervous system, damaging the protective covering of nerve fibers referred to as myelin. The damage to the myelin disrupts communication between the brain and the body, leading to a variety of symptoms such as muscle weakness, vision problems, coordination issues, fatigue, pain, numbness, tingling or other unusual sensations, dizziness, difficulty with balance and coordination, problems with memory and cognition, spasticity and difficulty walking and bladder problems, among others. Multiple sclerosis affects the central nervous system, which includes the brain and spinal cord. In MS, the individual’s immune system mistakenly attacks the protective covering of nerve fibers, known as myelin, which disruptscommunication between the brain and the rest of the body. There are several forms of MS, including Relapsing-Remitting MS (RRMS) which is characterized by episodes of new or worsening symptoms followed by periods of recovery; Secondary Progressive MS (SPMS) which follows RRMS and involves a gradual worsening of symptoms over time; Primary Progressive MS (PPMS) which involves steady progression of symptoms without relapses; and Clinically Isolated Syndrome (CIS), which is a first episode of neurological symptoms that lasts at least 24 hours.

[0303] The term “coadministration” shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided preferably that effective concentrations of coadministered compounds or compositions are found in the subject at a given time. The term coadministration also encompasses, in certain instances, the serial administration of agents which are administered serially in a patient to produce an intended effect, regardless of the time of administration and concentration of agent found in the subject. Co-administration of a compound according to the present invention in combination with a traditional anti-EBV agent or anti-HIV agent represent additional embodiments of the present invention. It is noted that pharmaceutical compositions which comprise a compound according to the present invention in combination with an additional bioactive agent, which agent may include a traditional anti-EBV and / or anti-HIV agent most often coadminister these agents from the pharmaceutical compositions based upon the dosage forms utilized by these compositions.

[0304] The term “independently” is used herein to indicate that a variable, which is independently applied, varies independently from application to application.

[0305] The term “alkyl” shall mean within its context a C1-C30, often a C1-C20 or C1-C10 linear, branch-chained or cyclic fully saturated hydrocarbon radical, which may be optionally substituted. It is noted that in the event that a carbon range is provided, that range signifies that each and every carbon is considered part of the range. For example a C1-C20 group describes a group with a single carbon, two carbon atoms, three carbon atoms, four carbon atoms, etc.The term “aromatic” or “aryl” shall mean within its context a substituted or unsubstituted monovalent carbocyclic aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl, anthracene, phenanthrene). Other examples include optionally substituted heterocyclic aromatic ring groups (“heteroaromatic” or “heteroaryl”) having one or more nitrogen, oxygen, or sulfur atoms in the ring, and preferably include five or six-membered heteroaryl groups, such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrazine, triazole, oxazole, among others, but can also include fused ring heteroaryl groups such as indole groups, among others. The preferred aryl group in compounds according to the present invention is a phenyl or a substituted phenyl group as described herein.

[0306] The term “heterocycle” shall mean an optionally substituted moiety which is cyclic and contains at least one atom other than a carbon atom, such as a nitrogen, sulfur, oxygen or other atom, which ring may be saturated and / or unsaturated. Fused rings are also contemplated by the present invention. A heterocycle according to the present invention is an optionally substituted imidazole, a piperazine (including piperazinone), piperidine, furan, pyrrole, imidazole, thiazole, oxazole or isoxazole group, among numerous others. The term heterocycle includes the term heteroaryl. In the present invention heterocycles often contain between 3 and 10 atoms in the cyclic ring(s), often between 4 and 10 atoms in the cyclic ring(s).

[0307] The term “unsubstituted” shall mean within context not substituted or only substituted with hydrogen atoms. The term “substituted” shall mean, within the chemical context of the compound defined, a substituent (each of which substituent may itself be substituted) selected from a hydrocarbyl (which may be substituted itself, preferably with an optionally substituted alkyl, hydroxy or fluoro group, among others), alkyl (generally, no greater than about 6 carbon units in length), including CF3, an optionally substituted aryl, halogen (F, Cl, Br, I), thiol, hydroxyl, carboxyl, C1-C3 alkoxy, alkoxycarbonyl, CN, nitro or an optionally substituted amine (e.g.. an alkyleneamine or a C1-C3 monoalkyl or dialkyl amine), among others as described herein. Various optionally substituted moieties may be substituted with 3 or more substituents, often no more than 3 substituents and preferably with 1 or 2

[0308] substituents.The term “acyl” is used throughout the specification to describe a group which contains a Ci to C20 linear, branched or cyclic alkyl chain. The acyl group in combination with a hydroxyl group results in an ester or carboxyester and the acyl group in combination with an exocyclic amine group results in an amide, which, after administration, may be cleaved to produce the free nucleoside form of the present invention. Acyl groups according to the present invention are represented by the structure:

[0309]

[0310] where R is a Ci to C20 linear, branched or cyclic alkyl group which is optionally substituted. Acyl groups according to the present invention also include, for example, those acyl groups derived from benzoic acid and related acids, 3 -chlorobenzoic acid, succinic, capric and caproic, lauric, myristic, palmitic, stearic and oleic groups, among numerous others and may include such related groups as sulfone groups such as mesylate groups. All groups may be appropriatedly substituted within context as otherwise described herein. One of ordinary skill in the art will recognize the acyl groups which will have utility in the present invention, either to synthesize the target pharmaceutical compounds or as prodrug of the nucleosides according to the present invention.

[0311] The term “amino acid” or “amino acid residue” shall mean, within context, a radical of a D- or L-amino acid which is covalently bound to form an amide, ester or a related group. Amino acids may also be used to provide amide groups, phosphoramidate or phosphordiamidate groups or other prodrug groups in compounds according to the present invention as otherwise described herein. Representative amino acids include both natural and unnatural amino acids, including, for example, alanine, P-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine, among others, as described herein.

[0312] The compounds of the present invention are useful for the treatment of EBV infections and / or HIV infections and for ameliorating the various symptoms which occur as aconsequence of these infections. Compounds and compositions according to the present invention are also useful in the prevention or decreasing the likelihood of infection and / or appearance of at least one or more of the various symptoms associated with these viral infections. In embodiments, the invention is directed to the reduction in and / or the treatment of EBV and one or more of its symptoms or alternatively, the reduction of and / or treatment of infection by HIV and in the treatment of the disease known as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including the treatment of a wide range of states of HIV infection: AIDS, ARC and actual or potential exposure to HIV (e.g., through blood transfusion, exchange of body fluids, bites, needle punctures, exposure to infected patient blood during medical or dental procedures, and other means, such patients or subjects being considered at risk for HIV infection).

[0313] Other applications are also part of this invention. For example, the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds, for example as standards for the isolation of viral mutants and in further understanding these viruses and the mechanism of their infections.

[0314] The present invention also provides for the use of a compound of structural formula (I) and its various analogues to make a pharmaceutical composition useful for inhibiting EBV and / or HIV infection and in the treatment or amelioration of mononucleosis, AIDS or ARC and one or more of the various symptoms associated with each.

[0315] It is noted that the compounds of the present invention also may be administered in the form of well-known “pharmaceutically acceptable” salts. The latter is intended to include all acceptable salts of compounds according to the present invention.

[0316] Therapeutically effective amounts of the compounds of the present invention may be administered to patients in various dosage forms, including orally, parenterally, by inhalation spray, topically, transdermally, buccally, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles including nanoparticle drug delivery approaches. The term “pharmaceutically acceptable” is meant to infer that the carrier, diluent, excipient or other additive is biologically compatible with the other ingredients of the formulation and not deleterious to the patient or recipient. Pharmaceutical compositions are in pharmaceutical dosage form and may be administered in the form oforally-administrable suspensions or tablets, nasal sprays and injectible preparations (injectible aqueous or oleagenous suspensions or suppositories), among others. This method of treatment is part of the invention. The administration approaches used (e.g., orally as solution or suspension, immediate release tablets, nasal aerosol or inhalation, injectible solutions or suspensions or rectally administered in the form of suppositories) involve techniques that are well-known in the art of pharmaceutical formulation.

[0317] The compounds of this invention can be administered orally to humans in a preferred form (such as tablets) and in an effective amount within a preferred dosage range of about 0.05 to 200 mg / kg, more preferably about 0.1 to about 25 mg / kg body weight in divided doses. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including compound activity, compound metabolism and duration of action, patient age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the condition of the patient undergoing therapy. Typically pharmaceutical dosages of actives are administered in effective amounts of actives within ranges of from less than 0.5 mg to 1 g or more, from 1 mg to 1 g, 1 mg to 750 mg, 2.5 mg to 600 mg, 5 mg to 500 mg, 10 mg to 250 mg, 25 mg to 100 mg.

[0318] The present invention also includes therapeutically effective combinations of anti-EBV agents or anti-HIV agents of formula I with one or more other therapeutic agents such as traditional anti-EBV agents, AIDS antivirals, other antiviral agents, immunomodulators, antiinfectives, antibiotics, vaccines or other therapeutic agents. Some examples are provided herein below.

[0319] Traditional anti-EBV agents which may be used in methods or pharmaceutical compositions according to the present invention include, for example, acyclovir, valocyclovir, penciclovir, famciclovir, ganciclovir, valgancyclovir, omaciclovir, valomaciclovir, maribavir, cidofovir, KAY-2-41, KAY-39-149, (l-[(2S,4S-2-(hydroxymethyl)-l,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(lH,3H)-dione) or its oral prodrug , among others.

[0320] ANTIVIRAL AGENTS, ANTI-INFECTIVES, IMMUNOMODULATORS, OPPORTUNISTIC INFECTION DRUGS, OTHER RELEVANT DRUGS IN AIDSDrug Name Manufacturer Therapeutic Use 097 Hoechst / Bayer HIV infection, AIDS, ARC (NNRT inhibitor) Amprenivir Glaxo Wellcome HIV infection, AIDS, 141W94, GW141 ARC (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington Labs (Irving, ARC

[0321] TX)

[0322] Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT

[0323] AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC

[0324] Adefovir dipivoxil Gilead Sciences HIV infection

[0325] AL-721 Ethigen (Los Angeles, ARC, PGL HIV positive,

[0326] CA) AIDS

[0327] Alpha Interferon Glaxo Wellcome Kaposi’s sarcoma, HIV in combination w / Retrovir Ansamycin Adria Laboratories ARC

[0328] LM 427 (Dublin, OH)

[0329] Erbamont (Stamford, CT)

[0330] Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH labile Concepts (Rockville,

[0331] alpha aberrant MD)

[0332] Interferon

[0333] AR 177 Aronex Pharm HIV infection, AIDS, ARC

[0334] Beta-fluoro-ddA National Cancer Institute AIDS -associated diseases BMS-232623 Bristol-Myers HIV infection, AIDS, (CGP-73547) Squibb / Novartis ARC (protease inhibitor)

[0335] BMS-234475 Bristol-Myers HIV infection, AIDS, (CGP-61755) Squibb / Novartis ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus Medlmmune CMV retinitis Immune globin

[0336] Cytovene Syntex Sight threatening CMV Ganciclovir Peripheral CMV Retinitis

[0337] ddl Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT / d4T

[0338] DMP-450 AVID (Camden, NJ) HIV infection, AIDS, ARC (protease inhibitor) Efavirenz (DMP-266) DuPont Merck HIV infection, AIDS, ARC (non-nucleoside RT inhibitor

[0339] ELIO Elan Corp, PLC HIV infection (Gainesville, GA)

[0340] Famciclovir Smith Kline Herpes zoster, herpes simplex

[0341] FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC

[0342] Recombinant Human Triton Biosciences AIDS, Kaposi’s sarcoma, Interferon Beta (Almeda, CA) ARC

[0343] Interferon alfa-n3 Interferon Scienes ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive; combination with AZT / ddEddC Isentress (Raltegravir) Merck HIV infection, AIDS, ARC (integrase inhibitor)ISIS-2922 ISIS Pharmaceuticals CMV retinitis

[0344] KNI-272 Natl. Cancer Institute HIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron Pharmaceuticals HIV infection, AIDS, ARC (protease inhibitor) Nevirapine Boeheringer Ingleheim HIV infection, AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH)

[0345] Peptide T Peninsula Labs (Belmont, AIDS

[0346] Octapeptide Sequence CA)

[0347] Trisodium Astra Pharm. Products, CVV retinitis, HIV Phosphonoformate Inc. infection, other CMV PNU- 140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection, AIDS, (Houston, TX) ARC

[0348] Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann-LaRoche HIV infection, AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Di dehy drodeoxythymi dine ARC

[0349] Valaciclovir Glaxo Wellcome Genital HSV & CMV infections Virazole Ribavirin Viratek / ICN (Costa Asymptomatic HIV Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS,

[0350] ARCZalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi’s sarcoma, in combination with other therapies

[0351] Tenofovir diisoproxil Gilead HIV infection, AIDS, fumarate salt (Viread®) (RT inhibitor) Combivir® GSK HIV infection, AIDS, (RT inhibitor) Abacavir succinate (or GSK HIV infection, AIDS, Ziagen®) (reverse transcriptase inhibitor)

[0352] Fuzeon® (or T-20) Roche / Trimeris HIV infection, AIDS, viral Fusion inhibitor AS-101 Wyeth- Ay er st AIDS

[0353] Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC

[0354] (Irving, TX)

[0355] CL246, 738 American Cyanamid AIDS, Kaposi’s sarcoma Lederle Labs

[0356] ELIO Elan Corp, PLC HIV infection (Gainesville, GA)

[0357] FP-21399 Fuki Immuno PHARM Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w / TNF

[0358] Granulocyte Genetics Institute AIDS

[0359] Macrophage Colony Sandoz

[0360] Stimulating Factor

[0361] Granulocyte Hoeschst-Roussel AIDS

[0362] Macrophage Colony Immunex

[0363] Stimulating Factor

[0364] Granulocyte Schering-Plough AIDS, combination Macrophage Colony w / AZT

[0365] Stimulating Factor

[0366] HIV Core Particle Rorer Seropositive HIVImmunostimulant

[0367] IL-2 Cetus AIDS, in combination Interleukin-2 w / AZT

[0368] IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w / AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts (aldeslukin)

[0369] Immune Globulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA) combination w / AZT (human)

[0370] IMREG-I Imreg (New Orleans, LA) AIDS, Kaposi’s sarcoma,

[0371] ARC, PGL

[0372] IMREG-2 Imreg (New Orleans, LA AIDS, Kaposi’s sarcoma,

[0373] ARC, PGL

[0374] Imuthiol Diethyl Merieux Institute AIDS, ARC

[0375] Dithio Carbamate

[0376] Alpha-2 Interferon Schering Plough Kaposi’s sarcoma w / AZT, AIDS Methi onine-Enkephali n TNI Pharmaceutical AIDS, ARC (Chicago, IL)

[0377] MTP-PE Ciba-Geigy Corp. Kaposi’s sarcoma Muramyl-Tripeptide

[0378] Granulocyte Amgen AIDS, in combination Colony Stimulating Factor w / AZT

[0379] Remune Immune Response Corp. Immunotherapeutic rCD4 Genentech AIDS, ARC Recombinant Soluble

[0380] Human CD4-IgG

[0381] rCD4-IgG Hybrids AIDS, ARC Recombinant Soluble Biogen AIDS, ARC

[0382] Human CD4

[0383] Interferon Alfa 2a Hoffman-LaRoche Kaposi’s sarcoma, AIDS,

[0384] AR, combination w / AZT SK&F 1-6528 Smith Kline HIV infection Soluble T4

[0385] Thymopentin Immunobiology Research HIV infection Institute (Annandale, NJ)Tumor Necrosis Factor Genentech ARC, in combination (TNF) w / gamma Interferon

[0386] AK602 Kumamto HIV infection (entry and University fusion inhibitor) Japan

[0387] Alovudine Medivir, UK Ltd. HIV infection (nucleoside

[0388] RT inhibitor) Amdoxovir RFS Pharma, LLC Treatment of HIV and HBV infections (nucleoside RT Inhibitor) AMD070 AnorMED, Inc. HIV infection (entry and fusion inhibitor) Atazanavir (Reyataz) Bristol -Myers Squibb HIV infection (protease inhibitor)

[0389] AVX754 (apricitabine) Avexa Ltd. HIV infection (nucleoside

[0390] RT inhibitor Bevirimat Panacos Pharmaceuticals HIV infection (maturation inhibitor) BI-201 BioInvent HIV infection (gene therapy, blocks HIV tat gene).

[0391] BMS-378806 Bristol - Myers Squibb HIV infection (entry inhibitor)

[0392] BMS-488043 Bristol - Myers Squibb HIV infection (entry and fusion inhibitor) BMS-707035 Bristol - Myers Squibb HIV infection (integase inhibitor)

[0393] C31G Cellegy Pharmaceuticals, HIV infection and other Inc sexually transmitted diseases (STDs) Carbopol 974P ReProtect, LLC Sexual transmission of HIV

[0394] Calanolide A Sarawak MediChem HIV infection (nonPharmaceuticals, Inc. nucleoside RT inhibitor)Carrageenan FMC Biopolymer HIV microbicide Cellulose sulfate Polydex Pharmaceuticals, Prevention of HIV Ltd. infection and other sexually transmitted diseases Cyanovirin-N Cellegy Pharmaceuticals, Prevention of sexual Inc. transmission of HIV infection Darunavir Tibotec HIV infection (coadministered with ritonavir) Delavirdine Pfizer HIV infection (nonnucleoside RT inhibitor) Dextran sulfate Ueno Fine Chemicals Prevention of Industry, Ltd. transmission of HIV Didanosine (Videx, Bristol - Myers Squibb HIV infection Videx EC) (nucleoside RT inhibitor) Efavirenz Bristol - Myers Squibb HIV infection (nonnucleoside RT inhibitor) Elvucitabine Achillion HIV infection Pharmaceuticals (nucleoside RT inhibitor) Emtricitabine Gilead Sciences HIV infection (nucleoside RT inhibitor) Fosamprenavir (Lexiva) GlaxoSmithKline HIV infection (protease inhibitor) Fozivudine tidoxil Heidelberg Pharma HIV infection (entry and fusion inhibitor) GS 9137 Gilead Sciences HIV infection (integase inhibitor)

[0395] GSK-873,140 GlaxoSmithKline HIV infection (entry and (aplaviroc) fusion inhibitor) GSK- 364735 GlaxoSmithKline HIV infection (integase inhibitor) GW640385 (brecanavir) GlaxoSmithKline HIV infection (protease inhibitor)HG0004 Human Genome Sciences HIV infection (entry and fusion inhibitor) HGTV43 Enzo Therapeutics HIV infection (antisense drug) Hydroxyethyl cellulose Union Carbide Prevent sexual transmission of HIV INCB9471 Incyte Corporation HIV infection (entry and fusion inhibitor) KP-1461 Koronis Pharmaceuticals HIV infection (nucleoside RT inhibitor) Lopinavir Abbott Laboratories HIV infection (protease inhibitor) Mifepristone (VGX410, Viral Genomix HIV infection (gene RU486) therapy, interferes with vpr)

[0396] MK-0518 Merck HIV infection (integase inhibitor)

[0397] PA-457 (bevirimat) Panacos Pharmaceuticals, Treatment of HIV Inc. (maturation inhibitor) Poly(I)-Poly(C12U) Hemispherx Biopharma, Biological response (Ampligen) Inc. modifier

[0398] PPL- 100 Merck HIV infection (protease inhibitor)

[0399] PRO 140 Progenies HIV infection (entry and Pharmaceuticals, Inc. fusion inhibitor) PRO 542 Progenies HIV infection (entry and Pharmaceuticals, Inc. fusion inhibitor) PRO 2000 Indevus Pharmaceuticals, Microbicide

[0400] Inc.

[0401] Racivir Pharmasset, Inc. HIV infection (nucleoside RT inhibitor) SCH-D (vicriviroc) Schering - Plough Corp HIV infection (entry and fusion inhibitor) SP01A Samaritan HIV infection (entry and Pharmaceuticals fusion inhibitor)SPL7013 Starpharma Microbicide

[0402] TAK-652 Takeda HIV infection (entry and fusion inhibitor) Tipranavir (Aptivus) Boehringer Ingelheim HIV infection (protease Pharmaceuticals inhibitor)

[0403] TNX-355 Tanox, Inc. HIV infection (entry and fusion inhibitor) TMC125 (etravirine) Tibotec HIV infection (nonnucleoside RT inhibitor) UC-781 Cellegy Pharmaceuticals, Microbicide

[0404] Inc

[0405] UK-427,857 Pfizer HIV infection (entry and (Maraviroc) fusion inhibitor)

[0406] Abbott Treating seizures in Valproic acid

[0407] HIV infection VRX496 VIRxSYS Gene therapy Zalcitabine (Hivid) Roche HIV infection (nucleoside T inhibitor)

[0408] Valganciclovir Roche Antiviral (CMV retinitis in (Valcyte) AIDS)

[0409] Clindamycin with

[0410] Primaquine Pharmacia Upjohn PCP

[0411] Fluconazole Pfizer Cryptococcal meningitis, candidiasis

[0412] Pastille Squibb Corp. prevention of oral Nystatin Pastille candidiasis

[0413] Omidyl Merrell Dow PCP

[0414] Eflorni thine

[0415] Pentamidine LyphoMed (Rosemont, IL) PCP treatment Isethionate (IM & IV)

[0416] Trimethoprim Antibacterial Trimethoprim / sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatmentPentamidine Fisons Corporation PCP prophylaxis isethionate

[0417] Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole-R51211 Janssen Pharm Histoplasmosis;

[0418] cryptococcal meningitis Trim etr exate Warner-Lambert PCP

[0419] Daunorubicin NeXstar, Sequus Karposi’s sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia assocated Erythropoietin w / AZT therapy Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia associated w / AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Nutrition Norwich Eaton Diarrhea and Pharmaceuticals malabsorption in AIDS Aldesleukin Chiron Corp Biological response (Proleukin) modifier Amphotericin B Pfizer, Bristol - Myers Antifungal (Abelecet, Squibb

[0420] AmBisome,

[0421] Amphocin, Amphotec,

[0422] Fungizone)

[0423] Azithromycin Pfizer Antibacterial antibiotic (Zithromax)

[0424] Calcium Bioform Medical, Inc. Dermal filler hydroxyapatite

[0425] (Radiesse

[0426] Doxorubicin Ortho Biotech, Alza Antineoplastic (liposomal) (Doxil) Corporation

[0427] Dronabinol (Marinol) Unimed Pharmaceuticals,

[0428] Inc. Antiemetics Entecavir (Baraclude) Bristol-Myers Squibb Antiviral

[0429] Epoetin alfa (Epogen, Ortho Biotech Anemia

[0430] Procrit)Etoposide (Etopophos Pfizer, Bristol-Myers Antineoplastic (phosphate salt), Squibb

[0431] Toposar, VePesid)

[0432] Fluconazole (Diflucan) Pfizer Antifungal Interferon alfa-2 Roche, Schering -Plough Biological response (Intron A (2b), modifiers Roferon-A (2a)

[0433] Isoniazid (Nydrazid) Sandoz, Hoffmann La- Antimy cob acteri al Roche

[0434] Itraconazole Ortho Biotech, Janssen Antifungal (Sporanox) Pharmaceutica

[0435] Megestrol (Megace, Bristol - Myers Squibb Anticachectic Megace ES)

[0436] Paclitaxel (Onxol, Bristol - Myers Squibb, Antineoplastic Taxol) IV AX Pharmaceuticals

[0437] Peginterferon alfa-2 Roche, Schering -Plough Antiviral

[0438] (PEG-Intron (2b),

[0439] Pegasys (2a))

[0440] Pentamidine American Pharmaceutical Antiprotozoal (Nebupent) Partners, Fujisawa Health

[0441] Care, Inc.

[0442] Poly-L-lactic acid Dermik Laboratories Dermal Filler (Sculptra)

[0443] Rifabutin (Mycobutin) Pharmacia Corporation Antimy cob acteri al Rifampin (Rifadin, Aventis Pharmaceuticals Antimy cob acteri al Rimactane)

[0444] Somatropin Pharmacia Corporation, Synthetic human growth Serono Inc hormone Sulfamethoxazole / Alpha care Inc, Women Antibacterial Trimethoprim First Health Care, King

[0445] (Bactrim, Septra) Pharmaceuticals

[0446] (Serostim)

[0447] Testosterone Pfizer Inc, Ummed Androgens (Androderm, Pharmaceuticals, Inc., Alza

[0448] Androgel, Depo- Corporation, Watson

[0449] Testosterone) LaboratoriesTrimetrexate United States Bioscience Antiprotozoal

[0450] (Neutrexin) Inc, Medimmune, Inc.

[0451] The combinations of the compounds of this invention with AIDS antivirals (including anti-HIV integrase-based antivirals), other antivirals, immunomodulators, anti-infectives, antibiotics, vaccines, other therapeutic agents are not limited to the list in the above Table, but includes, in principle, any combination with any pharmaceutical composition useful for the treatment against infection by HIV or for treating AIDS or ARC. Preferred combinations are simultaneous or alternating treatments of a compound of the present invention and a protease inhibitor (e.g., indinavir, nelfinavir, ritonavir, saquinavir and others), a reverse transcriptase inhibitor [nucleoside (e.g., AZT, 3TC, ddC, ddl, d4T, abacavir and others, and / or non-nucleoside (e.g., efavirenz, nevirapine, and others), or some combination of two or more of these inhibitors (see Table above).

[0452] In such combinations, as noted, the compound of the present invention and other active agents may be separately administered or concurrently administered (coadministered). In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0453] • (-)PDioxolane-G; DXG;

[0454] • (-)P-Arctigenin; Arctigenin ;

[0455] • (-)-Carbovir; (-)-C-D4G; (-)-Carbovir;

[0456] • (-)-P-D-2,6-Diaminopurine dioxolane;Amdoxovir; DAPD; APD

[0457] • (+)-2'-Deoxy-3'-oxa-4'-thiocytidine; dOTC (+)

[0458] • (+)-2'-Deoxy-3'-oxa-4'-thio-5-fluorocytidine; dOTFC (+)

[0459] • (+ / -)-Cyclobut-G; A-69992; (+ / -)-Lobucavir; C-Oxt-G; Cyclobut-G ; C-Oxetanocin-G (R)-PMPA; (R)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA-(R); Tenofovir

[0460] a-APA; R89439; Loviride

[0461] a-L-AZT; AZT-a-L

[0462] a-L-DXC; a-L-Dioxalane-C; DXC-a-L-a-L-FTC; FTC-a-L-l,l'-Azobisformamide; ADA; Azodicarbonamide1-Deoxynojirimycin ; Deoxynojirimycin

[0463] 141W94; VX-478; Amprenavir; Agenerase®; Approved

[0464] 1592U89 Succinate; Abacavir Succinate; Ziagen® Approved

[0465] 1-P-D-arabinofuranosyl-5-(2-bromovinyl)uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU

[0466] 2', 3 '-Didehydro-3 '-deoxy cytidine; D4C

[0467] 2', 3 '-Dideoxy didehydroguanosine; D4G

[0468] 2', 3 '-Didehydro-3 '-deoxythymidine; D4T; Stavudine; Zerit® Approved

[0469] 2',3'-Dideoxy-3'-fluoro-4-thiothymidine; 3'-F-4-Thio-ddT

[0470] 2',3'-Dideoxy-3'-fluoro-5 -bromouridine; FddBrU

[0471] 2',3'-Dideoxy-3'-fluoro-5 -chlorocytidine; 3'-F-5-Cl-ddC

[0472] 2',3'-Dideoxy-3'-fluoro-5 -chlorouridine; 935U83; 5-Chl oro-2', 3'-dideoxy-3 '-fluorouridine; FddClU; Raluridine

[0473] 2', 3 '-Dideoxyadenosine; D2A; ddAdo; ddA

[0474] 2-Glycine amide-5-chlorophenyl 2-pyrryl ketone; GCPK

[0475] 2'-FddA(B-D-threo); F-ddA; 2'-F-dd-ara-A; 9-(2'-Fluoro-2',3'-dideoxy-B-D-threopentafuranosyl)adenine; Lodensine

[0476] 3'-Azido-2',3'-dideoxyuridine; CS-87; 3'-N3ddU; AZdU; Uravidine

[0477] 3 '-Deoxythymidine; ddT

[0478] 3'-FddT; Alovudine; FddT; FddThD; 3'-FLT; FLT

[0479] 3TC; Lamivudine; Epivir® Approved;

[0480] Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved

[0481] Azidothymidine

[0482] 4-Methyl-5-(pyrazinyl)-3H-l,2-dithiole-3-thione; Oltipraz

[0483] 5-Fluoro-2',3'-dideoxycytidine; 5-F-ddC

[0484] 6-O-Butanoylcastanospermine; BuCast; MDL 28,574; Celgosivir

[0485] 8-Chloro-TIBO; Tivirapine; R86183

[0486] Abacavir & Lamivudine & Zidovudine; Trizivir® ABC & (-)-3TC & AZT

[0487] ABT-378; Lopinavir; Component of Kaletra; Aluviran®

[0488] ABT-378 & ABT-538; Kaletra®; Lopinavir & Ritonavir; Aluviran® & Norvir® Adefovir; PMEA; GS-0393

[0489] Adefovir dipivoxil; BisPom PMEA; GS-840; Preveon®

[0490] AG- 1343; Viracept®; Nelfinavir; ApprovedAtazanavir; CGP-73547; BMS-232632; BMS 232632; Zrivada; Latazanavir; Reyataz® AZT; Zidovudine; Azidothymidine; Retrovir®

[0491] Baicalin; TJN-151

[0492] Betulinic acid; Mairin

[0493] BI-RG-587; Nevirapine; Viramune® Approved

[0494] BILA 1906 BS, BILA 2011 BS; Palinavir, BILA 2185 BS

[0495] Calanolide A ; NSC675451, Calanolide B

[0496] Capravirine; S-1153

[0497] Castanospermine

[0498] CGP 61755; Lasinavir, CGP 64222

[0499] Coactinon; I-EBU; HEPT deriv.; MKC-442; Emivirine

[0500] Conocurvone; NSC650891

[0501] Coviracil; (-)FTC; (-)-2',3'-Dideoxy-5-fluoro-3'-thiacytidine; Emtricitabine; Emtriva C-Oxetanocin-G; A-69992; (+-)Lobucavir; C-Oxt-G; Cyclobut-G; (+-)Cyclobut-G Crixivan®; Indinavir; MK639; L-735,524; Approved

[0502] Cyclosporin A; Sandimmune®

[0503] [Me-Ile-4]Cyclosporin A; SDZ NIM 811

[0504] D4A (L); L-2',3'-Didehydro-2',3'-dideoxyadenosine

[0505] D4FC; D-D4FC; 2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine; DPC 817 D4FC (L); L-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine

[0506] D4G (L); L-2',3'-Didehydro-2',3'-dideoxyguanosine

[0507] D4I (L); L-2',3'-Didehydro-2',3'-dideoxyinosine

[0508] ddC; Dideoxycytidine; Zalcitabine; Hivid®

[0509] ddl; Dideoxyinosine; Didanosine; Videx®

[0510] DMP-266; Sustiva®; Efavirenz; Approved

[0511] DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide; Fuzeon®

[0512] Ebselen

[0513] Etoposide

[0514] Eulicin

[0515] Fenalamide Al; Phenalamide Al; Stipiamide

[0516] Fleephilone

[0517] Fortovase®; Invirase®; Saquinavir; Ro31-8959; Approved

[0518] Foscamet; Phosphonoformic acid; Foscavir;

[0519] HarziphiloneHypericin

[0520] Isentress (Raltegravir)

[0521] L-FddC; p-L-5F-ddC

[0522] Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved

[0523] P9941

[0524] PNU- 140690; U- 140690; Tipranavir

[0525] Resobene

[0526] Ribavirin; Virazole

[0527] SC-52151; Telinavir

[0528] Suramin Sodium

[0529] Thalidomide

[0530] Viread®; Tenofovir Disoproxil

[0531] An alternative list of drugs and / or bioactive agents useful in the treatment of HIV infections, or conditions or disease states which are secondary to HIV infections is set forth herein below. One or more of these agents may be used in combination (coadminstered) with at least one anti-HIV agent as otherwise disclosed herein to treat HIV or one of its secondary conditions or disease states, including AIDS / ARC, Kaposi’s sarcoma, hepatitis B virus infections, other microbial infections (such as tuberculosis) etc. When used, these compounds are also included in effective amounts.

[0532] ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir / Lamivudine / Zidovudine; Abacavir sulfate; Abacavir sulfate / Lamivudine;

[0533] Abacavir / Lamivudine; Abelecet; Acyclovir; Adefovir dipivoxil; Adriamycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AmBisome; Amdoxovir; Amphocin; Amphotec;

[0534] Amphotericin B; Ampligen; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude;

[0535] Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxylapatite; Carbopol 974P; Carrageenan; Carraguard; Cellulose sulfate;

[0536] Clarithromycin; Combivir; Copegus; Cotrimoxazole; Crixivan; Cyanovirin-N; Cytovene; DAPD; DLV; DS; Darunavir; Delavirdine; Depo-Testosterone; Dextran sulfate; Didanosine; Diflucan; Doxil; Doxorubicin (liposomal); Dronabinol; EFV; Efavirenz; Elvucitabine;

[0537] Emtricitabine; Emtri ci tabine; Tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir;Epivir; Epoetin alfa; Epogen; Epzicom; Etopophos (phosphate salt); Etoposide; Etravirine; FTC; Fluconazole; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Globulin, Immune; Growth hormone (human); Hepsera; Hivid; Human growth hormone; IL-2; INH; Immune Globulin Intravenous (Human); Indinavir; Interferon alfa-2; Interleukin-2, recombinant human; Intron A (2b); Invirase; Isentress; Isoniazid; Itraconazole; KP-1461;

[0538] Lamivudine / Zidovudine; Lexiva; Lopinavir / Ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Norvir; Nydrazid; Peptide T; PMPA Prodrug (Viread)’ Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Proleukin;

[0539] Racivir; Radiesse; Rrebetol; Rescriptor; Retrovir; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampin; Rimactane; Ritonavir; Roferon-A (2a); Saquinavir; SCH-D (vicriviroc);

[0540] Somatropin; Stavudinie; Sulfamethoxazole / Trimethoprim; Sustanon; Sustiva; TNX-355; Taxol; Tenofovir; Tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar;

[0541] Trimetrexate; Trizivir; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; VePesid;

[0542] Vicriviroc; Videx; Viracept (Tenofovir DF); Viramune; Virazole; Viread; Vitrasert;

[0543] Zalcitabine; Zerit; Ziagen; Zidovudine; Zithromax; Zovirax.

[0544] The following representative examples are provided to illustrate details of the present invention. These examples are not intended to be limitations on the scope of the present invention and they should not be so construed. Furthermore, the compounds described in the following examples are not to be viewed as forming the only set of compounds that is considered as the invention, and any combination of components of the compounds or their moieties may itself form a set. This has been addressed previously in this patent document. Those skilled in the art will readily comprehend that known variations of reaction conditions and synthetic conversions described in the following preparative procedures can be used to readily prepare these other compounds routinely.

[0545] Discussion of the Present Invention and Results

[0546] For the past two decades, the inventors’ group has been continuously exploring di oxolane nucleos(t)ides that have shown potent antiviral and anticancer activity. ' The inventors’ group has previously reported numerous D & L dioxolane-derived nucleo(t)side analogs, which have shown promising antiviral activity. Recently, the group invented bromovinylanalog, L-BHDU (see FIGURE 2),29'31and its phosphate ester prodrug POM-L-BHDU-MP, ’ a promising preclinical candidate against infection of varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). Additionally, a vinyl bromide analog, L-HDVD, was discovered that has shown broad-antiviral potency against EBV, Kaposi’ sarcoma-associated herpesvirus (KSHV), and HSV-1. Two D-dioxolane-derived nucleosides, amidoxovir (DAPD, diaminopurine dioxolane nucleoside)26and DOT (a dioxolane thymidine nucleoside), were synthesized, which demonstrated potent antiviral activity against HIV. Amidoxovir advanced to a phase II clinical trial; however, due to toxicity, it was discontinued.34’35Troxacitabine, an L-dioxolane pyrimidine analog, has shown promising anticancer activities across numerous cancers and has exhibited anti-HIV and anti-HBV

[0547] ■ • 36-38

[0548] activity.

[0549] Dioxolanes, heterocyclic acetal cyclopentyl rings, offer a potential replacement of sugar scaffold which lacks the crucial 3'-OH necessary to propagate DNA / RNA elongation. Replacing a ribose with a dioxolane ring in nucleosides creates a specificity and selectivity to viral DNA / RNA without causing toxicity to humans. The incorporation of a dioxolanederived nucleotide into an elongating viral DNA chain may proceed with viral chain termination, which ultimately results in the inhibition of viral growth. Based on the same structures, oxathiolane, similar to di oxolane though with a 3' sulfur in-lieu of oxygen, has expressed potent antiviral activity. Lamivudine and emtricitabine derived from oxathiolane-derived nucleosides have been approved for the treatment of HBV and HIV infections, respectively.39

[0550] Still, there is a need to generate and explore efficacious and selective dioxolane nucleosides for antiviral use, for which additional alterations either on the dioxolane ring or nucleobase are required. Often, the increased complexity of nucleoside is associated with enhanced viral specificity and selectivity. Nitrogen substitutions on the nucleobase, either in purines or pyrimidines, result in substantial effects on activity with the removal of a potential hydrogen bond acceptor / donor, which may significantly affect the therapeutic properties of the molecule. Based on similar substitution, 7-deazapurines (pyrrolo[2,3-t / ]pyrimidine) have gained much attention as antiviral and anticancer agents.40It is a modified base analog of adenine wherein the 7thposition nitrogen is replaced by a carbon atom, which makes the fivemembered ring more flexible and provides a possibility of replacing additional substituents at the C-7 position.40Also, the replacement of 7thpositioned nitrogen by carbon modifies theelectronic properties of the five-membered ring and results in a more enriched electron ring system that may increase the chance of cation-rr or n-n interactions within the binding of receptors sites. Additionally, substitution at the 7-position of 7-deazapurine base dramatically changes the therapeutic properties of this class of molecules. Tubercidin, a 7-deazaadenosine analog (Figure 2), and its derivatives have shown nanomolar potency against HCV and anti-cancer activity.40’41Taking the lead from the above-described molecule, several analogs of modified 7-deazapurines nucleoside with a D-dioxolane (12-19) have been synthesized, and their antiviral potency was evaluated against EBV and HIV. The synthesis of the targeted 7-deazapurine dioxolane was commenced with the previously reported dioxolane ketone (1). 7-position substitution was performed by halogens to retain an altered hydrogen binding competence of the molecules and 2-amino (17) & fluoro (18), including 6-7V-Me (19) composite nucleosides, were synthesized to understand their selectivity to viral DNA.

[0551] Chemistry

[0552] To accomplish the synthesis of targeted 7-deazapurine dioxolane nucleoside analogs (12-19), dioxolane ketone 1 was synthesized according to the literature reported protocol by Sznaidman et al. As shown in FIGURE 3, Scheme I, reduction of ketone 1 was performed with IM solution of lithium tri-Zc / V-but oxy aluminum hydride (LTBA) in THF to afford the racemic alcohol 2. Compound 1 was treated with LTBA at -15 C to produce alcohol 2. First attempts were made to purify the racemic alcohol 2. However, during the purification of 2 via silica gel chromatography, a degradation of 2 was observed. Therefore, it was thought to move with an in-situ acetylation of 2, providing the stable acetylated compound 3. Alcohol 2 was treated with acetic anhydride in the presence of 4-(dimethylamino) pyridine (DMAP) to give a diastereomeric mixture of a & fl isomers (2:1 ratio) of 3 in 39% yield. The al fl diastereomers of 3 were inseparable via column chromatography and utilized as a mixture for the next step coupling reaction.

[0553] Coupling dioxolane acetate 3 with the 7-deazapurines proved to be a tedious and extensive challenging process. In initial attempts, following our earlier reported protocol43’446-chloro-7-deazapurine was refluxed in hexamethyldisilazane with catalytic ammonium sulfate to produce the silylated 7-deazapurine, which was used immediately in the next step. Compound 3 was treated with iodotrimethylsilane (TMSI) to produce the intermediate 4,followed by the immediate addition of the silylated 7-deazapurine. However, multiple attempts had been tried for the coupling of 4 with appropriate silylated 6-chloro-7-deazapurine, but in each case a complex mixture was obtained. Therefore, it was concluded that the 7thposition nitrogen on the purine ring might be essential for silylation, and the absence of the 7thposition nitrogen in the case of 7-deazapurine may inhibit coupling reaction and result in multiple spot formation.

[0554] Next, an anion-generated SN2 approach was adopted for the coupling of 6-chloro-7-deazapurine with intermediate 4. In this attempt, 6-chloro-7-deazapurine was treated with NaH (60% in oil) in acetonitrile, and to this solution, freshly prepared 4 was dropwise added, and the mixture was allowed to stir for 3 hours to afford a couple of nucleosides (5-11) intermediates in a poor yield of 4-5%. However, in this coupling condition, four major products were formed rather than the expected two 1 ' <z / / ? / products (intermediate 5). It was speculated that the additional products may be a result of epimerization. Furthermore, potassium hydroxide with phase-transfer catalyst conditions was tried to provide the major / ?-coupled nucleoside product.45’466-chloro-7-deazapurine was treated with potassium hydroxide in the presence of the phase transfer catalyst tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) in acetonitrile, and to this, freshly prepared 4 was added to produce desired / ?-coupled intermediate 5 in 14% yield. This altered coupling method produced exclusively two diastereomeric major 1' a and coupled products, which were separated via flash silica gel column chromatography. The coupling method of 4 with an appropriate substituted 7-deazapurine analog in the presence of KOH was found to be efficient and repeatable. This method was utilized to construct other coupled intermediates (6-11) with a range of 14% and 30% yield, respectively. To furnish the desired targeted final nucleoside 15, 4-chloro-2-fluoro-7H-pyrrolo[2,3-d] pyrimidine was synthesized by fluorination via Sandmeyer reaction 47

[0555] as per the reported protocol by Babu et al.

[0556] Furthermore, the ^-conformation of the coupled nucleosides was determined via similarly reported NMR data of dioxolane-derived purine nucleosides.1H NMR data showed significant differences in shifting for the position of 4' proton based on either 1' a or / ? conformation of the coupled nucleosides.43Likewise, this relationship was also observed in the synthesized intermediates of 7-deazapurine dioxolane nucleosides (5-11). Interestingly, it was observed that the conformation compounds were crystallized at room temperature, while the a coupled product remained a viscous oil.Deprotection and 6-position amination of compounds 5-11 were carried out to afford the desired targeted nucleosides. In a steel bomb under higher pressure, compounds 5-11 were treated with a 28% aqueous solution of NH4OH in dioxane to substitute an amine or methylamine group for the chloro group at the 6-position to render the final targeted nucleosides in 22-38% yield. During the amination step, ester hydrolysis was simultaneously performed to produce the final compound (12-18). Notably, to synthesize compound 19 (Y=NH-Me), intermediate 6 was treated with N-m ethyl amine instead of an aqueous solution of NH4OH to give A-methyl prodrug of guanosine analog 19 in 40% yield.

[0557] Anti-Viral Activity

[0558] The antiviral potency of all synthesized nucleosides was evaluated in vitro cell-based assay. P3HR-1 cells were seeded in 48-well plates at a density of 1 x 106cells / mL. EBV replication was induced by adding 20 ng / mL 12-O-tetradecanoylphorbol 13-acetate (TP A; Sigma-Aldrich, Bornem, Belgium) to the growing cells. The next day, cells were washed and resuspended in a fresh medium in the presence or absence of various concentrations of synthesized nucleosides (12-19). Ganciclovir (GCV) was used as a standard drug. At day 5 postinduction, total cellular DNA was extracted (QIAamp DNA kit; Qiagen Benelux B.V, Venlo, Netherlands), and viral DNA was quantified by quantitative PCR (qPCR) using an ABI Prism 7500 Sequence Detection System (Applied Biosystems, Foster City, CA).

[0559] Thermocycling conditions for all qPCRs were done following the manufacturer’s instructions. Forward and reverse primers, as well as TaqMan probe sequences allowing the detection of the target BNRF1 of EBV, have been described by Friedrichs et al. The concentrations required to effectively reduce EBV DNA synthesis in TPA-stimulated cells by 50% and 90% (EC50 and EC90) were extrapolated from the standard curve using linear regression analysis. The results were obtained as the means from at least three independent experiments. The selectivity index (SI) of the compound was determined by the ratio of CC50 / EC50. For both efficacy and cytotoxicity assays, the 50% reduction in efficacy (EC50) and cell viability (CC50) was determined using GraphPad software (San Diego, California, graphpad.com). FIGURE 4, Table 1 shows the antiviral activity of 7-deazanucleosides (12-19) against EBV in P3HR cell lines and HIV-FL in TZM-GFP cells.

[0560] Out of the synthesized nucleoside analogs, compound 15 demonstrated an EC50 of 0.17 pM with a CC50 of 49.9 pM against EBV compared to GCV (EC50 = 2.5 pM). 7-brormo-deazapurine-D-dioxolane nucleoside (15) expressed 14 times more potency with a selectivity index (SI) of 294 than the FDA-approved drug GCV (SI > 40). Furthermore, the extended structure-activity relationship (SAR) revealed that the substitution of fluoro at the 7-position also expressed a good antiviral profile of compound 13 with an EC50 of 1.2 pM compared to GCV. However, 7-chloro substitution at deazapurine (14) resulted in diminished antiviral activity (ECso= 12.5 pM); on the other hand, 7-iodo substitution (16) retained a good antiviral activity with an EC50 of 0.47 pM. (SI = 45) The 7-position unsubstituted analog (12) was found inactive against EBV. The SAR concludes that the substitutions at the 7-position of deazapurine (substituent X) significantly affect the antiviral activity of this series of molecules, and substitution of various functional groups or elements at the 7-position appear to provide a better antiviral candidate. In addition, these synthesized analogs were not the substrate of the adenosine deaminase. Further, the 2-6 diamino analog (17) expressed less antiviral activity, with an EC50 value of 11.9 and SI > 8. The cytotoxicity profile of the 2-amino substituted compound 17 was found to be improved (CC50 > 100). Therefore, it is anticipated that the 7-position substitution in 2-4 amino analogs may express an enhanced antiviral activity against EBV. Furthermore, to understand the influence of 2-position substitution on the antiviral activity of 7-deazapurine-D-dioxolane analogs, a 2-fluoro-6-amino analog (18) was synthesized, which demonstrated a milder EC50 of 15.5 pM that proves interaction of 2-substituted 7-deazapurine-D-doxolane analog with the viral DNA. The antiviral evaluation and SAR conclude that either substitution at 2 and 7 positions or exclusively 2 or 7 positions on 7-deazapurine of D-di oxolane nucleosides may be beneficial in identifying a preclinical candidate against EBV and accelerating the effort of antiviral drug discovery. Additionally, 6-V-methyl prodrug of guanosine analogs (19) was synthesized to understand the antiviral profile of guanosine-derived analogs; however, the synthesized compound 19 was not found active.

[0561] Given the encouraging antiviral activity of 7-deazapurine-D-dioxolane nucleosides, an extended evaluation of compounds 12-16 was examined against HIV in the TZM-GFP cells. First, TZM-GFP cells were seeded in the 96-well plate (10,000 / well), and after 24 h, selected compounds and HIV FL [multiplicity of infection (MOI) =0.1] virus were added to the plate. Compound ZW-780 was used as a positive control. At 48 hours post-infection (hpi), the GFP cells were measured by Cytation 5, and a 50% reduction in efficacy (EC50) and cell viability (CC50) was determined using GraphPad software (San Diego, California,graphpad.com). FIGURE 5, Table 2 shows the antiviral activity of the 7-deazapurine analogs (12-16) against HIV Fl virus in TZM-GFP cells.

[0562] Compounds 12 and 13 demonstrated good activity against HIV with an EC50 value of 5.85 & 3.96 pM compared to standard compound ZW-780 (EC50 = 0.60 pM) without cytotoxicity up to >100 pM. The initial phosphorylation is often the rate-limiting step in activating both natural and synthetic nucleosides, posing a significant challenge to their biological activity.49To bypass this step, phosphoramidate prodrugs have been utilized.50After witnessing the potent antiviral activity of compounds 12, 13, 15, and 16, the synthesis of phosphoramidate prodrug of these nucleosides has been completed and were found to be more potent than the parent compounds. It is well-proven that the phosphoramidate prodrug also caps the polarity of 5'-hydroxy of nucleosides, which may also increase the pharmacokinetic profile, cellular uptake, and bioavailability of select 7-dazapurine-D-dioxolane analogs of this report.

[0563] EXPERIMENTAL PROTOCOL

[0564] General Analytical Methods

[0565] Reagents and anhydrous solvents were purchased from commercial sources and used without further purification. Moisture-sensitive reactions were performed using oven-dried glassware under a nitrogen or argon atmosphere. Reactions were monitored by thin-layer chromatography plates (TLC silica gel GF 250 microns) that were visualized using a Spectroline UV lamp (254 nm) and developed with 15% solution of sulfuric acid in methanol. Column chromatography was performed on silica gel 60A, 40-63 pM (230 X 400 mesh, Sorbent Technologies). Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges or on RediSep® gold Cl 8 reverse phase columns. Melting points were recorded on a Mel-temp II laboratory device and are uncorrected. Nuclear magnetic spectra were recorded on Varian Inova 500 spectrometer at 500 MHz for1H NMR, 202 MHz for31P NMR, and 125 MHz for 13

[0566] C NMR with tetramethylsilane as an internal standard. Chemical shifts (8) are quoted as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet) and dt (double triplet). Optical rotations were measured on a JASCO DIP-370 digital polarimeter. Structural assignments were determined with additional information fromgCOSY, gHSQC, and gHMBC experiments. High-resolution mass spectroscopy (HRMS) spectra were measured on Bruker Ultra-high resolution QTOF MS Impact II spectrometer. Samples were infused at 3 pL / min, and spectra were obtained in the positive or negative ionization mode with a typical resolution of 20,000 or greater. The optical purity of chiral intermediates and final chiral compounds was determined by the chiral HPLC. Chiral HPLC / UV was determined with a Waters HPLC coupled to a photodiode array. 10 pL of samples, 0.5 mg / mL in methanol, were injected using a CHIRALCEL OX-H, 5pmm (4.6 X 250mm) column at 30 °C with a flow rate of 3.0 mL / min.

[0567] Synthetic Protocol and Analytical Data

[0568] 2.4.1. ((21?)-4-acetoxy-l,3-dioxolan-2-yl)methyl isobutyrate (3). To a stirred solution of 1 (11.0 g, 58.45 mmol) in THF (50 mL) under N2 cooled to -78°C, Lithium tri- / c / 7-butoxyaluminum hydride (LTBA) (72 mL, IM in THF) was added dropwise over 1 hour at -10 °C. After that, the mixture was stirred for an additional 2 hours at -10 °C to afford intermediate 2. DMAP (9.0 g, 73.07 mmol) was added, and the mixture was stirred for 30 minutes; after that, acetic anhydride (28 mL, 292.27 mmol) was added dropwise. The mixture was stirred for 16 h at room temperature and quenched with saturated NH4CI (20 mL). A suspension was obtained and filtered through a celite bed to yield a clear biphasic mixture. The organic layer was separated and concentrated under reduced pressure to give a brown residue, which was dissolved in EtOAc (500 mL). The organic layer was washed with water (30 mL x 2), brine (30 mL x 2), and finally with a saturated aqueous solution of NaHCCf (aq.

[0569] 30 mL), and then concentrated under reduced pressure. The crude residue was purified via column chromatography (6% EtOAc / hexanes) gave diastereomers 3a / 3b as an inseparable yellow oil. Yield: (5.2 g, 39%); 'H NMR (500 MHz, CDCI3) (mix of diastereomers) 86.34-6.28 (m, 1H), 5.35, 5.25 (t, J= 4.0 Hz, 1H), 4.33-3.90 (m, 4H), 2.58-2.51 (m, 1H), 2.04-2.02 (m, 3H), 1.13-1.11 (m, 6H);13C NMR (125 MHz, CDC13) 6 176.5, 176.5, 170.2, 170.1, 103.6, 102.6, 102.3, 94.5, 94.0, 71.3, 70.8, 64.1, 63.5, 63.4, 63.2, 33.8, 21.1, 21.0, 18.9, 18.8; HRMS (ESI-TOF) m / z: [M + Na]+Calcd for Ci0Hi6O6Na 255.0839; found 255.0836.

[0570] 2.5. Synthesis of the target compounds 5 — 11:

[0571] 2.5.1. ( (2 / ?.4 / ?)-4-( 4-chlor o-7 / / -py r rolo [2 ,3-d\ py rimidin-7-yl)- 1 ,3-dioxolan-2-yl)methylisobutyrate (5). To a stirred solution of 3 (1.0 g, 4.31 mmol) in anhydrous CHCI3(36 mL) under N2 cooled to -20°C, iodotrimethylsilane (TMSI, 0.75 mL, 5.17 mmol) was added. The mixture was stirred at -20°C for 3 hours to afford intermediate 4. In a separate round bottom flask, KOH powder (725 mg, 12.93 mmol) was taken under N2 in anhydrous ACN (25 mL) and stirred for 30 minutes. After that, 0.1 mL of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) was added, and the mixture was stirred vigorously for 30 minutes, until the clumps of KOH disappeared. To this mixture, 6-chloro-7-deazapurine (725 mg, 4.31 mmol) was added, and the reaction was vigorously stirred for an additional 20 minutes. The mixture was cooled to 0°C, and the crude 4 was added slowly over 5 minutes and stirred for 1 hour. The murky suspension was passed through a medium frit, quenched with aq. Na2S20s (25 mL), was washed with water (2 x 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified via column chromatography (11% EtOAc / Hexanes) to give 5 as a white crystalline powder. Yield: (200 mg, 14%); 'HNMR (500 MHz, CDC13) 68.63 (s, 1H), 7.58 (d, J= 3.5Hz, 1H), 6.80 (d, J = 5.5 Hz, 1H), 6.67 (d, J= 4.0 Hz, 1H), 5.29 (t, J= 3.5 Hz, 1H), 4.45-4.28 (m, 4H), 2.62-2.54 (m, 1H), 1.16 (dd,J= 7.0 & 19.5 Hz, 6H);13C NMR (125 MHz, CDC13) 6 176.6, 152.4, 151.4, 151.2, 125.9, 117.9, 103.1, 101.5, 79.6, 71.3, 63.0, 33.9, 19.0, 19.0; HRMS (ESI-TOF) m / z: [M + Na]+Calcd for CuHieC CUNa 348.0722; found 348.0722.

[0572] 2.5.2. ( (2 / ?.4 / ?)-4-( 2-a in ino-4-chloro-7 / / -py r rolo [2 ,3-d\ pyrimidin-7-yl)- 1 ,3-dioxolan-2-yl)methylisobutyrate (6). Compound 6 was synthesized according to the above procedure described for the synthesis of 5. Yield: (200 mg, white solid, 14%); 'HNMR (500 MHz, CDCI3) 87.12 (d, J= 4.0 Hz, 1H), 6.54-6.53 (m, 1H), 6.40 (d, J= 3.5 Hz, 1H), 5.30 (bs, 2H), 5.22 (t, J = 4.0 Hz, 1H), 4.37-4.28 (m, 2H), 4.25-4.17 (m, 2H), 2.58-2.52 (m, 1H), 1.13 (dd, J = 7.0 & 18.0 Hz, 6H);13C NMR (125 MHz, CDC13) 6 176.6, 159.0, 154.0, 152.8, 122.1, 110.6, 102.8, 79.2, 70.7, 63.2, 33.8, 19.0, 18.9; HRMS (ESI-TOF) m / z: [M + Na]+Calcd for Ci4Hi7ClN4O4Na 363.0831; found 363.0826.

[0573] 2.5.4. ( (2 / ?.4 / ?)-4-( 4-chlor o-2-fl uoro-7 / / -py r rolo [2 ,3-d\ pyrimidin-7-yl)- 1 ,3-dioxolan-2-yl)methylisobutyrate (7). Compound 7 was synthesized according to the above procedure described for the synthesis of 5. Yield: (200 mg, white powder, 14%); m.p.: (37-40°C); 'H NMR (500 MHz, CDC13) 68.60 (s, 1H), 7.35 (d, J= 3.0 Hz, 1H), 6.84 (d, J= 6.5 Hz, 1H), 5.24 (t, J= 3.5 Hz, 1H), 4.38 (dd, J= 1.5 Hz & 10.0 Hz, 1H), 4.35-4.28 (m, 2H), 4.26 (dd, J = 4.5 & 10.0 Hz, 1H), 2.62-2.54 (m, 1H), 1.16 (dd, J= 7.0 & 21.5 Hz, 6H);13C NMR (125 MHz, CDCI3) 6 176.6, 158.6, 156.8, 126.3, 116.3, 103.2, 102.0, 101.2, 79.7, 71.3, 62.9, 33.9,18.9;19F NMR (470 MHz, CDC13) 6 -51.65 (s, IF); HRMS (ESI-TOF) m / z: [M + Na]+ Calcd for Ci4Hi5ClFN3O4Na 366.0627; found 366.0617.

[0574] 2.5.3. ( (2 / ?.4 / ?)-4-( 4-chlor o-5-fl uoro-7 / / -py r rolo [2.3-d\ pyrimidin-7-yl)- 1 ,3-dioxolan-2-yl)methylisobutyrate (8). Compound 8 was synthesized according to the above procedure described for the synthesis of 5. Yield: (210 mg, pale yellow solid, 14%); m.p.: (74-76 °C);

[0575] XH NMR (500 MHz, CDC13) 87.52 (d, J= 4.0Hz, 1H), 6.66 (s, 1H), 6.65 (s, 1H), 5.27 (t, J = 3.5 Hz, 1H), 4.42-4.26 (m, 4H), 2.60-2.55 (m, 1H), 1.16 (dd, J= 7.0 & 17.5 Hz, 6H);13C NMR (125 MHz, CDCI3) 6 176.6, 151.9, 150.9, 147.2, 143.1, 141.1, 108.7, 107.4, 103.1, 79.2, 71.2, 62.7, 33.9, 18.9;19F NMR (470 MHz, CDCI3) 6 -166.17 (t, J= 2.35Hz, IF);

[0576] HRMS (ESI-TOF) m / z: [M + H]+Calcd for C14H16CIFN3O4344.0808; found 344.0805.

[0577] ((21?,41?)-4-(4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-l,3-dioxolan-2-yl)methyl isobutyrate (9) Compound 9 was synthesized according to the above procedure described for the synthesis of 5. Yield: (190 mg, off white powder, 13%). M.p. 102-105 °C; *HNMR (500 MHz, CD3OD 68.58 (s, 1H), 7.81 (s, 1H), 6.78 (d, J= 4.6 Hz, 1H), 5.27 (t, J= 2.6 Hz, 1H), 4.52 (d, J= 10.2 Hz, 1H), 4.35-4.27 (m, 3H), 2.55 (p, J= 7.0 Hz, 1H), 1.14 (d, J= 7.0 Hz, 3H), 1.04 (d, J= 7.0 Hz, 3H);13C NMR (125 MHz, CD3OD) 5 176.7, 151.2, 150.8, 145.8, 124.7, 113.6, 104.8, 103.1, 79.8, 70.8, 61.9, 33.7, 18.0, 17.9; HRMS-ESI (m / z): [M + H]+calculated for [Ci4Hi6Cl2N3O4]+360.0512; found 360.0513.

[0578] 2.5.5. ((2 / ?.4 / ?)-4-(5-br()ni()-4-chl()ro-7 / / -pyrrolo|2.3- |pyriniidin-7-yl)- 1 ,3-dioxolan-2-yl)methyl isobutyrate (10). Compound 10 was synthesized according to the above procedure described for the synthesis of 5. Yield: (232 mg, off white powder, 13%); m.p.: (108-112 °C);

[0579] XH NMR (500 MHz, CDC13) 68.61 (s, 1H), 7.69 (s, 1H), 6.79 (d, J= 4.8 Hz, 1H), 5.26 (s, 1H), 4.42-4.25 (m, 4H), 2.62 (p, J= 6.8 Hz, 1H), 1.20 (d, J= 6.9 Hz, 3H), 1.14 (d, J= 6.9 Hz, 3H);13C NMR(125 MHZ, CDCI3) 6 176.7, 152.6, 151.6, 150.6, 126.1, 115.2, 103.3, 89.9, 79.5, 71.6, 62.3, 33.9, 19.2, 19.1; HRMS (ESI-TOF) m / z: [M + Na]+Calcd for Ci4Hi5BrClN3O4Na 425.9832; found 425.9814.

[0580] 2.5.6. ( (2 / ?.4 / ?)-4-( 4-chlor o-5-iodo-7 / / -py r rolo [2 ,3-d] pyrimidin-7-yl)- 1 ,3-dioxolan-2-yl)methyl isobutyrate (11). Compound 11 was synthesized according to the above procedure described for the synthesis of 5. Yield: (160 mg, white powder, 8%); m.p.: (142-146 °C); 'HNMR (500 MHz, CDC13) 68.62 (s, 1H), 7.80 (s, 1H), 6.78 (d, J= 5.5 Hz, 1H), 5.28 (t, J = 2.8 Hz, 1H), 4.43-4.27 (m, 4H), 2.66 (p, J= 7.0 Hz, 1H), 1.22 (d, J= 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H);13C NMR(125 MHz, CDC13) 6 176.8, 152.9, 151.1, 150.8, 131.7, 117.1, 103.2, 79.60, 71.6, 62.2, 53.4, 33.9, 19.2, 19.1; HRMS (ESI-TOF) m / z: [M + Na]+ Calcd for Ci4Hi5ClN3O4Na 473.9693; found 473.9669.

[0581] 2.6. Synthesis of the target compounds 12 — 19:

[0582] 2.6.1. ((2 / ?.4 / ?)-4-(4-:iinino-7 / / -pyriolo|2.3- |pyriinidin-7-yl)-l .3-di()xol:in-2-yl)ineth:inol (12). In a sealed tube 5 (180 mg, 0.55 mmol) was taken in dioxane (2 mL) and a solution of 28% NH4OH in water (4 mL) were added. The solution was allowed to stir under higher pressure for 24 hours at 100°C. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo. The residue was purified via column chromatography (5% MeOH / DCM) and trituration with ether / hexane to give 12 as an off-white fluffy solid. Yield: (50 mg, 38%); m.p.: 138-148 °C; [a]26D = -47.03 (c 0.5, MeOH); 'H NMR (500 MHz, CD3OD) 88.06 (s, 1H), 7.38 (d, J= 3.5Hz, 1H), 6.59-6.57 (m, 2H), 5.08 (t, J= 3.0Hz, 1H), 4.36-4.33 (m, 1H), 4.25-4.22 (m, 1H), 3.72 (d, J= 6.0Hz, 2H);13C NMR (125 MHz, CD3OD) 6 157.6, 151.0, 149.6, 121.5, 105.2, 103.0, 100.2, 79.7, 70.8, 61.8;

[0583] HRMS (ESI-TOF) m / z: [M + Na]+Calcd for CioHi2N403Na 259.0802; found 259.0801.

[0584] 2.6.5. ((2 / ?.4 / ?)-4-(4-:iiiiiiio-5-nuoro-7 / / -pyrrolo|2.3- |pyriniidin-7-yl)-l .3-dioxolan-2-yl)methanol (13). In a sealed tube 8 (200 mg, 0.58 mmol) was taken in dioxane (2 mL) and NH40H (4 mL) were added. The solution was allowed to stir under higher pressure at 100 °C for 24h. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo to give a crude yellow solid. The solid was dissolved in 80 °C water (3 mL) and stirred until full dissolution of solid was observed and coiled to room temperature to afford 13 as an off-white beige powder. Yield: (116 mg, 79%); m.p.: (178-180 °C); [a]25D = -77.52 (c = 0.5 in MeOH);XHNMR (500 MHz, MeOH) 68.06 (s, 1H), 7.21 (d, J= 1.5 Hz, 1H), 6.63 (d, J= 5.5 Hz, 1H), 5.04 (t, J = 2.5 Hz, 1H), 4.31 (d, J = 5.5 Hz, 1H), 4.22-4.19 (m, 1H), 3.72 (d, J = 2.5 Hz, 2H);13C NMR (125 MHz, CD3OD) 6 152.4, 144.9, 142.9, 105.2, 103.9, 103.7, 79.3, 70.7, 61.5;19F NMR (470 MHz, CD3OD) 6 -169.37 (s, IF); HRMS (ESI-TOF) m / z: [M + H]+Calcd for Ci0HnFN4O3255.0888; found 255.0883.

[0585] ((2R,4R)-4-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-l,3-dioxolan-2-yl)methanol (14). Compound 14 was synthesized according to above explained syntheticprocedure of compound 13. In a sealed tube 9 (200 mg, 0.58 mmol) was taken in dioxane (2 mL) and NH4OH (4 mL) were added. The solution was allowed to stir under higher pressure at 100 °C for 24h. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo to give a crude yellow solid. The solid was dissolved in 80 °C water (3 mL) and stirred until full dissolution was observed. Purification via cooling recrystallization afforded 14 as an off-white beige powder. Yield: (109 mg, 72% yield). M.p.

[0586] 179-182 °C 'HNMR (500 MHz, CD3OD) 88.13 (s, 1H), 7.52 (s, 1H), 6.64 (s, 1H), 5.11 (s, 1H), 4.38 (d, J= 9.5 Hz, 1H), 4.27 (dd, J= 6.4, 9.7 Hz, 1H), 3.78 S, 2H);13C NMR (125 MHz, CD3OD) 6 157.2, 152.3, 152.2, 148.8, 118.8, 105.3, 104.5, 79.6, 70.9, 61.4; HRMS-ESI (m / z): [M + Na]+calculated for [C10Hi iN4O3Na]+293.0417; found 293.0399.

[0587] 2.6.6. ((2 / ?.4 / ?)-4-(4-:iinin()-5-bi()ino-7 / / -pyriolo|2.3- |pyriinidin-7-yl)-l .3-dioxolan-2-yl)methyl isobutyrate (15). Compound 15 was synthesized according to above explained synthetic procedure of compound 13. In a sealed tube 10 (110 mg, 0.27 mmol) was taken in dioxane (1 mL) and NH4OH (2 mL) were added. The solution was allowed to stir under higher pressure at 100 °C for 24h. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo to give a crude yellow solid. The solid was dissolved in 80 °C water (3 mL) and stirred until full dissolution was observed.

[0588] Purification via cooling recrystallization afforded 15 as a light yellow powder. Yield: (35 mg, 33%); m.p.: (184-186 °C); [a]25D= -11.64 (c = 0.25 in MeOH);XH NMR (500 MHz, DMSO-d6. 88.08 (s, 1H), 7.48 (s, 1H), 6.76 (brs, 2H) 6.54 (s, 1H), 5.09 (s, 1H), 4.96 (s, 1H), 4.30 (d, J= 8.0 Hz, 1H), 4.15 (s, 1H), 3.56 (s, 2H);13C NMR (125 MHz, DMSO-t / 6) 8 157.5, 153.2, 149.9, 121.4, 105.7, 101.1, 87.8, 79.3, 71.1, 61.8; HRMS (ESI-TOF) m / z: [M + H]+Calcd for CioHi2N403Br 315.0087; found 315.0072.

[0589] 2.6.7. ((2 / ?.4 / ?)-4-(4-:iniin()-5-i()do-7 / / -pyrrolo|2.3- |pyi iniidin-7-yl)- 1.3-dioxolan-2-yl)methyl isobutyrate (16). Compound 16 was synthesized according to above explained synthetic procedure of compound 13. In a sealed tube 11 (98 mg, 0.21 mmol) was taken in dioxane (1 mL) and NH40H (2 mL) were added. The solution was allowed to stir under higher pressure at 100 °C for 24h. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo to give a crude yellow solid. The solid was dissolved in 80 °C water (3 mL) and stirred until full dissolution was observed. The mixture stored in the freezer for 16 h, the obtained crystals were filtered and dried to to afford16 as an white powder. Yield: (14 mg, 15%); m.p.: (222-223 °C); 'HNMR (500 MHz, DMSO-tL): 58.08 (s, 1H), 7.52 (s, 1H), 6.65 (brs, 2H), 6.52 (s, 1H), 5.09 (s, 1H), 4.96 (s, 1H), 4.29 (d, J= 8.6 Hz, 1H), 4.14 (s, 1H), 3.55 (s, 2H);13C NMR (125 MHz, DMSO-t / 6): 6 157.7, 152.7, 150.4, 126.7, 105.7, 103.3, 79.3, 71.0, 61.8, 53.0; HRMS (ESI-TOF) m / z: [M + H]+Calcd for CioHiiIN403Na 384.9774; found 384.9749.

[0590] 2.6.2. ((2 / ?.4 / ?)-4-(2.4-diainino-7 / / -pyriolo|2.3- |pyriinidin-7-yl)-l .3-dioxolan-2-yl)methanol (17). In a sealed tube 6 (200 mg, 0.59 mmol) was taken in dioxane (2 mL) and a solution of 28% NH4OH in water (4 mL) was added. The solution was allowed to stir under higher pressure for 72 hours at 135 °C. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo. Purification was carried out via preparatory TLC (10% MeOH / DCM) to give 17 as a yellow powder. Yield: (20 mg, 14%); m.p.: (140-145°C); [a]25D= -73.61 (c = 0.5 in MeOH);XH NMR (500 MHz, CD3OD) 66.98 (d, J= 4.0 Hz, 1H), 6.40-6.39 (m, 2H), 5.05 (t, J= 3.5 Hz, 1H), 4.29 (d, J= 2.0 & 9.5 Hz, 1H), 4.19-4.16 (m, 1H), 3.70 (d, J= 3.5 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 159.5, 158.1, 152.2, 118.1, 104.9, 100.5, 96.5, 79.6, 70.4, 62.1; HRMS (ESI-TOF) m / z: [M + H]+Calcd for C10H14N5O3252.1091; found 252.1091.

[0591] 2.6.4. ((2 / ?.4 / ?)-4-(4-:iiiiiiio-2-nuoro-7 / / -pyrrolo|2.3- |pyriniidin-7-yl)-l .3-dioxolan-2-yl)methanol (18). In a sealed tube 7 (100 mg, 0.29 mmol) was taken in dioxane (2 mL) and a solution of 28% NH4OH in water (4 mL) was added. The solution was allowed to stir under higher pressure for 24 hours at 100 °C. After that, the solution was allowed to cool to room temperature, and the solvent was evaporated in vacuo to give a crude yellow solid. The solid was dissolved in 80°C isopropanol (3 mL) and stirred until full dissolution was observed and cooled to rtto obtain 18 as a white powder. Yield: (35 mg, 47%); m.p.: (160-165 °C); [a]27D = -63.10 (c = 0.5 in MeOH);XHNMR (500 MHz, MeOH) 67.14 (d, J= 3.5 Hz, 1H), 6.52 (d, J= 3.5 Hz, 1H), 6.42 (d, J = 5.5 Hz, 1H), 5.05 (s, 1H), 4.32-4.18 (m, 2H), 3.72 (d, J= 3.0 Hz, 2H);13C NMR(125 MHZ, CD3OD) 6 183.2, 153.8, 120.3, 105.2, 101.2, 100.0, 95.2, 79.8, 70.6, 61.6;19F NMR (470 MHz, CD3OD) 6 -129.05 (s, IF); HRMS (ESI-TOF) m / z: [M - H]’ Calcd for C10H10FN4O3253.0742; found 253.0746.

[0592] 2.6.3. ((2 / ?.4 / ?)-4-(2-:iinin()-4-(inethyl:iinin())-7 / / -pyrrolo|2.3- |pyi iniidin-7-yl)-l .3-dioxolan-2-yl)methanol (19). In a sealed tube 6 (100 mg, 0.29 mmol) was taken in methylamine in ethanol (33% / wt, 8 mL). The solution was allowed to stir under higher pressure for 24 hours at 160 °C. After that, the solution was allowed to cool to roomtemperature, and the solvent was evaporated in vacuo. The crude residue was purified via preparatory TLC (7.5% MeOH / DCM) to afford 19 as an off-white powder. Yield: (20 mg, 26%); m.p.: (145-155 °C); [a]25D= -91.64 (c = 0.5 in MeOH); 'HNMR (500 MHz, CD3OD) 6 6.93 (d, J= 4.0 Hz, 1H), 6.39-6.37 (m, 1H), 6.35 (d, J= 3.5 Hz, 1H), 5.05 (t, J= 3.5 Hz, 1H), 4.28 (dd, J = 2.0 & 9.5 Hz, 1H), 4.18-4.15 (m, 1H), 3.69 (d, J = 3.0 Hz, 2H), 2.96 (s, 3H);13C NMR(125 MHz, CD3OD) 6 160.1, 158.1, 117.3, 104.9, 100.1, 100.0, 96.9, 79.6, 70.4, 62.2, 26.5; HRMS (ESI-TOF) m / z: [M + H]+Calcd for C11H16N5O3266.1248; found 266.1243.

[0593] Biology

[0594] Compounds and formulations: All tested compounds were prepared as 10 mM stocks in DMSO and stored at -80 °C. The control compounds, GCV (Sigma-Aldrich) and ZW-780 (Millipore Sigma, Burlington, MA), are commercially available. Stock compounds were diluted in DMSO and / or complete tissue culture media prior to being added to cells.

[0595] Cells lines: P3HR1 cells (ATCC HTB-62) were purchased from the American Types Culture Collection (ATCC) and grown in RPMI 1640 with 10% heat-inactivated fetal bovine serum (FBS) and 100 lU / mL penicillin and 100 pL / mL streptomycin. TZM-GFP cells were purchased from the ATCC and grown in RPMI 1640 with 10% heat-inactivated fetal bovine serum (FBS) and 100 lU / mL penicillin and 100 pL / mL streptomycin

[0596] In vitro antiviral susceptibility assay: a) For EBV assay, 24- well plated seeded with IxlO6cells per well in 1 mL of medium. Cells were induced with 25 ng / mL 12-G-tetradecanoylphorbol 13 -acetate (TP A, Sigma-Aldrich), and incubated with various concentrations of compounds (25, 5, 1, 0.2, 0.04, 0 pM). TPA was removed after 24 hours, and the same concentration of compounds was replaced. Cells were harvested on day 5 by removing a 200 pL aliquot of resuspended cells and medium for extraction, b) For HIV assay, TZM-GFP cells were seeded in the 96-well plate (10,000 / well), and after 24 h, selected compounds and HIV FL (MOI=0.1) virus were added to the plate. Reference compound ZW-780 (PF-74) was used as a positive control. At 48 hours post-infection (hpi), the GFP cells were measured by Cytation 5, and a 50% reduction in efficacy (EC50) and cell viability (CC50) was determined using graphpad software (San Diego, California,

[0597] www.graphpad.com).Real-time PCR detection of viral DNA: EBV DNA was extracted with a QIAGEN Dneasy Blood and Tissue Kit. The DNA volume was 30 pL. DNA concentration (ng / pL) was determined with a Nanophotometer (IMPLEN). The Real-time PCR was performed using QuantiTect Sybr Green PCR Kit. The amplicon was a 71 bp portion of the EBNA1 gene. The primers were purchased from IDT. The forward primer was 5‘-GAC TGT GTG CAG CTT TGA CGA T-3’; the reverse primer was 5’ -CGG CAG CCC CTT CCA-3’. The 20 pL PCR sample contained lOOng DNA, 10 pL Universal PCR Master Mix, primer (0.5 uM final concentration), 1 pL BamHI-HF (Restriction Enzyme, BioLabs) and RNase-free water. The PCR program consisted of 1 cycle at 50° C, 2 minutes of UNG pretreatment followed by 1 cycle at 95° C for 15 minutes. Then 40 cycles of 94° C for 15 seconds, 55° C for 30 seconds, and 72° C for 30 seconds were carried out.

[0598] Evaluation of Cytotoxicity: The cytotoxic effects of test compounds for P3HR1 and TZN-GFP cells were determined by CellTiter 96 Non-Radioactive Cell Proliferation assay system (Promega) using either 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide, disodium salt (XTT) or 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods under the same conditions as the antiviral assay but in the absence of virus. Cells were seeded at a density of 1 x 105(P3HR1) or 2 x 104(TZM-GFP) cells per well in 96-well plates and allowed to incubate overnight. On the second day, different concentrations of test compounds were added to respective cells. Following 4 days of incubation at 37°C in a CO2 incubator, the MTT or XTT reagent was added, and the cells were incubated for 3 hours at 37°C. Subsequently, the absorbance of the samples was measured using a microplate reader (Biotek). The cytotoxic concentration (CC50) was determined based on the viability of mock-infected cells.

[0599] CONCLUSION

[0600] By way of the present application, the inventors have described the SAR and antiviral activity of unexplored D-dioxolane-derived 7-deazapurines nucleosides (12-19) against EBV and HIV viruses. The targeted nucleoside synthesis has been carried out via acetylation of ketone (1) to furnish critical intermediate 3. Iodination of 3 followed by SN2 coupling was performed to afford the coupled Lnucleosides intermediates, 5-11, which on amination and deprotection, yielded target nucleoside analogs 12-19. In vitro 7-bromo-deazaadenine (15) and 7-iodo-deazaadenine (16) derivatives exhibited potent anti-EBV activity. Compound 15 expressed a high SI and was 14-fold more potent than the FDA-approved drug GCV.Furthermore, compounds 12 & 13 demonstrated moderate antiviral activity against HIV. This communication suggests that phosphoramidate, phosphate, and phosphonates ester prodrugs of 12, 13, 15, and 16 may demonstrate enhanced antiviral profile of reported nucleosides and extended SAR of D-dioxolan derived-7 -deazapurine analogs may pave a path in the finding new antivirals against EBV and HIV.

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Claims

Claims:

1. A compound according to the chemical structure I:Where X and Z are each independently C or N;Q and T are each C or N, with the proviso thatwhen Q is C, T is N,is a double bond between Q and the carbon atom between Q and X and a double bond between X and the carbon atom between X and T, andwhen Q is N, T is C, X is C, R2 is H, Z is N, R3 is absent andis a single bond between Q and the carbon atom between Q and X, a double bond between T and the carbon atom between T and X and a double bond between X and the carbon atom between X and Q;Y is H, NRYRY, ORYor SRY, often NHRY, ORYor SRY;Each RYis independently H, C1-C12 alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl),-(CH2)i-Aryl or -(CH2)i-Heterocycle;Ri is H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo (F, Cl, Br or I), C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;R2 is absent (when X is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, Ci-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i-Heterocycle;R3 is absent (when Z is N), H, C1-C12 alkyl (often C1-C3 alkyl or CH3), NHR, CN, halo, C1-C7 acyl (often acetyl), -(CH2)i-Aryl, -(CH2)i -Heterocycle;R4 is H when T is N, or H, OH, CN, CH3, vinyl, alkyne when T is C; andR is H, Ci-Ce alkyl (often C1-C3 alkyl or CH3), C1-C7 acyl (often acetyl), -(CH2)i-Aryl or-(CH2)i-Heterocycle;R1is H or a RPROgroup;RPROis an acyl group according to the chemical structure:, where R3is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups; or RPROis a group according to the chemical structure:R is a C1-C30 alkyl group, often a C1-C20 alkyl group or a C1-C10 alkyl group which is optionally substituted with 1-6, often 1-3 hydroxy or halo groups;RN1and RN2are each independently H or a Ci-Ce alkyl or acyl group optionally substituted with 1-3 hydroxy or halo groups; andR is H, a Ci-Ce alkyl group optionally substituted with 1-3 hydroxy or halo groups, an O-R group where R3is the same as above or a NRN1RN2group where RN1and RN2are the same as above; orgroup;Where x is 0 or 1; andRN1and RN2are the same as above; orRPROis agroup;Where RAAis H, a Ci-Ce alkyl group which is optionally substituted with from 1-3 hydroxyl groups or 1-3 halogroups or an amino acid side chain selected from the group consisting of is a side chain derived from an amino acid, said amino acid side chain being preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol ordithiol (from cysteine or cystine), ethylcarboxyamide (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyl eneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; andR4a is H or a C1-C20 (often a Ci-Ce) alkyl group which is optionally substituted with from 1-3 hydroxyl groups and 1-3 halo groups; orRPROis a phosphate ester, phosphodiester, phosphoramidate or phosphordiamidate group according to the chemical structure:Where R5 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryl oxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionally substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups, or the two R5 groups link together to form a five- or sixmembered heterocyclic group, with the proviso that no more than one R5 or Rs group is H; Each R6is independently H (with the proviso that not more than one Re or R5group is H), a group according to the chemical structure:, or an amide group derived from an amino acid (a natural or unnatural amino acid such as, for example, alanine, P-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine, amongothers) according to the structure:Where i is 0, 1, 2 or 3 (preferably 0 or 1);R7 is H, a Ci to C20 alkyl group, alkoxy, including an alkoxyalkyl group, aryloxyalkyl group (for example phenoxymethyl), alkoxycarbonyloxy group (e.g., (isopropoxycarbonyl)oxy]-methoxy), an optionally substituted aryl (especially including an optionally substituted phenyl group or a C1-C12 alkylene phenyl group), each of which groups may be optionally substituted with from one to three Ci-Ce (preferably C1-C3) alkyl, alkoxy (often methoxy), hydroxy, halogen (preferably F, Cl or Br), nitro, cyano, or C2-C6 acyl (often acetyl), ester or carboxyester groups;R7is H or C1-C3 alkyl, preferably H;Rs is a side-chain of an amino acid, preferably selected from the group consisting of methyl (from alanine), propyleneguanidine (from arginine), methylenecarboxyamide (from asparagine), ethanoic acid (from aspartic acid), methylthiol or dithiol (from cysteine or cystine), ethyl carb oxy ami de (glutamine), propanoic acid (glutamic acid), H (glycine), methyleneimidazole (histidine), 1 -methylpropane (isoleucine), 2-methylpropane (leucine), butyleneamine (lysine), ethylmethylthioether (methionine), benzyl (phenylalanine), pyrrolidone (proline, where RAAforms a cyclic pyrrolidone ring with the adjacent nitrogen group), hydroxypyrrolidone (from hydroxyproline, where RAAforms a cyclic hydroxypyrrolidone ring with the adjacent nitrogen group), methanol (serine), 1-hydroxyethane (threonine), methyeneindole (tryptophan), methylene phenol (tyrosine) and isopropyl (valine), among others; andR” is H, a Ci to C20 alkyl (linear, branched or cyclic alkyl) or a phenyl or heteroaryl group, each of which groups is optionally substituted, ora pharmaceutically acceptable salt, solvate or polymorph thereof.

2. The compound of claim 1 according to chemical structure I,Wherein Q and X are C;R2is H or halo (F, Cl, Br or I);Y isNHR;Z is N (R3 is absent),Ri is H, NHR or halo (F, Cl, Br or I);R is H or CH3; ora pharmaceutically acceptable salt, solvate or polymorph thereof.

3. The compound of claim 1 according to chemical structure I,Wherein X is C, Q is C, R2 is H, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2 is F, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2is Cl, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2 is Br, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2 is I, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2is H, Y is NH2, Z is N and Ri is NH2;X is C, Q is C, R2 is H, Y is NH2, Z is N and Ri is F; orX is C, Q is C, R2 is H, Y is NHMe, Z is N and Ri is NH2; ora pharmaceutically acceptable salt, solvate or polymorph thereof.

4. The compound of claim 1 according to chemical structure I,Wherein X is C, Q is C, R2 is H, Y is NH2, Z is N and Ri is H;X is C, Q is C, R2 is F, Y is NH2, is Z is N and Ri is H;X is C, Q is C, R2 is Br, Y is NH2, Z is N and Ri is H; orX is C, Q is C, R2 is I, Y is NH2, Z is N and Ri is H, ora pharmaceutically acceptable salt, solvate or polymorph thereof.

5. The compound according to claim 3 wherein R2is H, Y is NH2and Riis H.

6. The compound according to claim 3 wherein R2 is F, Y is NH2 and Ri is H.

7. The compound according to claim 3 wherein R2 is Br, Y is NH2, and Ri is H.

8. The compound according to claim 3 wherein R2 is I, Y is NH2 and Ri is H.

9. The compound according to claim 1 wherein X is C, Q is N, Z is N (R3 is absent), R2 is H, and Y, Ri and R1are the same as set forth in claim 1.

10. A compound of claim 1 according to the chemical structure IA:IAWhere X, Y, Z, R R2, R3 and R1are the same as set forth in claim 1.

11. A compound of claim 1 according to the chemical structure IB:Where Y, Ri, R4 and R1are the same as set forth in claim 1.

12. A compound of claim 1 according to the chemical structure II:Where R2 is H or halo (F, Cl, Br or I);Y is Cl;Ri is H, NHR or halo (F, Cl, Br or I); andR is H or CH3; ora pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 wherein:R2 is H, Y is Cl and Ri is H;R2 is F, Y is Cl and Ri is H;R2is Cl, Y is Cl, Ri is H;R2 is Br, Y is Cl, Ri is H;R2is I, Y is Cl, Ri is H;R2is H, Y is Cl, Ri is NH2;R2is H, Y is Cl, Ri is F;R2 is H, Y is Cl, Ri is NHMe; ora pharmaceutically acceptable salt, solvate or polymorph thereof.

14. The compound according to claim 12 wherein:R2 is H, Y is Cl and Ri is H;R2 is F, Y is Cl and Ri is H;R2 is Br, Y is Cl, Ri is H orR2is I, Y is Cl, Ri is H.

15. A pharmaceutical composition for use in the treatment of an Epstein-Barr virus (EBV) infection or a human immunodeficiency virus (HIV) viral infection comprising an effective amount of a compound according to any one of claims 1-14 in combination with a pharmaceutically acceptable carrier, additive or excipient.

16. A pharmaceutical composition for use in the treatment of an Epstein-Barr virus (EBV) infection or a human immunodeficiency virus (HIV) viral infection comprising an effective amount of a compound according to any one of claims 2-11 in combination with a pharmaceutically acceptable carrier, additive or excipient.

17. The composition according to claim 15 or 16 further including at least one traditional anti-EBV agent.

18. The composition according to claim 15 or 16 further including at least one traditional anti-HIV agent.

19. The composition according to claim 16 further including at least one traditional anti-EBV agent.

20. The composition according to claim 16 further including at least traditional anti-HIV agent.

21. A method of treating an Epstein-Barr virus (EBV) infection a symptom thereof in a patient or subject in need comprising administering an effective amount of a compound according to any one of claims 1-12 or a pharmaceutical composition according to any one of claims 15, 16, 17 or 19 to said patient or subject.

22. A method of treating an Epstein-Barr virus (EBV) infection in a patient or subject in need comprising administering an effective amount of a compound according to any one of claims 3-11 or a pharmaceutical composition according to claims 16 or 19 to said patient or subject.

23. A method of treating a human immunodeficiency virus (HIV) infection or a symptom thereof in a patient or subject in need comprising administering an effective amount of acompound according to any one of claims 1-14 or a pharmaceutical composition according to any one of claims 15-20 to said patient or subject.

24. A method of treating a human immunodeficiency virus (HIV) infection or a symptom thereof in a patient or subject in need comprising administering an effective amount of a compound according to any one of claims 3-11 or a pharmaceutical composition according to any one of claims 15-17 or 19 to said patient or subject.

25. A method of treating at least one symptom of Multiple Sclerosis in a patient or subject in need comprising administering to said patient or subject an effective amount of a compound according to any one of claims 1-14 or a pharmaceutical composition according to any one of claims 15-17 or 19.

26. The method according to claim 24 wherein said MS symptom is at least one symptom selected from the group consisting of muscle weakness, vision problems, coordination issues, fatigue, pain, numbness, tingling or other unusual sensations, dizziness, difficulty with balance and coordination, problems with memory and cognition, spasticity and difficulty walking and bladder problems.

27. A method of reducing the likelihood of Multiple Sclerosis occurring in a patient or subject at risk for Multiple Sclerosis comprising administering to said patient or subject an effective amount of a compound according to any one of claims 1-14 or a pharmaceutical28. The method according to claim 24 wherein said Multiple Sclerosis is Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS) or Clinically Isolated Syndrome (CIS).

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