IP Library › Granted Patent US 7,524,849

Granted Patent B2

US 7,524,849 · App. 10/950,375 · Granted Apr 28, 2009

5-arylpyrimidines as anticancer agents

Assignee: Wyeth Holdings Corporation

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Patent No.: US 7,524,849
App. No.: 10/950,375
Granted: Apr 28, 2009
Kind: B2

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Abstract

This invention relates to certain 5-arylpyrimidine compounds or a pharmaceutically acceptable salt thereof, and compositions containing said compounds or a pharmaceutically acceptable salt thereof, wherein said compounds are anti-cancer agents useful for the treatment of cancer in mammals. This invention further relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal and further provides a method for the treatment or prevention of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR, in a mammal in need thereof which method comprises administering to said mammal an effective amount of said compounds or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by promotion of microtubule polymerization which comprises administering to said mammal an effective amount of said compounds and pharmaceutically acceptable salts thereof.

Claims (556)

1. A compound of Formula (I)

wherein:

Z is selected from:

and C 6 -C 8 cycloalkyl;

R is a moiety

n is an integer of 2, 3, or 4;

L 1 and L 2 , are each independently H, F, Cl or Br;

L 3 and L 4 are H;

X is Cl or Br;

Y is O, S, or —NR 2 ;

Q is OH or —NR 3 R 4 ;

R 1 is H or C 1 -C 3 alkyl;

R 2 is H or C 1 -C 3 alkyl;

R 3 and R 4 are each independently H or C 1 -C 3 alkyl; or R 3 and R 4 when optionally taken together with the nitrogen atom to which each is attached form a saturated 4 to 6 member heterocyclic ring which contains 1-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms within the ring where said ring is optionally substituted with R 7 ;

R 5 is CF 3 or C 2 F 5 ;

W′ is —NHR 6 , —N(CN)R 6 , aryl of 6 to 12 carbon atoms optionally substituted with 1-3 groups independently selected from halogen, azido, nitro, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, formyl, C 1 -C 3 alkoxycarbonyl, carboxyl, C 1 -C 3 alkanoyl, C 1 -C 3 alkylthio, C 1 -C 3 alkylamido, phenyl, phenoxy, benzyl, benzoxy, furyl, and cyclopropyl groups; or heteroaryl of 5 to 10 ring atoms having from 1 to 4 heteroatoms selected from S, O and N and optionally substituted with 1-3 groups independently selected from halogen, azido, nitro, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, formyl, C 1 -C 3 alkoxycarbonyl, carboxyl, C 1 -C 3 alkanoyl, C 1 -C 3 alkylthio, C 1 -C 3 alkylamido, phenyl, phenoxy, benzyl, benzoxy, furyl, and cyclopropyl groups;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein Formula (I) is represented by formula (Ia)

or pharmaceutically acceptable salts thereof.

3. A compound according to claim 1 , wherein Formula (I) is represented by formula (Ib)

or pharmaceutically acceptable salts thereof.

4. A compound according to claim 1 wherein R is

or pharmaceutically acceptable salts thereof.

5. A compound according to claim 1 wherein Z is C 6 -C 8 cycloalkyl or pharmaceutically acceptable salts thereof.

6. A compound according to claim 2 wherein

R is the moiety:

n=3;

R 1 is H or methyl;

R 5 is CF 3 ;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is F;

L 3 is H;

L 4 is H;

X is Cl;

Y is O;

W′ is N-methylamino, N-methylcyanamido, 1-pyrazolyl, 2-pyrazinyl, 2-pyridyl, 2-pyrimidinyl, or 3-isoquinolinyl groups

or pharmaceutically acceptable salts thereof.

7. A compound according to claim 3 wherein:

R is the moiety:

n=3;

R 1 is H or methyl;

R 5 is CF 3 ;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is F;

L 3 is H;

L 4 is H;

X is Cl;

Y is O;

W′ is N-methylamino, N-methylcyanamido, 1-pyrazolyl, 2-pyrazinyl, 2-pyridyl, 2-pyrimidinyl, or 3-isoquinolinyl groups

or pharmaceutically acceptable salts thereof.

8. A compound according to claim 5 wherein

R is the moiety:

n=3;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is F;

L 3 is H;

L 4 is H;

X is Cl;

Y is O;

W′ is N-methylamino, N-methylcyanamido, 1-pyrazolyl, 2-pyrazinyl, 2-pyridyl, 2-pyrimidinyl, or 3-isoquinolinyl groups

or pharmaceutically acceptable salts thereof.

9. The compound according to claim 1 , 4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide or pharmaceutically acceptable salts thereof.

10. The compound according to claim 1 , 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N 2 -methyl-N 4 -(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine or pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , (4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide or pharmaceutically acceptable salts thereof.

12. The compound according to claim 1 , 4-chloro-5-{4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide or pharmaceutically acceptable salts thereof.

13. The compound according to claim 1 , {4-chloro-5-{4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}methylcyanamide or pharmaceutically acceptable salts thereof.

14. The compound according to claim 1 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

15. The compound according to claim 1 , 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

16. The compound according to claim 1 , 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)-2,2′-bipyrimidin-4-amine or pharmaceutically acceptable salts thereof.

17. The compound according to claim 1 , 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

18. The compound according to claim 1 , 6-chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

19. The compound according to claim 1 , N-{3-[4-(4-chloro-6-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}-N-methylamine or pharmaceutically acceptable salts thereof.

20. The compound according to claim 1 , 6-chloro-5-{4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

21. The compound according to claim 1 , 6-chloro-5-{4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

22. The compound according to claim 1 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

23. The compound according to claim 1 , 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-quinolin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

24. The compound according to claim 1 , 2-(5-Azidopyridin-2-yl)-6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine; or pharmaceutically acceptable salts thereof.

25. The compound according to claim 2 , (4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[(1S)-2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide or pharmaceutically acceptable salts thereof.

26. The compound according to claim 2 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

27. The compound according to claim 2 , 6-chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

28. The compound according to claim 2 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

29. The compound according to claim 3 , (4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[(1R)-2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide or pharmaceutically acceptable salts thereof.

30. The compound according to claim 3 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

31. The compound according to claim 3 , 6-chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[(1R)-2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

32. The compound according to claim 3 , 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

33. A compound of Formula (I)

wherein:

Z is:

R is a moiety

n is an integer of 2, 3, or 4;

L 1 and L 2 , are each independently H, F, Cl or Br;

L 3 and L 4 are H;

X is Cl or Br;

Y is O, S, or —NR 2 ;

Q is OH or —NR 3 R 4 ;

R 1 is H or C 1 -C 3 alkyl;

R 2 is H or C 1 -C 3 alkyl;

R 5 is CF 3 or C 2 F 5 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof

produced by the process which comprises the step of reacting a compound of the formula

where A is a leaving group with a compound of the formula HY—(CH 2 ) n Q in the presence of a strong base optionally in the presence of an aprotic solvent to give a compound of Formula (I).

34. A compound produced by the process according to claim 33 wherein the leaving group A is F and Y is O.

35. A compound produced by the process according to claim 33 wherein the strong base is selected from an alkali metal hydroxide, alkali metal carbonate and alkali hydride.

36. A process for the preparation of a compound of Formula (I)

wherein:

Z is:

R is a moiety

n is an integer of 2, 3, or 4;

L 1 and L 2 , are each independently H, F, Cl or Br;

L 3 and L 4 are H;

X is Cl or Br;

Y is O, S, or —NR 2 ;

Q is OH or —NR 3 R 4 ;

R 1 is H or C 1 -C 3 alkyl;

R 2 is H or C 1 —C 3 alkyl;

R 5 is CF 3 or C 2 F 5 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof;

comprising the step of reacting a compound of the formula

where A is a leaving with a compound of the formula HY—(CH 2 ) n Q in the presence of a strong base optionally in the presence of an aprotic solvent to give a compound of Formula(I).

37. A process according to claim 36 wherein the leaving group A is F and Y is O.

38. A process according to claim 36 wherein the strong base is selected from an alkali metal hydroxide, alkali metal carbonate and alkali hydride.

39. A process according to claim 36 wherein the aprotic solvent is selected from dimethylsulfoxide and dimethylformamide.

40. A process according to claim 36 wherein the aprotic solvent is selected from dimethylsulfoxide and dimethylformamide.

41. A pharmaceutical composition which comprises an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

42. A method of treating non-small cell lung carcinoma in a mammal by administering an effective amount of a compound of Formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof.

43. A method of treating colon carcinoma in a mammal by administering an effective amount of a compound of Formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof.

44. A method of treating glioblastoma in a mammal by administering an effective amount of a compound of Formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof.

45. A method of treating non-small cell lung carcinoma in a mammal in need thereof by administering an effective amount of a compound of formula (II):

wherein:

Z is selected from:

and C 6 -C 8 cycloalkyl;

R is a moiety

X is Cl or Br;

L 1 , L 2 , L 3 and L 4 are each independently H, F, Cl or Br;

A is H, F, Cl, Br, or Y(CH 2 ) n Q;

Y is O, S, or —NR 2 ;

n is an integer of 2, 3, or 4;

Q is OH or —NR 3 R 4 ;

R 1 is H or C 1 -C 3 alkyl;

R 2 is H or C 1 -C 3 alkyl;

R 5 is CF 3 or C 2 F 5 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

46. A method according to claim 45 wherein formula II is represented by formula IIa

or pharmaceutically acceptable salts thereof.

47. A method according to claim 45 wherein formula II is represented by formula IIb

or pharmaceutically acceptable salts thereof.

48. A method according to claim 45 wherein R is

or pharmaceutically acceptable salts thereof.

49. A method according to claim 46 wherein:

R is a moiety

n=3;

Y is O;

Q is —NR 3 R 4 ;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

50. A method according to claim 47

R is a moiety

n=3;

Y is O;

Q is —NR 3 R 4 ;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

51. A method according to claim 46

wherein:

R is a moiety

A is F;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

52. A method according to claim 47

wherein:

R is a moiety

A is F;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

53. A method according to claim 46 wherein compounds are selected from

4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide,

4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl]ethylcyanamide,

6-Chloro-2-pyrazin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)-2,2′-bipyrimidin-4-amine,

6-Chloro-2-pyridin-4-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyridin-3-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyridin-2-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyridin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-quinolin-2-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-isoquinolin-1-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-isoquinolin-3-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-thien-2-yl-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(2-furyl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrazol-1-yl)-N-[2,2,2-trifluoro-1-methylethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrrol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

4-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide,

6-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N 2 -methyl-N 4 -(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine,

(4-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide,

4-Chloro-5-{4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide, {4-Chloro-5-{4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}methylcyanamide,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine,

6-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine,

6-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)-2,2′-bipyrimidin-4-amine,

6-Chloro-5-{4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine,

6-Chloro-5-{4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl}-2-pyrazin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine,

6-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-quinolin-2-yl-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine,

6-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine,

6-Chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine,

N-{3-[4-(4-Chloro-6-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}-N-methylamine,

6-Chloro-2-(1-methyl-1H-imidazol-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(4-methylpyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(5-nitropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine and

2-(5-Azidopyridin-2-yl)-6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine

or pharmaceutically acceptable salts thereof.

54. A method according to claim 46 wherein the compounds are selected from:

6-Chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyridin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrazol-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

(4-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[(1S)-2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine and

6-Chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine; or pharmaceutically acceptable salts thereof.

55. A method according to claim 47 wherein the compounds are selected from:

6-Chloro-2-pyrazin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-pyridin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

6-Chloro-2-(1H-pyrazol-1-yl)-N-[(1R)-2,2,2-trifluoro-1-methylethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine,

(4-Chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-{[(1R)-2,2,2-trifluoro-1-methylethyl]amino}pyrimidin-2-yl)methylcyanamide,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine,

6-Chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyridin-2-yl-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine and

6-Chloro-5-{2,6-difluoro-4-[3-(dimethylamino)propoxy]phenyl}-2-(1H-pyrazol-1-yl)-N-[(1R)-2,2,2-trifluoro-1-methylethyl)pyrimidin-4-amine or pharmaceutically acceptable salts thereof.

56. A method of treating colon carcinoma in a mammal by administering an effective amount of a compound of formula (II):

wherein:

Z is selected from:

and C 6 -C 8 cycloalkyl;

R is a moiety

X is Cl or Br;

L 1 , L 2 , L 3 and L 4 are each independently H, F, Cl or Br;

A is H, F, Cl, Br, or Y(CH 2 ) n Q;

Y is O, S, or —NR 2 ;

n is an integer of 2, 3, or 4;

Q is OH or —NR 3 R 4 ;

R 1 is H or C 1 -C 3 alkyl;

R 5 is CF 3 or C 2 F 5 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

57. A method according to claim 56 wherein formula II is represented by formula IIa

or pharmaceutically acceptable salts thereof.

58. A method according to claim 56 wherein formula II is represented by formula IIb

or pharmaceutically acceptable salts thereof.

59. A method according to claim 56 wherein R is

or pharmaceutically acceptable salts thereof.

60. A method according to claim 57 wherein:

R is a moiety

n=3;

Y is —O—;

Q is —NR 3 R 4 ;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

61. A method according to claim 58

R is a moiety

n=3;

Y is O;

Q is —NR 6 R 7 ;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

R 7 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

62. The method according to claim 57

wherein:

R is a moiety

A is F;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

63. The method according to claim 58

wherein:

R is a moiety

A is F;

R 1 is H or methyl;

R 5 is CF 3 ;

R 6 is C 1 -C 3 alkyl;

L 1 is F;

L 2 is H or F;

L 3 is H;

L 4 is H;

X is Cl or Br;

or pharmaceutically acceptable salts thereof.

64. A method according to claim 56 wherein compounds are selected from