Nucleosides with antiviral and anticancer activity

1. A compound of formula 1:

wherein:

R 1 is guanine, cytosine, thymine, 3-deazaadenine, or uracil;

R 2 is hydroxy;

R 6 is hydrogen or (C 1 -C 6 )alkyl;

R 3 is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl, or 2-cyanoethyl;

R 5 is NR a R b ;

R 7 is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;

X is oxy, thio, or methylene;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a and R b , together with the nitrogen to which they are attached form a nitrogen-linked Het;

each R w is independently hydrogen or (C 1 -C 6 )alkyl;

R x and R y are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, phenethyl, or (C 1 -C 6 )alkanoyl; or R x and R y together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;

R z is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R aa and R ab are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; or R aa and R ab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;

R ac is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ad is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ae is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

wherein any (C 1 -C 6 )alkyl of R a and R b is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

and wherein any aryl or Het may optionally be substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is guanine.

3. The compound of claim 1 wherein R 5 is NR a R b , wherein R a is phenylmethyl and R b is hydrogen.

4. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl.

5. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, cyano, aryl, or Het.

6. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more aryl or Het.

7. The compound of claim 6 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl, naphthyl, pyridyl, indolyl, isoindolyl, furyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, imidazolyl, thiazoyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino ring, which ring is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino.

8. The compound of claim 6 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl or indolyl ring, which ring is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino.

9. The compound of claim 6 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl ring.

10. The compound of claim 1 wherein R a is phenylmethyl, phenethyl, indolylmethyl, or 2-indolylethyl.

11. The compound of claim 1 wherein R b is hydrogen.

12. The compound of claim 1 wherein R 3 is hydroxy.

13. The compound of claim 1 wherein R 4 is methyl or ethyl.

14. The compound of claim 1 wherein R 7 is hydrogen or (C 1 -C 6 )alkyl.

15. The compound of claim 1 wherein:

R 2 is hydroxy;

R 6 is hydrogen or (C 1 -C 6 )alkyl;

R 3 is hydroxy;

R 7 is hydrogen or (C 1 -C 6 )alkyl;

R a is (C 1 -C 6 )alkyl substituted with a phenyl ring; and

R b is hydrogen.

16. The compound of claim 1 wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R a , R b , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl.