2',4'-substituted nucleosides as antiviral agents

A method for the treatment of a host infected with HBV, HCV, or HIV that includes administering an effective amount of a compound of the formula:

• wherein for structure A or A′
• (a) R2 is independently CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
• (b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
• (c) R3 is independently OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
• (d) R4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxylmethyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, loweralkylamino, or di(loweralkyl)amino;
• (e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
• (f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
• wherein for a and b
• Z is Nor CR8;
• R5, R6, and R7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as CCH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• R8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C65 halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• or
• base may be selected from a group of formula c
• wherein for structure c,
• if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G;
• or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR2, CO, CS, CNR, SO, S(O)2, SeO, Se(O)2, or C(G)2;
• each G is independently selected from the group consisting of H, halogen, OR, SR, NR2, NROR, N3, COOR, CN, CONR2, C(S)NR2, C(═NR)NR2, and R;
• and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O)2, SeO and Se(O)2;
• wherein, if X is a participant in a pi bond (double bond), X is C;
• or if X is not a participant in a pi bond (double bond), X is CR or N;
• wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR2;
• or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR;
• and
• dashed lines (---) indicate a possible pi or double bond;
• each R is independently selected from the group consisting of H, CF3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl;
• or
• base may be a structure selected from the group consisting of structures d-n
• wherein Z, X, and R″ are defined as in structure c;
• base may be a structure selected from the group consisting of structures o-ff
• wherein G and R are defined as in structure c;
• base may be a structure gg
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
• base may be a structure hh
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G)2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
• base may be a structure ii
• wherein R and G are defined as in structure c;
• base may be a structure jj
• wherein R and G are defined as in structure c;
• or
• base may be a structure kk
• wherein for structure kk:
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Y is selected from the group consisting of a bond, O, and CH2;
• Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH2 group;
• V is selected from the group consisting of N and C-G;
• Z is selected from the group consisting of N and C-G;
• G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO3H, —SO2NH2, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• provided that V and Z are not identical;
• provided that when V is C—H, Z is N;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• and
• each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure ll
• wherein for structure ll:
• R is C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Q′ is selected from the group consisting of NH, O, and S;
• G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO3H, —SO2NH2, alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure mm
• where in for structure mm
• Q is as defined for structure kk
• A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
• D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH2—(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
• each Q is independently selected from the group consisting of O, S, and NH;
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
• optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.

A use of the compound represented by formula A or A′ in the manufacture of a medicament for the treatment and/or prophylaxis of any condition the result of an infection by HBV, HCV, or HIV:

• wherein for structure A or A′
• (a) R2 is independently CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
• (b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
• (c) R3 is independently OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
• (d) R4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxylmethyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, loweralkylamino, or di(loweralkyl)amino;
• (e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
• (f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
• wherein for a and b
• Z is Nor CR8;
• R5, R6, and R7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as CCH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• R8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• or
• base may be selected from a group of formula c
• wherein for structure c,
• if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G;
• or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR2, CO, CS, CNR, SO, S(O)2, SeO, Se(O)2, or C(G)2;
• each G is independently selected from the group consisting of H, halogen, OR, SR, NR2, NROR, N3, COOR, CN, CONR2, C(S)NR2, C(═NR)NR2, and R;
• and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O)2, SeO and Se(O)2;
• wherein, if X is a participant in a pi bond (double bond), X is C;
• or if X is not a participant in a pi bond (double bond), X is CR or N;
• wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR2;
• or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR;
• and
• dashed lines (---) indicate a possible pi or double bond;
• each R is independently selected from the group consisting of H, CF3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl;
• or
• base may be a structure selected from the group consisting of structures d-n
• wherein Z, X, and R″ are defined as in structure c;
• base may be a structure selected from the group consisting of structures o-ff
• wherein G and R are defined as in structure c;
• base may be a structure gg
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
• base may be a structure hh
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G)2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
• base may be a structure ii
• wherein R and G are defined as in structure c;
• base may be a structure jj
• wherein R and G are defined as in structure c;
• or
• base may be a structure kk
• wherein for structure kk:
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Y is selected from the group consisting of a bond, O, and CH2;
• Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH2 group;
• V is selected from the group consisting of N and C-G;
• Z is selected from the group consisting of N and C-G;
• G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO3H, —SO2NH2, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• provided that V and Z are not identical;
• provided that when V is C—H, Z is N;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• and
• each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure ll
• wherein for structure ll:
• R is C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Q′ is selected from the group consisting of NH, O, and S;
• G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO3H, —SO2NH2, alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure mm
• where in for structure mm
• Q is as defined for structure kk
• A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
• D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH2—(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
• each Q is independently selected from the group consisting of O, S, and NH;
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
• optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.

A method of making a medicament that comprises combining a pharmaceutically effective carrier with a compound of the formula:

• wherein for structure A or A′
• (a) R2 is independently CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
• (b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
• (c) R3 is independently OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
• (d) R4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxylmethyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, loweralkylamino, or di(loweralkyl)amino;
• (e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
• (f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
• wherein for a and b
• Z is Nor CR8;
• R5, R6, and R7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as CCH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• R8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• or
• base may be selected from a group of formula c
• wherein for structure c,
• if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G;
• or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR2, CO, CS, CNR, SO, S(O)2, SeO, Se(O)2, or C(G)2;
• each G is independently selected from the group consisting of H, halogen, OR, SR, NR2, NROR, N3, COOR, CN, CONR2, C(S)NR2, C(═NR)NR2, and R;
• and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O)2, SeO and Se(O)2;
• wherein, if X is a participant in a pi bond (double bond), X is C;
• or if X is not a participant in a pi bond (double bond), X is CR or N;
• wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR2;
• or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR;
• and
• dashed lines (---) indicate a possible pi or double bond;
• each R is independently selected from the group consisting of H, CF3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl;
• or base may be a structure selected from the group consisting of structures d-n
• wherein Z, X, and R″ are defined as in structure c;
• base may be a structure selected from the group consisting of structures o-ff
• wherein G and R are defined as in structure c;
• base may be a structure gg
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
• base may be a structure hh
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G)2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
• base may be a structure ii
• wherein R and G are defined as in structure c;
• base may be a structure jj
• wherein R and G are defined as in structure c;
• or
• base may be a structure kk
• wherein for structure kk:
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Y is selected from the group consisting of a bond, O, and CH2;
• Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH2 group;
• V is selected from the group consisting of N and C-G;
• Z is selected from the group consisting of N and C-G;
• G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO3H, —SO2NH2, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• provided that V and Z are not identical;
• provided that when V is C—H, Z is N;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• and
• each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure ll
• wherein for structure ll:
• R is C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Q′ is selected from the group consisting of NH, O, and S;
• G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO3H, —SO2NH2, alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure mm
• where in for structure mm
• Q is as defined for structure kk
• A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
• D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH2—(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
• each Q is independently selected from the group consisting of O, S, and NH;
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
• optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.

A process, which comprises:

• (1) deoxygenating the 2′-C-position of a compound represented by 1 or 1′
• to obtain a compound represented by 2 or 2′
• and
• (2) derivatizing the compound represented by 2 or 2′ to obtain a compound represented by A or A′
• wherein for structures 1, 1′, 2, 2′, A, and A′
• (a) R2 is independently CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
• (b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
• (c) R3 is independently OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C1-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C1-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
• (d) R4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxylmethyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, loweralkylamino, or di(loweralkyl)amino;
• (e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
• (f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
• wherein for a and b
• Z is Nor CR8;
• R5, R6, and R7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as CCH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkylaryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• R8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C65 halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• or
• base may be selected from a group of formula c
• wherein for structure c,
• if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G;
• or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR2, CO, CS, CNR, SO, S(O)2, SeO, Se(O)2, or C(G)2;
• each G is independently selected from the group consisting of H, halogen, OR, SR, NR2, NROR, N3, COOR, CN, CONR2, C(S)NR2, C(═NR)NR2, and R;
• and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O)2, SeO and Se(O)2;
• wherein, if X is a participant in a pi bond (double bond), X is C;
• or if X is not a participant in a pi bond (double bond), X is CR or N;
• wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR2;
• or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR;
• and
• dashed lines (---) indicate a possible pi or double bond;
• each R is independently selected from the group consisting of H, CF3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl;
• or
• base may be a structure selected from the group consisting of structures d-n
• wherein Z, X, and R″ are defined as in structure c;
• base may be a structure selected from the group consisting of structures o-ff
• wherein G and R are defined as in structure c;
• base may be a structure gg
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
• base may be a structure hh
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G)2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
• base may be a structure ii
• wherein R and G are defined as in structure c;
• base may be a structure jj
• wherein R and G are defined as in structure c;
• or
• base may be a structure kk
• wherein for structure kk:
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Y is selected from the group consisting of a bond, O, and CH2;
• Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH2 group;
• V is selected from the group consisting of N and C-G;
• Z is selected from the group consisting of N and C-G;
• G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO3H, —SO2NH2, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• provided that V and Z are not identical;
• provided that when V is C—H, Z is N;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• and
• each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure ll
• wherein for structure ll:
• R is C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Q′ is selected from the group consisting of NH, O, and S;
• G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO3H, —SO2NH2, alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure mm
• where in for structure mm
• Q is as defined for structure kk
• A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
• D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH2—(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
• each Q is independently selected from the group consisting of O, S, and NH;
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
• optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.

A product or composition obtained by a process, which comprises:

• (a) deoxygenating the 2′-C-position of a compound represented by 1 or 1′
• to obtain a compound represented by 2 or 2′
• and
• (b) derivatizing the compound represented by 2 or 2′ to obtain a compound represented by A or A′
• wherein for structures 1, 1′, 2, 2′, A, and A′
• (a) R2 is independently CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
• (b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
• (c) R3 is independently OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C1-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C1-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
• (d) R4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxylmethyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, loweralkylamino, or di(loweralkyl)amino;
• (e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
• (f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
• wherein for a and b
• Z is Nor CR8;
• R5, R6, and R7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as CCH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkylaryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• R8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl;
• an optionally substituted cycloalkyl;
• an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C1-C4 alkyl-aryloxy, heteroaryl, optionally substituted C1-C4 alkyl-heteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, an optionally substituted fluoro C1-20 alkyl;
• or
• base may be selected from a group of formula c
• wherein for structure c,
• if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G;
• or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR2, CO, CS, CNR, SO, S(O)2, SeO, Se(O)2, or C(G)2;
• each G is independently selected from the group consisting of H, halogen, OR, SR, NR2, NROR, N3, COOR, CN, CONR2, C(S)NR2, C(═NR)NR2, and R;
• and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O)2, SeO and Se(O)2;
• wherein, if X is a participant in a pi bond (double bond), X is C;
• or if X is not a participant in a pi bond (double bond), X is CR or N;
• wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR2;
• or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR;
• and
• dashed lines (---) indicate a possible pi or double bond;
• each R is independently selected from the group consisting of H, CF3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl;
• or
• base may be a structure selected from the group consisting of structures d-n
• wherein Z, X, and R″ are defined as in structure c;
• base may be a structure selected from the group consisting of structures o-ff
• wherein G and R are defined as in structure c;
• base may be a structure gg
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
• base may be a structure hh
• wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G)2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
• base may be a structure ii
• wherein R and G are defined as in structure c;
• base may be a structure jj
• wherein R and G are defined as in structure c;
• or
• base may be a structure kk
• wherein for structure kk:
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Y is selected from the group consisting of a bond, O, and CH2;
• Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH2 group;
• V is selected from the group consisting of N and C-G;
• Z is selected from the group consisting of N and C-G;
• G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO3H, —SO2NH2, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• provided that V and Z are not identical;
• provided that when V is C—H, Z is N;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• and
• each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure ll
• wherein for structure ll:
• R is C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• Q′ is selected from the group consisting of NH, O, and S;
• G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO3H, —SO2NH2, alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• or
• base may be a structure mm
• where in for structure mm
• Q is as defined for structure kk
• A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
• D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH2—(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C=Q)-, or —CH═CH—NH—+group where X′ is halo;
• each Q is independently selected from the group consisting of O, S, and NH;
• R is selected from the group consisting of hydrogen and C1-C3 alkyl;
• X is selected from the group consisting of hydrogen, halo, and OW2;
• T1 and T2 are independently selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-thioalkoxy, amino, substituted amino, and halo;
• Y is selected from the group consisting of a bond, O, and CH2;
• and each of W, W1, and W2 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and a prodrug group;
• and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
• optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.