Nucleoside cyclicphosphates

1. A compound of formula I:

or a stereoisomer, salt, hydrate, solvate, deuterated analogue, or crystalline form thereof, wherein

R 1 is n-alkyl, branched alkyl, cycloalkyl, alkaryl, phenyl or naphthyl, where the phenyl or naphthyl is optionally substituted with at least one of F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , NHR′ 2 + , NR′ 3 + , C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′;

R 2 is of H, optionally substituted alkyl, cyano, CH 3 , vinyl, O-alkyl, O—(C 1 -C 6 alkyl), hydroxyl C 1 -C 6 alkyl, fluoromethyl, azido, CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , optionally substituted ethynyl alkyne, or halogen;

R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 , F, or CN;

X is F, OCH 3 , halogen, NH 2 , or N 3 ;

Base is of formula b:

wherein R 4 and R 5 are independently H, F, CI, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , NHR′ 2 + , NR′ 3 + , heterocycle, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′; and

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, an optionally substituted acyl, or an optionally substituted alkoxyalkyl, where for the instance of NR′ 2 or NHR′ 2 + , each R′ is independent of one another or both R′ are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR′ 3 + , each R′ is independent of one another or at least two R′ are joined to form a heterocycle comprising at least two carbon atom.

2. The compound of claim 1 which is of formula I-2:

or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof;

R 1 is n-alkyl, branched alkyl, cycloalkyl, alkaryl, phenyl or naphthyl, where the phenyl or naphthyl is optionally substituted with at least of F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′2, NHR′ 2 + , NR′ 3 + , heterocycle, C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′;

R 2 is H, a C 1 -C 6 alkyl, cyano, vinyl, O—(C 1 -C 6 alkyl), hydroxyl C 1 -C 6 alkyl, fluoromethyl, azido, CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;

R 3 is CH 3 , CH 2 F, CHF 2 or CF 3 ;

X is F; and

R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 2 X′, CHX′ 2 , CX′ 3 , vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; where X′ is F, Cl, Br, or I;

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, an optionally substituted acyl, or an optionally substituted alkoxyalkyl, where for the instance of NR′ 2 or NHR′ 2 + , each R′ is independent of one another or both R′ are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR′ 3 + , each R′ is independent of one another or at least two R′ are joined to form a heterocycle comprising at least two carbon atom.

3. A composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, and equivalent medium and a compound of claim 1 .

4. A method for treating hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which method comprises administering a therapeutically effective amount of the compound of claim 1 to a subject in need thereof.

5. A process for preparing the compound of claim 1 said process comprising reacting compound III with R 1 OP(NR 2 ) 2 to form compound II, and then oxidizing compound II to form the compound of formula I according to the following scheme

wherein R 1 , R 2 , R 3 , X, and Base are defined in claim 1 ; wherein R 1 OP(NR 2 ) 2 is a dialkylamino-R 1 phosphite, B is a Brönsted base, and [O] is an oxidant.

6. A compound of formula I-3:

or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof;

wherein

R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, phenyl or naphthyl, where the phenyl or naphthyl is optionally substituted with at least one of F, Cl, Br, I, OH, OR″, SH, SR″, NH 2 , NHR″, NR″ 2 , heterocycle, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R″, CONH 2 , CONHR″, CONR″ 2 , CH═CHCO 2 H, or CH═CHCO 2 R″, wherein R″ is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl;

R 2 is H, a C 1 -C 6 alkyl, cyano, vinyl, O—(C 1 -C 6 alkyl), hydroxyl C 1 -C 6 alkyl, fluoromethyl, azido, CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;

R 3 is CH 3 , CH 2 F, CHF 2 or CF 3 ;

X is F;

R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , NHR′ 2 + , NR′ 3 + , heterocycle, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′;

Z is N or CR 9 ; and

R 9 is H, F, OH, OR′, NH 2 , NHR′, NR′ 2 , C 1 -C 6 alkyl, or halogenated C 1 -C 6 alkyl;

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, an optionally substituted acyl, or an optionally substituted alkoxyalkyl, where for the instance of NR′ 2 or NHR′ 2 + , each R′ is independent of one another or both R′ are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR′ 3 + , each R′ is independent of one another or at least two R′ are joined to form a heterocycle comprising at least two carbon atom.

7. The compound of claim 6 , wherein

R 1 is H, lower alkyl, C 1 -C 6 alkylaryl, phenyl or naphthyl, where the phenyl or naphthyl is optionally substituted with at least one of F, Cl, Br, I, OH, OR″, SH, SR″, NH 2 , NHR″, NR″ 2 , C 1 -C 6 alkoxy, or halogenated C 1 -C 6 alkoxy, wherein R″ is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl;

R 2 is H;

R 3 is CH 3 ;

X is F;

R 7 is NHR′, NR′ 2 , NHR′ 2 + , or NR′ 3 + ;

R 8 is NH 2 ;

Z is N; and

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, an optionally substituted acyl, or an optionally substituted alkoxyalkyl, where for the instance of NR′ 2 or NHR′ 2 , each R′ is independent of one another or both R′ are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR′ 3 + , each R′ is independent of one another or at least two R′ are joined to form a heterocycle comprising at least two carbon atom.

8. A compound of formula I-4:

or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof;

wherein

R 1 is of H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, phenyl or naphthyl, where the phenyl or naphthyl is optionally substituted with at least one of F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , NHR′ 2 + , NR′ 3 + , heterocycle, C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′;

R 2 is H, C 1 -C 6 alkyl, cyano, vinyl, O—(C 1 -C 6 alkyl), hydroxyl C 1 -C 6 alkyl, fluoromethyl, azido, CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;

R 3 is CH 3 , CH 2 F, CHF 2 or CF 3 ; and

X is F;

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, an optionally substituted acyl, or an optionally substituted alkoxyalkyl, where for the instance of NR′ 2 or NHR′ 2 + , each R′ is independent of one another or both R′ are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR′ 3 + , each R′ is independent of one another or at least two R′ are joined to form a heterocycle comprising at least two carbon atom.

9. The compound of claim 8 , wherein

R 1 is H, C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, phenyl or naphthyl, where the phenyl or naphthyl in optionally substituted with at least one of F, Cl, Br, I, OH, OR″, SH, SR″, NH 2 , NHR″, NR″ 2 , NHR″ 2 + , NR″ 3 + , heterocycle, C 1 -C 6 alkoxy, or halogenated C 1 -C 6 alkoxy,

wherein R″ is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl;

R 2 is H;

R 3 is CH 3 ; and

X is F.

10. A compound selected from the group consisting of

and

or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof.

11. A composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, and equivalent medium and a compound of claim 10 .

12. A method for treating hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which method comprises administering a therapeutically effective amount of the compound of claim 10 to a subject in need thereof.