4′-difluoromethyl substituted nucleoside derivatives as inhibitors of influenza RNA replication

1. A compound of Formula I

wherein:

Y is H or P(═X)(R′)(R);

R is O—R 1 or NHR 1′ ;

R 1′ is —C(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 H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthylenyl, 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)methyl, (1H-indol-4-yl)methyl, —(CH2) m C(═O)R 1b , aryl and aryl lower alkyl, wherein aryl is 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, phenyl or phenyl lower alkyl, wherein phenyl and phenyl lower alkyl are optionally substituted with lower alkoxy;

 or one 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 ;

R w , R y , and R z are each independently H, OH or F;

R x is H, OH, or F;

or one R 3 and R x together form a bond;

or R 1 and R x together form a bond; and

X is O or S;

or a pharmacologically acceptable salt thereof.

2. The compound of claim 1 , wherein R W is H, R y is H, R x is OH, and R z is OH.

3. The compound of claim 1 , wherein R W is H, R y is OH, R x is OH, and R z is H.

4. The compound of claim 1 , wherein R W is H, R y is F, R x is OH, and R z is H.

5. The compound of claim 1 , wherein R W is H, R y is OH, R x is OH, and R z is H.

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

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

8. The compound of claim 1 , wherein R is O—R 1 , and R 1 is naphthylenyl.

9. 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.

10. A method of treating Influenza comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

11. A composition comprising the compound of claim 1 , admixed with at least one carrier, diluent or excipient.

12. A composition comprising the compound of claim 1 in combination with one or more antiviral compounds.

13. A composition comprising the compound of claim 1 in combination with one or more anti-Influenza compounds.

14. A composition comprising the compound of claim 1 in combination with one or more antiviral compounds, admixed with at least one carrier, diluent or excipient.

15. A composition comprising the compound of claim 1 in combination with one or more anti-Influenza compounds, admixed with at least one carrier, diluent or excipient.

16. A method of treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

17. A method for treating an Influenza infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I

wherein:

Y is H or P(═X)(R′)(R);

R is O—R 1 or NHR 1′ ;

R 1′ is —C(R 2a )(R 2b )C(═)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 H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthylenyl, 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)methyl, (1H-indol-4-yl)methyl, —(CH2) m C(═O)R 1b , aryl and aryl lower alkyl, wherein aryl is 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, phenyl or phenyl lower alkyl, wherein phenyl and phenyl lower alkyl are optionally substituted with lower alkoxy;

 or one 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 ;

R w , R y , and R z are each independently H, OH or F;

R x is H, OH, or F;

or one R 3 and R x together form a bond;

or R 1 and R x together form a bond; and

X is O or S;

or a pharmacologically acceptable salt thereof.

18. A compound of claim 1 , wherein the compound of formula I is selected from the group consisting of:

(2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(difluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol;

(2R,3R,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(difluoromethyl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol;

(2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(difluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; and

(2R,3R,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(difluoromethyl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol.

19. A method for treating an Influenza infection comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 18 .