2′,4′-substituted nucleosides as antiviral agents

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein:

(a) R 2 is CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;

(b) R is H, phosphate, H-phosphonate, acyl, alkyl, 0-substituted carboxyalkylamino, sulfonate ester, or benzyl, wherein the phenyl group of the benzyl is optionally substituted, a lipid, an L or D-amino acid, a carbohydrate, a peptide, or a cholesterol;

(c) R 3 is OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 1-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , or N(C 1-18 acyl) 2 ,

wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogens, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , or N(C 1-4 acyl) 2 ;

(d) R 4 is a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , an optionally substituted ethynyl, halogen, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, lower alkylamino, or di(C 1-8 alkyl)amino;

(e) R and R 3 can together form 5′,3′-cyclic phosphate;

(f) Base is a naturally occurring or modified pyrimidine base represented by the following structure:

wherein;

R 5 and R 6 , are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , alkyl of C 1 -C 6 , halogenated alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated lower alkoxy of C 1 -C 6 , 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; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, optionally substituted aryl, optionally substituted C 1 -C 4 alkylaryloxy, heteroaryl, optionally substituted C 1 -C 4 alkylheteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, or an optionally substituted fluoro C 1-20 alkyl.

2. The compound of claim 1 , wherein R 2 is F; R is H; and R 3 is OH.

3. The compound of claim 2 , wherein R 4 is a lower alkyl, CH 2 F, N 3 , halogen, alkenyl, alkynyl, or Br-vinyl.

4. The compound of claim 3 , wherein R 4 is N 3 .

5. The compound of claim 3 , wherein R 4 is a lower alkyl.

6. The compound of claim 5 , wherein R 4 is an ethyl.

7. The compound of claim 3 , wherein R 5 and R 6 , are independently H, OH, NH 2 , or alkyl of C 1 -C 6 .

8. The compound of claim 7 , wherein R 5 is NH 2 , and R 6 is H.

9. The compound of claim 4 , wherein the compound is:

10. A compound of the following formula:

or a pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable salt of a tautomer thereof, wherein:

(a) R 2 is F;

(b) R is H;

(c) R 3 is OH;

(d) R 4 is a lower alkyl, CN, vinyl, CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , an optionally substituted ethynyl, alkenyl or alkynyl;

(d) Base is a naturally occurring or modified purine base represented by the following structure:

wherein;

Z is N;

R 5 , R 6 and R 7 are independently H, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , 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.

11. The compound of claim 10 , wherein the compound is selected from the group consisting of: