Purine nucleoside analogues for treating flaviviridae including hepatitis c

A method of treating a host infected with HCV, comprising administering an effective amount of a ribofuranonucleoside of Formula (III):

• or a pharmacologically acceptable salt thereof, wherein:
• each R, R2*, and R3* independently is H, mono-, di-, or triphosphate;
• a stabilized phosphate;
• or phosphonate;
• optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;
• X is O, S(O)n, CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)2, wherein alkyl, alkenyl, or alkynyl may optionally be substituted;
• n is 0-2;
• each R2′ independently is H;
• optionally substituted alkyl, alkenyl, or alkynyl;
• —C(O)O(alkyl), —C(O)O(lower alkyl), —C(O)O(alkenyl), —C(O)O(alkynyl), —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —OH, —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), halogen, halogenated alkyl, CF3, azido, cyano, NO2, —S(alkyl), —S(alkenyl), —S(alkynyl), NH2, —NH(alkyl), —N(alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl)2;
• and
• Base is selected from the group consisting of:
• wherein
• each R′ and R″ independently is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N3, carboxy, C1-4 alkoxycarbonyl, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-6 alkoxy, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
• each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR4R4, O-acyl, S-acyl, CN, SCN, OCN, NO2, N3, NH2, NH(alkyl), N(alkyl)2, NH-cycloalkyl, NH-acyl, N═NH, CONH2, CONH(alkyl), or CON(alkyl)2;
• each R4 is independently H, acyl, or C1-6 alkyl;
• and
• each Z is O, S, NH, N—OH, N—NH2, NH(alkyl), N(alkyl)2, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO2, NH2, N3, NH═NH, NH(alkyl), N(alkyl)2, CONH2, CONH(alkyl), or CON(alkyl)2.

A method of treating a host infected with HCV, comprising administering an effective amount of a ribofuranonucleoside of Formula (IV):

• or a pharmacologically acceptable salt thereof, wherein:
• each R, R2*, and R3* independently is H, mono-, di-, or triphosphate;
• a stabilized phosphate;
• or phosphonate;
• optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;
• X is O, S(O)n, CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)2, wherein alkyl, alkenyl, or alkynyl may optionally be substituted;
• n is 0-2;
• each R3′ independently is H;
• optionally substituted alkyl, alkenyl, or alkynyl;
• —C(O)O(alkyl), —C(O)O(lower alkyl), —C(O)O(alkenyl), —C(O)O(alkynyl), —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —OH, —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), halogen, halogenated alkyl, CF3, azido, cyano, NO2, —S(alkyl), —S(alkenyl), —S(alkynyl), NH2, —NH(alkyl), —N(alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl)2;
• and
• Base is selected from the group consisting of:
• wherein
• each R′ and R″ independently is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N3, carboxy, C1-4 alkoxycarbonyl, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-6 alkoxy, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
• each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR4R4, O-acyl, S-acyl, CN, SCN, OCN, NO2, N3, NH2, NH(alkyl), N(alkyl)2, NH-cycloalkyl, NH-acyl, N═NH, CONH2, CONH(alkyl), or CON(alkyl)2;
• each R4 is independently H, acyl, or C1-6 alkyl;
• and
• each Z is O, S, NH, N—OH, N—NH2, NH(alkyl), N(alkyl)2, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO2, NH2, N3, NH═NH, NH(alkyl), N(alkyl)2, CONH2, CONH(alkyl), or CON(alkyl)2.

A compound of the general structure of Formula (I):

• or a pharmacologically acceptable salt thereof, wherein:
• R is H, mono-, di-, or triphosphate;
• a stabilized phosphate;
• or phosphonate;
• X is O, S(O)n, CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)2, wherein alkyl, alkenyl, or alkynyl may optionally be substituted;
• n is 0-2;
• such that when X is CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, CH-halogen, or C-(halogen)2;
• then each R1 and R1′ is independently H, OH, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —C(O)O-(alkyl), —C(O)O(lower alkyl), —C(O)O-(alkenyl), —C(O)O-(alkynyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl), halogen, halogenated alkyl, —NO2, —NH2, —NH(lower alkyl), —N(lower alkyl)2, —NH(acyl), —N(acyl)2, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, or SCH-halogen;
• wherein alkyl, alkenyl, and/or alkynyl may optionally be substituted;
• and
• such that when X is O, S(O)n, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, or SCH-halogen;
• then each R1 and R1′ is independently H, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —C(O)O-(alkyl), —C(O)O(lower alkyl), —C(O)O-(alkenyl), —C(O)O-(alkynyl), halogenated alkyl, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —C(H)═N—NH2, C(S)NH2, C(S)NH(alkyl), or C(S)N(alkyl)2, wherein alkyl, alkenyl, and/or alkynyl may optionally be substituted;
• each R2 and R3 independently is OH, NH2, SH, F, Cl, Br, I, CN, NO2, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, N3, optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, halogenated alkyl, —C(O)O-(alkyl), —C(O)O(lower alkyl), —C(O)O-(alkenyl), —C(O)O-(alkynyl), —O(acyl), —O(alkyl), —O(alkenyl), —O(alkynyl), —OC(O)NH2, NC, C(O)OH, SCN, OCN, —S(alkyl), —S(alkenyl), —S(alkynyl), —NH(alkyl), —NH(alkyl)2, —NH(alkenyl), —NH(alkynyl), an amino acid residue or derivative, a prodrug or leaving group that provides OH in vivo, or an optionally substituted 3-7 membered heterocyclic ring having O, S, and/or N independently as a heteroatom taken alone or in combination;
• each R2′ and R3′ independently is H;
• optionally substituted alkyl, alkenyl, or alkynyl;
• —C(O)O(alkyl), —C(O)O(lower alkyl), —C(O)O(alkenyl), —C(O)O(alkynyl), —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), halogen, halogenated alkyl, CF3, azido, cyano, NO2, —S(alkyl), —S(alkenyl), —S(alkynyl), NH2, —NH(alkyl), —N(alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl)2;
• and
• Base is selected from the group consisting of:
• wherein
• each R′ and R″ independently is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N3, carboxy, C1-4 alkoxycarbonyl, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-6 alkoxy, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
• each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR4R4, O-acyl, S-acyl, CN, SCN, OCN, NO2, N3, NH2, NH(alkyl), N(alkyl)2, NH-cycloalkyl, NH-acyl, N═NH, CONH2, CONH(alkyl), or CON(alkyl)2;
• each R4 is independently H, acyl, or C1-6 alkyl;
• and
• each Z is O, S, NH, N—OH, N—NH2, NH(alkyl), N(alkyl)2, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO2, NH2, N3, NH═NH, NH(alkyl), N(alkyl)2, CONH2, CONH(alkyl), or CON(alkyl)2.

A compound of the general structure of Formula (III):

• or a pharmacologically acceptable salt thereof, wherein:
• each R, R2*, and R3* independently is H, mono-, di-, or triphosphate;
• a stabilized phosphate;
• or phosphonate;
• optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;
• X is O, S(O)n, CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)2, wherein alkyl, alkenyl, or alkynyl may optionally be substituted;
• n is 0-2;
• each R2′ independently is H;
• optionally substituted alkyl, alkenyl, or alkynyl;
• —C(O)O(alkyl), —C(O)O(lower alkyl), —C(O)O(alkenyl), —C(O)O(alkynyl), —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —OH, —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), halogen, halogenated alkyl, CF3, azido, cyano, NO2, —S(alkyl), —S(alkenyl), —S(alkynyl), NH2, —NH(alkyl), —N(alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl)2;
• and
• Base is selected from the group consisting of:
• wherein
• each R′ and R″ independently is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N3, carboxy, C1-4 alkoxycarbonyl, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-6 alkoxy, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
• each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR4R4, O-acyl, S-acyl, CN, SCN, OCN, NO2, N3, NH2, NH(alkyl), N(alkyl)2, NH-cycloalkyl, NH-acyl, N═NH, CONH2, CONH(alkyl), or CON(alkyl)2;
• each R4 is independently H, acyl, or C1-6 alkyl;
• and
• each Z is O, S, NH, N—OH, N—NH2, NH(alkyl), N(alkyl)2, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO2, NH2, N3, NH═NH, NH(alkyl), N(alkyl)2, CONH2, CONH(alkyl), or CON(alkyl)2.

A compound of the general structure of Formula (IV):

• or a pharmacologically acceptable salt thereof, wherein:
• each R, R2*, and R3* independently is H, mono-, di-, or triphosphate;
• a stabilized phosphate;
• or phosphonate;
• optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;
• X is O, S(O)n, CH2, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—O-alkyl, CH—O-alkenyl, CH—O-alkynyl, CH—S-alkyl, CH—S-alkenyl, CH—S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)2, wherein alkyl, alkenyl, or alkynyl may optionally be substituted;
• n is 0-2;
• each R3′ independently is H;
• optionally substituted alkyl, alkenyl, or alkynyl;
• —C(O)O(alkyl), —C(O)O(lower alkyl), —C(O)O(alkenyl), —C(O)O(alkynyl), —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —OH, —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), halogen, halogenated alkyl, CF3, azido, cyano, NO2, —S(alkyl), —S(alkenyl), —S(alkynyl), NH2, —NH(alkyl), —N(alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl)2;
• and
• Base is selected from the group consisting of:
• wherein
• each R′ and R″ independently is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N3, carboxy, C1-4 alkoxycarbonyl, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-6 alkoxy, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
• each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR4R4, O-acyl, S-acyl, CN, SCN, OCN, NO2, N3, NH2, NH(alkyl), N(alkyl)2, NH-cycloalkyl, NH-acyl, N═NH, CONH2, CONH(alkyl), or CON(alkyl)2;
• each R4 is independently H, acyl, or C1-6 alkyl;
• and
• each Z is O, S, NH, N—OH, N—NH2, NH(alkyl), N(alkyl)2, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO2, NH2, N3, NH═NH, NH(alkyl), N(alkyl)2, CONH2, CONH(alkyl), or CON(alkyl)2.