4′-vinyl substituted nucleoside derivatives as inhibitors of respiratory syncytial virus RNA replication

1. A compound of formula I,

wherein:

Y is P(═X)(R)(R′);

R is O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;

R′ is N(R 4 )C(R 2a )(R 2b )C(═O)OR 3 , OP(═O)(OH)OP(═O)(OH)OH, or OR 3 ;

R 1 is naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo, lower haloalkyl, —N(R 1a ) 2 , acylamino, —SO 2 N(R 1a ) 2 , —C(═O)R 1b , —SO 2 R 1c , —NHSO 2 R 1c , nitro, cyano, or R 1″ ;

each R 1a is independently H or lower alkyl;

each R 1b is independently —OR 1a or —N(R 1a ) 2 ;

each R 1c is lower alkyl;

each R 2a and R 2b is independently H, lower alkyl, —(CH 2 ) r N(R 1a ) 2 , lower hydroxyalkyl, —CH 2 SH, —(CH 2 )S(O) p Me, —(CH 2 ) n NHC(═NH)NH 2 , (1H-indol-3-yl)Me, (1H-indol-4-yl)Me, —(CH 2 ) m C(═O)R 1b , aryl or aryl lower alkyl, wherein aryl and aryl lower alkyl are optionally substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano;

m is 0, 1, or 2;

n is 1, 2, or 3;

p is 1 or 2;

r is 1 or 2;

or R 2a is H and R 2b and R 4 together form (CH 2 ) n ;

each R 3 is independently H, lower alkyl, lower haloalkyl, or phenyl lower alkyl, wherein phenyl lower alkyl is optionally substituted with lower alkoxy;

or R 3 and R 1″ together form CH 2 ;

each R 4 is independently H, lower alkyl;

or R 2b and R 4 together form (CH 2 ) 3 ;

both of R w and R y are H;

R x is F or OH;

R z is OH;

or R 3 and R x together form a bond;

or R 1 and R x together form a bond;

X is O or S; and

Base is uracil, cytosine, guanine, adenine, thymine, or heterocycloalkyl, each of which may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano;

or a pharmacologically acceptable salt thereof.

2. The compound of claim 1 , wherein R′ is O—R 3 , R 3 is lower alkyl, R is —OR 1 , and R 1 and R x together form a bond.

3. The compound of claim 1 , wherein R is —OR 1 , R 1 is naphthyl substituted with R 1″ , R′ is —OR 3 , and R 3 and R 1″ together form CH 2 .

4. The compound of claim 1 , wherein X is O.

5. The compound of claim 1 , wherein X is S.

6. The compound of claim 1 , wherein R is O—R 1 , and R 1 is naphthyl.

7. The compound of claim 1 , wherein R′ is N(R 4 )C(R 2a )(R 2b )C(═O)OR 3 , R 4 is H, R 2a is H, R 2b is methyl, and R 3 is isopropyl.

8. The compound of claim 1 , wherein R′ is —OP(═O)(OH)OP(═O)(OH)OH.

9. The compound of claim 1 , wherein Base is cytidine optionally substituted with halo.

10. The compound of claim 1 , wherein Base is uridine optionally substituted with halo.

11. The compound of claim 1 , wherein R x is F.

12. A compound selected from the list consisting of:

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(i2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(3,3-dimethylbutoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(benzyloxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(hexoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(cyclopentoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(benzyloxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(hexoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyluridine-5′-{N,N′-bis[(S)-1-(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyl-5′-O-(2-oxido-4-H-1,3,2-benzodioxaphosphorin-2-yl)-uridine;

4′-Vinyl-5′-O-[bis(4-methoxyphenoxy)phosphinyl] uridine;

4′-Vinyluridine-3′,5′-cyclic phosphoric acid isopropyl ester;

4′-Vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate;

4′-Vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(benzyloxycarbonyl)ethyl phosphoramidate;

4′-Vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(3,3-dimethybutoxycarbonyl)ethyl phosphoramidate;

4′-Vinyl cytidine-5′-(O-1-naphthyl-N—(S)-1-(pentoxycarbonyl)ethyl phosphoramidate;

4′-Vinyl cytidine-5′-(O-1-naphthyl-N—(S)-1-(hexoxycarbonyl)ethyl phosphoramidate;

4′-Vinyl cytidine-5′-(O-1-naphthyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl phosphoramidate;

4′-Vinylcytidine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-benzyloxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-(hexoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinylcytidine-5′-{N,N′-bis[(S)-1-(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};

4′-Vinyl-5′-O-(2-oxido-4-H-1,3,2-benzodioxaphosphorin-2-yl)-cytidine;

4′-Vinyl-5′-O-[bis(4-methoxyphenoxy)phosphinyl] cytidine;

4′-Vinylcytidine-3′,5′-cyclic phosphoric acid isopropyl ester;

4′-Vinyl adenosine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinyladenosine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinyladenosine-5′-{N,N′-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate;

4′-Vinyl-5′-O-(2-oxido-4-H-1,3,2-benzodioxaphosphorin-2-yl)-adenosine;

4′-Vinyl-5′-O-[bis(4-methoxyphenoxy)phosphinyl] adenosine;

4′-Vinyladenosine-3′,5′-cyclic phosphoric acid isopropyl ester;

4′-Vinylguanosine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinylguanosine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′-Vinylguanosine-5′-{N,N′-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate;

4′-Vinyl-5′-O-(2-oxido-4-H-1,3,2-benzodioxaphosphorin-2-yl)-guanosine;

4′-Vinyl-5′-O-[bis(4-methoxyphenoxy)phosphinyl] guanosine;

4′-Vinylguanosine-3′,5′-cyclic phosphoric acid isopropyl ester;

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-(O-1-naphthyl-N—(S)-1-(benzyloxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-{N,N′-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate};

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-{N,N′-bis[(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};

3′-Deoxy-3′-fluoro-4′-vinyluridine-5′-{N,N′-bis[(S)-1-(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-(O-1-naphthyl-N—(S)-1-(benzyloxycarbonyl)ethyl phosphoramidate;

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-{N,N′-bis[(S)-1-(propoxycarbonyl)ethyl]phosphorodiamidate};

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-{N,N′-bis[(S)-1-(2,2-dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-{N,N′-bis[(S)-1-(hexoxycarbonyl)ethyl]phosphorodiamidate}; and

3′-Deoxy-3′-fluoro-4′-vinylcytidine-5′-{N,N′-bis[(S)-1-(cyclopentoxycarbonyl)ethyl]phosphorodiamidate}.

13. A method for treating an RSV infection comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

14. A composition comprising the compound of claim 1 .

15. A composition comprising the compound of claim 12 .