Farnesyltransferase inhibitors

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein

E is a six-membered aromatic carbocyclic ring in which F and G are C;

L 1 is O;

L 2 is selected from the group consisting of a bond, C 2 alkenylene, C 2 alkynylene, O, NR 9 , C(O), S, S(O), SO 2 , SO 2 NR 9 , NR 9 SO 2 , C(O)NR 9 , NR 9 C(O), and CO 2 ;

X is NR 7 ;

R 1 is selected from the group consisting of aryl and arylalkyl;

R 2 is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, aminoalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, hydroxy, and hydroxyalkyl;

R 3 is selected from the group consisting of aryl, heterocycle, and cycloalkyl, wherein the heterocyle may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl;

R 4-6 are each independently selected from the group consisting of hydrogen, NR 9 C(O), C(O)NR 9 , alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, alkynyl, amido, amino, aminoalkyl, aminosulfonyl, aryl, arylalkyl, aryloxy, arylsulfonyl, azido, carboxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, nitroalkyl, oxo, and thio(oxo);

R 7 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, and trialkylsilyl;

R 9 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, amidoalkyl, aminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, hydroxyalkyl; and

each R 12 is independently selected from the group consisting of hydrogen, alkoxy, alkyl, amino, halo, and hydroxy;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

q is 0, 1, 2, 3 or 4.

2. A compound according to claim 1 of formula (II)

or a therapeutically acceptable salt thereof, wherein

E, F, G, L 1 , L 2 , X, R 2 ,R 3 , R 4-6 , R 12 , and p are as defined in claim 1 and

R 18 , R 19 , and R 20 are each independently selected from the group consisting of hydrogen, cyano, and halo.

3. A compound according to claim 2 wherein

L 2 is selected from the group consisting of a bond, NR 9 SO 2 , and C(O)NR 9 ;

wherein each group is drawn with its left end attached to F and its right end attached to R 3 ;

R 2 is selected from the group consisting of hydrogen and hydroxy;

R 3 is selected from the group consisting of aryl and heterocycle wherein the heterocyle may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl;

R 12 is hydrogen; and

p is 0 or 1.

4. A compound according to claim 3 wherein one of R 4-6 is cyano.

5. A compound according to claim 4 wherein

R 18 is cyano; and

R 19 and R 20 are hydrogen.

6. A compound according to claim 5 selected from the group consisting of

6-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)-3′-methoxy(1,1′-biphenyl)-3-carbonitrile;

6-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)-3′-ethoxy(1,1′-biphenyl)-3-carbonitrile;

3-(1,3-benzodioxol-5-yl)-4-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)benzonitrile;

3′-chloro-6-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)(1,1′-biphenyl)-3-carbonitrile;

N-(5-cyano-2-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)phenyl)-2-thiophenesulfonamide;

N-(5-cyano-2-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)phenyl)-4-methylbenzenesulfonamide;

5-cyano-2-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)-N-(4-methylpyridin-2-yl)benzamide;

N-(3-chlorophenyl)-5-cyano-2-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)benzamide;

4-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)-3-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)benzonitrile; and

4-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)-3-(6-propoxypyridin-3-yl)benzonitrile.

7. A compound according to claim 3 wherein one of R 4-6 is halo.

8. A compound according to claim 7 wherein R 3 is heterocycle wherein the heterocvlc may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl.

9. A compound according to claim 8 wherein

R 8 is cyano; and

R 19 and R 20 are hydrogen.

10. A compound according to claim 9 selected from the group consisting of

4-(((2-(1,3-benzodioxol-5-yl)-4-chlorobenzyl)oxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

and 4-(((4-chloro-2-(5-formyl-2-thienyl)benzyl)oxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile.

11. A compound according to claim 7 wherein R 3 is aryl.

12. A compound according to claim 11 wherein the aryl is unsubstituted or substituted with one substituent selected from the group consisting of alkanoyl, alkoxy, alkyl, amino, cyano, formyl, halo, and haloallcyl.

13. A compound according to claim 12 wherein

R 18 is cyano; and

R 19 and R 20 are hydrogen.

14. A compound according to claim 13 selected from the group consisting of

4-(((2′,5-dichloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-2′-methyl(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-2′-methoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((3′,5-dichloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′-methyl(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′-(trifluoromethyl)(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′-methoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′-fluoro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((4′,5-dichloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((4-chloro-2-(1-naphthyl)benzyl)oxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((3′-amino-5-chloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

3′-chloro-6′-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)(1,1′-biphenyl)-3-carbonitrile;

4-(((2′-acetyl-5-chloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((4′-acetyl-5-chloro(1,1′-bipbenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((4′-tert-butyl-5-chloro(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′-ethoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazoi-5-yl)methyl)benzonitrile;

N-(5′-chloro-2′-(((4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy)methyl)(1,1′-biphenyl)-3-yl)acetamide;

4-(((5-chloro-4′-(trifluoromethyl)(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile; and

4-(((5-chloro-3′-formyl(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile.

15. A compound according to claim 11 wherein the aryl is substituted with two or three substituents independently selected from the group consisting of alkoxy, alkyl, and halo.

16. A compound according to claim 15 wherein

R 18 is cyano; and

R 19 and R 20 are hydrogen.

17. A compound according to claim 16 selected from the group consisting of

4-(((5-chloro-3∝,4′-dimethyi(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-2′,5′-dimethoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′,4′-dimethoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-(((5-chloro-3′,4′,5′-trimethoxy(1,1′-biphenyl)-2-yl)methoxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile;

4-((1-methyl-1H-imidazol-5-yl)((2′,3′,5-trichloro(1,1′-biphenyl)-2-yl)methoxy)methyl)benzonitrile;

4-((1-methyl-1H-imidazol-5-yl)((3′,5,5′-trichloro(1,1′-biphenyl)-2-yl)methoxy)methyl)benzonitrile; and

4-((1-methyl-1H-imidazol-5-yl)((3′,4′,5-trichloro(1,1′-biphenyl)-2-yl)methoxy)methyl)benzonitrile.

18. A compound according to claim 1 of formula (III)

or a therapeutically acceptable salt thereof, wherein

L 1 , X, and R 2 axe as defined in claim 1 ; and

R 21 is selected from the group consisting of aryl and heterocycle wherein the heterocyle may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl.

19. A compound according to claim 18 wherein

L 1 is O;

X is NR 7 ; and

R 2 is selected from the group consisting of amino, halo and hydroxy.

20. A compound according to claim 19 wherein

R 2 is hydroxy; and

R 21 is aryl.

21. A compound according to claim 20 selected from the group consisting of

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-methoxy-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′,4′-difluoro-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile;

3′-chloro-6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-fluoro-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′,5′-difluoro-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile;

3′,4′-dichloro-6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile;

3′,5′-dichloro-6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-fluoro-1,1′-bipbenyl-3-carbonitrile;

3′-chloro-6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile;

4-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3-(1-naphthyl)benzonitrile; and

(S)-6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile.

22. A compound according to claim 19 wherein

R 2 is hydroxy; and

R 21 is heterocycle wherein the heterocyle may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl.

23. A compound a ccording to claim 22 selected from the group consisting of

3-(1,3-benzodioxol-5-yl)-4-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)benzonitrile;

4-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3-quinolin-8-ylbenzonitrile; and

4-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)benzonitrile.

24. A compound according to claim 19 wherein

R 2 is halo; and

R 21 is aryl.

25. A compound according to claim 24 selected from the group consisting of

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-methoxy-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′,4′-difluoro-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile;

3′-chloro-6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-fluoro-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′,5′-difluoro1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile;

3′,4′-dichloro-6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile;

3′,5′-dichloro-6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile;

6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3′-fluoro-1,1′-biphenyl-3-carbonitrile; and

3′-chloro-6-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-1,1′-biphenyl-3-carbonitrile.

26. A compound according to claim 19 wherein

R 2 is halo; and

R 21 is heterocycle wherein the heterocyle may be substituted or unsubstituted and is selected from the group consisting of benzodioxolyl, thiophenyl, quinolinyl, pyridinyl, and dihydropyridinyl.

27. A compound according to claim 26 selected from the group consisting of

3-(1,3-benzodioxol-5-yl)-4-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)benzonitrile;

4-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3-quinolin-8-ylbenzonitrile; and

4-(2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)benzonitrile.

28. A compound according to claim 19 wherein

R 2 is amino; and

R 21 is aryl.

29. A compound according to claim 28 which is

6-(2-amino-2-(4-cyanophenyl)-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile.

30. A compound which is

6-(2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile.

31. A compound which is

6-((2S)-2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethoxy)-4′-(trifluoromethoxy)-1,1′-biphenyl-3-carbonitrile.

32. A pharmac eutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.

33. A method for reducing tumor size by inhibiting farnesyltransferase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1 , or a therapeutically acceptable salt thereof.

34. A method for treating cancer by inhibiting farnesyltransferase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1 , or a therapeutically acceptable salt thereof.