Therapeutic furopyrimidines and thienopyrimidines

A compound of formula II:

• wherein:
• R100 is alkyl, alkenyl, or alkynyl, which R100 may be unsubstituted or substituted;
• R101 is H, alkyl, —C(O)alkyl, or benzoyl;
• R102 is H, OH, Oalkyl, —OC(O)alkyl, —Obenzoyl, —CH2OH, CH2NH2, N3, CH2N3, or NH2;
• R103 is H, OH, or NH2;
• provided both R102 and R103 cannot be the same group except hydrogen;
• R104 is NR110R111, NR110—NR111R112, NR110N═NR111, NR110N═CHR111, NR110N═O, NR110C(O)NR111R112R113, NR110C(S)NR111R112, NR110C(═NH)NR111R112, NR110C(O)NR111NR112, R110, NR110OR111, O—C(O)R110, OC(O)—OR110, O—NH—C(O)Oalkyl, ONHC(O)Oaryl, ONR110R111, S—NR110R111, S—ONR110R111, or SO2NR110R111;
• R105 is H, NH2, halogen, N3, NHR106, NHC(O)R106, NR110R111, NHSO2R106, NHCONHR106, NH—C(S)NHR106, CH2NHR106, NHNH2, CN, alkyl, alkynyl, CH2aryl, OH, or SR106;
• R106 is H or alkyl;
• Z100 is OH, —O—[P(═O)(OH)O—]n—H, —CH2— [P(═O)(OH)O—]n—H, —O—P(═O)(R107)R108, —CH2—P(═O)(R17)R108, —O[P(═O)(R109)O—]n—H, or —CH2—[P(═O)(R109)O—]n—H;
• R107 and R108 in phosphonic acid or phosphoric acid independently represent a protected or unprotected substituted or unsubstituted hydroxyl group to be decomposed under physiological conditions;
• R109 is a hydroxyl group that may be protected or substituted with a group to be decomposed under physiological conditions;
• R110, R111, R112 and R113 are independently H, alkyl, substituted alkyl, cycloalkyl, heterocyclic, alkoxy, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl, NH2, OH or NO;
• R114 is H, alkyl, substituted alkyl, C(O)R109, aryl, substituted aryl, or heterocycle;
• n is 0-3;
• X is O, S, NH, or CH2;
• W is CR114, N, or C-halo;
• and
• Y is O, S, or NR114;
• or a pharmaceutically acceptable salt or prodrug thereof.

A compound which is 4-Cyclopropylamino-7-β-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;

• 4-Azetidino-7-β-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Pyrrolidino-7-β-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Methoxy-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-[(N-1-Hydroxyethyl)hydrazino]-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-[(N-1-Methyl)hydrazino]-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Dimethylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Aminoethylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Hydrazino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• ((2S,5R)-(5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-4-methyl-2,5-dihydrofuran-2-yl)methanol;
• 2-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
• 2,4-Diamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-β-(2′-C-ethyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-α-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-α-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-β-(2′-O-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 7-β-(2′-C-Methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-thione;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-thieno[3,2-d]pyrimidine;
• 4-Amino-7-α-(2′-C-methyl-D-ribofuranosyl)-thieno[3,2-d]pyrimidine;
• (cis)(4-(4-Aminofuro[3,2-d]pyrimidin-7-yl)cyclopent-2-enyl)methanol;
• (5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-tetrahydrothiophen-2-yl)methanol;
• 2-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol;
• 2-Amino-7-β-(D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
• 7-β-(2′-C-Methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-monophosphate;
• 2-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one-5′-monophosphate;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-monophosphate;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-triphosphate;
• 4-Amino-7-P-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-triphosphate;
• (2-(4-Aminofuro[3,2-d]pyrimidin-7-yl)ethoxy)methylphosphonic acid;
• Methyl 2-(((5-(4-aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)-3-methylbutanoate;
• Methyl 2-(((5-(4-aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)propanoate;
• S,S′-2,2′-(((5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate);
• S,S′-2,2′-(((5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)-bis(ethane-2,1-diyl)diethanethioate;
• S,S′-2,2′-(((3,4-Dihydroxy-5-(4-methoxyfuro[3,2-d]pyrimidin-7-yl)-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis-(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate);
• S,S′-2,2′-(((3,4-Dihydroxy-4-methyl-5-(4-(methylamino)furo[3,2-d]pyrimidin-7-yl)-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate);
• S,S′-2,2′-((5-(2-Amino-4-oxo-3,4-dihydrofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate);
• or a pharmaceutically acceptable salt or prodrug thereof.

A compound which is 4-Methoxy-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;

• 4-[(N-1-Hydroxyethyl)hydrazino]-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-[(N-1-Methyl)hydrazino]-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Dimethylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Aminoethylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Hydrazino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 2-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
• 2,4-Diamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-β-(2′-C-ethyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 4-Amino-7-α-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
• 7-β-(2′-C-Methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-thione;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-thieno[3,2-d]pyrimidine;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-thieno[3,2-d]pyrimidine;
• 2-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol;
• 7-β-(2′-C-Methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
• 4-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-monophosphate;
• 2-Amino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one-5′-monophosphate;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-monophosphate;
• 4-Methylamino-7-β-(2′-C-methyl-D-ribofuranosyl)-furo[3,2-d]pyrimidine-5′-triphosphate;
• 4-Amino-7-β-(2′-C-methyl-D-ribofaranosyl)-furo[3,2-d]pyrimidine-5′-triphosphate;
• Methyl 2-(((5-(4-aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)-3-methylbutanoate;
• Methyl 2-(((5-(4-aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)propanoate;
• S,S′-2,2′-(((5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl) bis(2,2-dimethylpropanethioate);
• S,S′-2,2′-(((5-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)-bis(ethane-2,1-diyl) diethanethioate;
• S,S′-2,2′-(((3,4-Dihydroxy-5-(4-methoxyfuro[3,2-d]pyrimidin-7-yl)-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis-(oxy)bis(ethane-2,1-diyl) bis(2,2-dimethylpropanethioate);
• S,S′-2,2-(((3,4-Dihydroxy-4-methyl-5-(4-(methylamino)furo[3,2-d]pyrimidin-7-yl)-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl) bis(2,2-dimethylpropanethioate);
• S,S′-2,2′-((5-(2-Amino-4-oxo-3,4-dihydrofuro[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl) bis(2,2-dimethylpropanethioate);
• or a pharmaceutically acceptable salt or prodrug thereof.

A method for treating a viral infection in an animal comprising administering to the animal an effective amount of a compound of formula I:

• wherein:
• Y is O or S;
• R is OR3, SR3, NR3R4, NR3NR4R5, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH2)n—CH(NHR3)CO2R4, (CH2)n—S-alkyl, (CH2)n—S-aryl, Cl, F, Br, I, CN, COOR3, CONR3R4, NHC(═NR3)NHR4, NR3OR4, NR3NO, NHCONHR3, NR3N═NR4, NR3N═CHR4, NR3C(O)NR4R5, NR3C(S)NR4R5, NR3C(O)OR4, CH═N—OR3, NR3C(═NH)NR4R5, NR3C(O)NR4NR5R6, O—C(O)R3, OC(O)—OR3, ONH—C(O)O-alkyl, ONHC(O)O-aryl, ONR3R4, SNR3R4, S—ONR3R4, or SO2NR3R4;
• n is 1-5;
• R1 is H, NR3R4, Cl, F, OR3, SR3, NHCOR3, NHSO2R3, NHCONHR3, CN, alkyl, aryl, ONR3R4, or NR3C(O)OR4;
• R2 is a nucleoside sugar group;
• and
• R3, R4, R5, and R6 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl and NO;
• or R3 and R4 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;
• or R4 and R5 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;
• or a pharmaceutically acceptable salt or prodrug thereof;
• wherein the viral infection is selected from the group consisting of:
• hepatitis B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile virus.

A method for inhibiting a viral RNA or DNA polymerase comprising contacting the polymerase in vitro or in vivo with an effective inhibitory amount of a compound of formula I:

• wherein:
• Y is O or S;
• R is OR3, SR3, NR3R4, NR3NR4R5, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH2),n—CH(NHR3)CO2R4, (CH2)n—S-alkyl, (CH2)n—S-aryl, Cl, F, Br, I, CN, COOR3, CONR3R4, NHC(═NR3)NHR4, NR3OR4, NR3NO, NHCONHR3, NR3N═NR4, NR3N═CHR4, NR3C(O)NR4R5, NR3C(S)NR4R5, NR3C(O)OR4, CH═N—OR3, NR3C(═NH)NR4R5, NR3C(O)NR4NR5R6, O—C(O)R3, OC(O)—OR3, ONH—C(O)O-alkyl, ONHC(O)O-aryl, ONR3R4, SNR3R4, S—ONR3R4, or SO2NR3R4;
• n is 1-5;
• R1 is H, NR3R4, Cl, F, OR3, SR3, NHCOR3, NHSO2R3, NHCONHR3, CN, alkyl, aryl, ONR3R4, or NR3C(O)OR4;
• R2 is a nucleoside sugar group;
• and
• R3, R4, R5, and R6 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl and NO;
• or R3 and R4 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;
• or R4 and R5 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;
• or a pharmaceutically acceptable salt or prodrug thereof.