Granted Patent B2

US 8,329,727 · App. 12/577,865 · Granted Dec 11, 2012

Assignees: Gilead Sciences, Inc.; K.U. Leuven Research & Development; Gerhard Puerstinger

Abstract

Claims (76)

1. A method of treating a viral infection from a virus belonging to the family of the Flaviviridae or the Picornaviridae, said method comprising administering to a subject in need of treatment an anti-virally effective amount of (i) a compound having the structural formula (A),

wherein:

the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3 double bonds;

R 1 is selected from the group consisting of aryl, heterocycle, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, C 1 -C 10 alkyl-amino, C 1 -C 10 dialkylamino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each is optionally substituted with one or more R 6 ;

Y is selected from a single bond, O, S(O) m , NR 11 , C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene, wherein each alkylene, alkenylene or alkynylene optionally includes 1 to 3 heteroatoms selected from O, S or N;

R 2 and R 4 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═S)R 9 , —SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, and heterocycle, or when one of R 25 or R 26 is present, R 2 or R 4 is selected from the group consisting of (═O), (═S), and ═NR 27 ;

X is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene and C 2-10 alkynylene, where each optionally includes one or more heteroatoms selected from the group consisting of O, S, or N, provided any such heteroatom is not adjacent to the N in the imidazopyridyl ring;

m is any integer from 0 to 2;

R 3 is a heterocycle substituted with one or more R 17 , provided that R 3 optionally substituted with at least one R 17 is not pyridinyl or 5-chlorothienyl;

R 5 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═O)R 9 , —C(═S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, and heterocycle;

each R 6 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —CO 2 R 18, —NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, —C(═O)R 18 , —C(═S)R 18 , —SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C 1-18 )alkyl, aryl(C 1-18 )alkyloxy, aryl(C 1-18 )alkylthio, heterocycle and C 1-18 hydroxyalkyl, where each is optionally substituted with one or more R 19 ;

R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocycle, —C(═O)R 12 ; —C(═S) R 12 , and an amino acid residue linked through a carboxyl group thereof, or R 7 and R 8 are taken together with the nitrogen to form a heterocycle;

R 9 and R 18 are independently selected from the group consisting of hydrogen, —OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —NR 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, —CH 2 OCH(═O)R 9a , and —CH 2 OC(═)OR 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;

R 11 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C(═)R 12 , heterocycle, and an amino acid residue;

R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;

R 15 and R 16 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;

each R 17 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 2-18 halogenated alkenyl, C 2-18 halogenated alkynyl, C 2-18 halogenated alkoxy, C 1-18 halogenated alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, NO 2 , NR 7 R 8 , haloalkyl, C(═)R 18 , C(═S)R 18 , SH, aryl, aryloxy, arylthio, CO 2 H, CO 2 R 18 , arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocyclic, and C 1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, C 1-18 hydroxyalkyl, arylsulfoxide, arylsulfone, or arylsulfonamide is optionally substituted with one or more R 19 ;

each R 19 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C(═O)R 18 , —C(═S )R 18 , -OalkenylC(═O)OR 18 , -OalkylC(═O)NR 20 R 21 , -OalkylOC(═O)R 18 , —C(═S)R 18 , SH, —C(═O)N(C 1-6 alkyl), —N(H)S(O)(O)(C 1-6 alkyl), aryl, heterocycle, C 1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C 1-18 )alkyloxy, aryloxy, aryl(C 1-18 alkyl)oxy, arylthio, aryl(C 1-18 )alkylthio and aryl(C 1-18 )alkyl, where each is optionally substituted with 1 or more ═O, —NR 20 R 21 , —CN, C 1-18 alkoxy, heterocycle, C 1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R 17 by alkyl, alkoxyalkoxy or halogen;

R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C(═O)R 12 , carboxylester-substituted heterocycle, and —C(═S)R 12 ;

R 25 and R 26 are not present, or are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, aryl and heterocycle, where each is optionally independently substituted with 1 to 4 of C 1-6 alkyl, C 1-6 alkoxy, halo, —CH 2 OH, benzyloxy, and —OH; and

R 27 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)—C 1-6 alkyl, aryl, and aryl(C 1-18 )alkyl; and salts, tautomers, and stereoisomers thereof;

or (ii) a compound having the structural formula (C),

wherein:

R 1 is selected from the group consisting of aryl, heterocycle, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, C 1 -C 10 alkyl-amino, C 1 -C 10 dialkylamino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each is optionally substituted with one or more R 6 ;

Y is selected from a single bond, O, S(O) m , NR 11 , C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene, wherein each alkylene, alkenylene or alkynylene optionally includes 1 to 3 heteroatoms selected from O, S or N;

R 2 and R 4 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═S)R 9 , —SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, and heterocycle;

X is selected from the group consisting of C 1 -C 10 alkylene, C 2-10 alkenylene and C 2-10 alkynylene, where each optionally includes one or more heteroatoms selected from the group consisting of O, S, or N, provided any such heteroatom is not adjacent to the N in the imidazopyridyl ring;

m is any integer from 0 to 2;

R 3 is aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl,)aryl-N(R 10 )—, or heterocycle, each of which is optionally substituted with one or more R 17 , provided that for cycloalkenyl the double bond is not adjacent to a nitrogen, provided M-Q-R 3 is not biphenyl, and provided that R 3 substituted with at least one R 17 is not pyridinyl or 5-chlorothienyl;

R 5 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C(═O)R 9 , —C(═O)OR 9 , —C(═S)R 9 , —SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, and heterocycle;

each R 6 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —CO 2 R 18 , —NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, —C(═O)R 18 , —C(═S)R 18 , —SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C 1-18 )alkyl, aryl(C 1-18 )alkyloxy, aryl(C 1-18 )alkylthio, heterocycle and C 1-18 hydroxyalkyl, where each is optionally substituted with one or more R 19 ;

R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocycle, —C(═O)R 12 ; —C(═S) R 12 , and an amino acid residue linked through a carboxyl group thereof, or R 7 and R 8 are taken together with the nitrogen to form a heterocycle;

R 9 and R 18 are independently selected from the group consisting of hydrogen, —OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —NR 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, —CH 2 OCH(═O)R 9a , and —CH 2 OC(═O)OR 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;

R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C(═O)R 12 , heterocycle, and an amino acid residue;

R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;

R 15 and R 16 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and an amino acid residue;

each R 17 is independently MQ- wherein M is a ring optionally substituted with one or more R 19 , and Q is a bond or a linking group connecting M to R 3 that has 1 to 10 atoms and is optionally substituted with one or more R 19 ;

each R 19 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C(═O)R 18 , —C(═O)OR 18 , -OalkenylC(═O)OR 18 , -OalkylC(═O)NR 20 R 21 , -OalkylOC(═O)R 18 , —C(═S)R 18 , —SH, —C(═O)N(C 1-6 alkyl), —N(H)S(O)(O)(C 1-6 alkyl), aryl, heterocycle, C 1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C 1-18 )alkyloxy, aryloxy, aryl(C 1-18 alkyl)oxy, arylthio, aryl(C 1-18 )alkylthio and aryl(C 1-18 )alkyl, where each is optionally substituted with 1 or more ═O, —NR 20 R 21 , —CN, C 1-18 alkoxy, heterocycle, C 1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R 17 by alkyl, alkoxyalkoxy or halogen;

R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C(═O)R 12 , and —C(═S)R 12 ; and

salts, tautomers, and stereoisomers thereof.

2. The method of claim 1 , wherein the viral infection is an infection of a hepatitis-C virus.

3. The method of claim 1 , further comprising administering at least one additional antiviral therapy to the subject.

4. The method of claim 3 , wherein the additional therapy is selected from the group consisting of an interferon alpha and ribavirin.

5. The method of claim 1 , wherein the viral infection is an infection from a Coxsackie virus.

6. The method of claim 1 , wherein the viral infection is an infection from a Bovine Viral Diarrhea Virus.

7. The method of claim 1 , wherein the compound of formula (A) is administered.

8. The method of claim 7 , wherein, in the compound of formula (A), R 3 is isoxazolyl substituted with one to three R 17 .

9. The method of claim 7 , wherein, in the compound of formula (A), YR 1 is halophenyl or halomethyl-substituted phenyl.

10. The method of claim 9 , wherein halophenyl is ortho-fluorophenyl.

11. The method of claim 7 , wherein, in the compound of formula (A), R 17 is aryl or a heterocycle further substituted with 1, 2 or 3 R 19 .

12. The method of claim 7 , wherein, in the compound of formula (A), YR 1 is not an unsubstituted C 3-10 cycloalkyl.

13. The method of claim 7 , wherein, in the compound of formula (A), R 19 is trihalomethyl, trihalomethoxy, alkoxy or halogen.

14. The method of claim 7 , wherein, in the compound of formula (A), R 1 is aryl or aromatic heterocyle substituted with 1, 2 or 3 R 6 and wherein R 6 is halogen, C 1-18 alkoxy or C 1-18 haloalkyl.

15. The method of claim 7 , wherein, in the compound of formula (A), Y is a bond.

16. The method of claim 7 , wherein, in the compound of formula (A), X is selected from the group consisting of —CH 2 —, —CH(CH 3 )—,—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 , —(CH 2 ) 2-4 —O—(CH 2 ) 2-4 —, —(CH 2 ) 2-4 S—(CH 2 ) 2-4 —,—(CH 2 ) 2-4 —NR 10 —(CH 2 ) 2-4 ), C 3-10 cycloalkylidene, C 2-6 alkenylene and C 2-6 alkynylene, wherein R 1  is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C(═O)R 12 , heterocyclic, and an amino acid residue.

17. The method of claim 7 , wherein, in the compound of formula (A), X is methylene.

18. The method of claim 7 , wherein, in the compound of formula (A), R 3 is a heterocycle substituted with 0 to 3 R 17 .

19. The method of claim 18 , wherein the R 3 is an aromatic heterocycle.

20. The method of claim 19 , wherein the heterocycle contains 1, 2 or 3 N, S or O atoms in the ring, is linked to X through a ring carbon atom and contains 4 to 6 total ring atoms.

21. The method of claim 7 , wherein, in the compound of formula (A), R 17 is selected from the group consisting of C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy; arylalkylthio and heterocycle, each being unsubstituted or substituted with 1 or more R 19 .

22. The method of claim 7 , wherein, in the compound of formula (A), R 9 and R 18 are H, OH or alkyl.

23. The method of claim 7 , wherein, in the compound of formula (A), R 5 is H.

24. The method of claim 7 , wherein, in the compound of formula (A), R 6 is halogen.

25. The method of claim 7 , wherein, in the compound of formula (A), R 7 , R 8 , R 11 , R 15 ,R 16 ,R 20 and R 21 are independently H or C 1-18 alkyl.

26. The method of claim 7 , wherein, in the compound of formula (A), R 12 is alkyl.

27. The method of claim 7 , wherein, in the compound of formula (A), R 19 is selected from the group consisting of H; C 1-18 alkyl; C 2-18 alkenyl; C 2-18 alkynyl; C 1-18 alkoxy; alkenyloxy; alkynyloxy; C 1-18 alkylthio; C 3-10 cycloalkyl; C 4-10 cycloalkenyl; C 4-10 cycloalkynyl; halogen; OH; CN; cyanoalkyl; NO 2 ; NR 20 R 21 ; haloalkyl; haloalkyloxy; C(═O)R 18 ; C(═O)OR 18 ; OalkenylC(═O)OR 18 ; -OalkylC(═O)NR 20 R 21 ; aryl; heterocycle; -OalkylOC(═O)R 18 ; C(═O)N(C 1-6 alkyl), N(H)S(O)(O)(C 1-6 alkyl); arylalkyloxy; aryloxy; arylalkyloxy; and arylalkyl; each of which is unsubstituted or substituted with 1 or more ═O; NR 20 R 21 ; CN; alkoxy; heterocycle; C 1-18 haloalkyl; heterocycle alkyl; heterocycle linked to R 17 by alkyl; alkoxyalkoxy or halogen.

28. The method of claim 27 , wherein R 19 is independently selected from the group consisting of halogen, NR 20 R 21 , alkoxy, haloalkyl and haloalkyloxy.

29. The method of claim 7 , wherein, in the compound of formula (A), R 25 and R 26 are not present.

30. The method of claim 7 , wherein, in the compound of formula (A), haloalkyl or haloalkyloxy is —CF 3 or —OCF 3 .

31. The method of claim 7 , wherein, in the compound of formula (A), Y is a single bond, and R 1 is phenyl.

32. The method of claim 1 , wherein the compound of formula (C) is administered.

33. The method of claim 32 , wherein, in the compound of formula (C), Y is a single bond, and R 1 is aryl.

34. The method of claim 32 , wherein, in the compound of formula (C), X is C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene.

35. The method of claim 32 , wherein, in the compound of formula (C), R 3 is a heterocyle.

36. The method of claim 32 , wherein, in the compound of formula (C), R 3 is a heterocycle substituted with R 17 where Q is a bond and M is aryl.

37. The method of claim 32 , wherein, in the compound of formula (C), R 3 is isoxazole substituted with R 17 where Q is a bond and M is aryl.

Assignments (9)

Continuity (8)