Pyrimidine-2,4-diamines and their uses

1. A compound of formula (I)

or a salt or N-oxide thereof;

wherein R 3 is aryl or heteroaryl, each optionally substituted; X 3 and X 4 are

independently CH or N;

X 5 is selected from the group consisting of CR 12 R 13 , O, S, SO, SO 2 , and NR 14 wherein R 12 and R 13 are independently selected from H, OH, and lower alkyl, or together form an oxo group;

R 4 is selected from the group consisting of OH, acyl, formyl, sulfonyl, alkoxy, carboxylate, haloalkyl, halogen, cyano, nitro, trifluoromethoxy, difluoromethoxy, and fluoromethoxy;

R′, R 5 , R 6 and R 14 are independently selected from the group consisting of H, lower alkyl, R p , cycloalkyl and aryl, and wherein at least one of R′, R 5 , R 6 and R 14 is R p linked via —C(O)O—, —C(S)O—, -C(O)S—, —C(S)S—, —C(O)NH— or —C(S)NH—;

R p is —(CR 1 R 2 ) n —R;

R is selected from the group consisting of acetate, amino, dialkylamino, —C(O)OH, alkyl, allyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, phenylalkaryl and heteroarylalkyl, each of which is optionally substituted;

R 1 and R 2 are each independently selected from the group consisting of H, OH, —OR 11 , NR 15 R 15 , halo, lower alkyl, C(O)O-alkyl, —C(O)OH, —OP(═O)(OR 11 ) 2 , —OC(═O)OR 11 , —OC(═O)R 11 , cycloalkyl, aryl, and heteroaryl or together form an oxo, wherein each R 15 is independently selected from the group consisting of H, lower alkyl, prenyl, allyl, —C(O))-alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl, or two of R 15 combine to form an optionally substituted cycloheteroalkyl;

each R 11 is independently H or lower alkyl;

n is an integer from 0 to 10;

R 7 and R 8 are independently selected from the group consisting of H, halogen, lower alkyl, cycloalkyl, aryl, and heteroaryl; and

R 9 and R 10 are independently selected from the group consisting of H, halogen, —OH, -alkoxy, lower alkyl, cycloalkyl, aryl, and heteroaryl wherein R 7 and R 8 , or R 9 and R 10 together form an oxo group, and wherein R 9 or R 10 are not —OH or alkoxy when X 5 is NR 14 .

2. A compound of formula (II)

or a salt and/or N-oxide thereof,

wherein X 1 is selected from the group consisting of O, S, and NR 11 wherein R 11 is H or lower alkyl;

X 2 is O or S;

X 3 and X 4 are independently CH or N;

X 5 is selected from the group consisting of CR 12 R 13 , O, S , SO, SO 2 , and NR 14 wherein R 12 and R 13 are independently selected from H, OH, and lower alkyl, or together form an oxo group, and R 14 is H or lower alkyl;

R is selected from the group consisting of acetate, amino, dialkylamino, —C(O)OH, alkyl, allyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, phenylalkaryl and heteroarylalkyl, each of which is optionally substituted;

R 1 and R 2 are each independently selected from the group consisting of H, OH, —OR 11 , NR 15 R 15 , halo, lower alkyl, —C(O)O-alkyl, —C(O)OH, —OP(═O)(OR 11 ) 2 , —OC(═O) OR 11 , —OC(═O)R 11 , cycloalkyl, aryl, and heteroaryl or together form an oxo, wherein each R 15 is independently selected from the group consisting of H, lower alkyl, prenyl, allyl —C(O)O-alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl, or two of R 15 combine to form an optionally substituted cycloheteroalkyl;

R 3 is aryl or heteroaryl, each optionally substituted;

R 4 is selected from the group consisting of OH, acyl, formyl, sulfonyl, alkoxy, carboxylate, haloalkyl, halogen, cyano, nitro, trifluoromethoxy, difluoromethoxy, and fluoromethoxy;

R 5 and R 6 are independently selected from H, lower alkyl, cycloalkyl or aryl;

R 7 , R 8 , R 9 , and R 10 are independently selected from the group consisting of H, OH, halogen, lower alkyl, cycloalkyl, aryl, and heteroaryl, or wherein R 7 and R 8 or R 9 and R 10 together form an oxo group; and

n is an integer from 0 to 10.

3. The compound of claim 2 , wherein X 1 is 0.

4. The compound of claim 3 , wherein X 2 is 0.

5. The compound of claim 2 , wherein R 3 is optionally substituted aryl.

6. The compound of claim 5 , wherein aryl is alkoxyphenyl, dialkoxyphenyl, or trialkoxyphenyl.

7. The compound of claim 6 , wherein trialkoxyphenyl is trimethoxyphenyl.

8. The compound of claim 2 , wherein R 4 is OH, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

9. The compound of claim 8 , wherein R 4 is F.

10. The compound of claim 2 , wherein R 5 and R 6 are H.

11. The compound of claim 2 , wherein X 4 is CH.

12. The compound of claim 2 , wherein X 4 is N.

13. The compound of claim 2 , wherein X 5 is CH 2 or O.

14. The compound of claim 2 , wherein R 7 and R 8 are H or together form the oxo group.

15. The compound of claim 2 , wherein R 9 and R 10 are methyl.

16. The compound of claim 2 , wherein R is cycloheteroalkyl.

17. The compound of claim 16 , wherein R is substituted or unsubstituted morpholine, or substituted or unsubstituted pyrrolidine.

18. The compound of claim 2 , wherein R is heteroaryl.

19. The compound of claim 18 , wherein heteroaryl is substituted or unsubstituted indole.

20. The compound of claim 2 , wherein R is selected from the group consisting of acetate, amino, and dialkylamino.

21. The compound of claim 2 , wherein n is 1, 2, or 3.

22. The compound of claim 1 , wherein X 1 is NR 11 .

23. The compound of claim 22 , wherein X 2 is O.

24. The compound of claim 22 , wherein X 2 is S.

25. The compound of claim 1 , wherein X 1 is S.

26. The compound of claim 25 , wherein X 2 is O.

27. A compound of formula (III):

or a salt and or N-oxide thereof;

wherein R is selected from the group consisting of acetate, amino, dialkylamino, —C(O)OH, straight or branched, saturated or unsaturated alkyl, allyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl, each of which is optionally substituted;

X 1 is O or NR 11 ;

R 11 is H or lower alkyl; and

n is and integer between 0 and 10.

28. The compound of claim 27 , wherein R is morpholine.

29. The compound of claim 27 , wherein R is 1-methylpiperidine.

30. The compound of claim 27 , wherein R is piperazine or 3- piperazinepropane sulfonate.

31. The compound of claim 27 , wherein R is dimethylamine.

32. The compound of claim 27 , wherein R is tryptamine or N-tert-butylaceyltryptamine.

33. The compound of claim 27 , wherein n is 0, 1, 2, or 3.

34. A method for of treating breast cancer, the method comprising:

administering to a subject an effective amount of a compound of claim 1 or a acceptable salt or N-oxide thereof and pharmaceutically-acceptable carrier or diluent.

35. The method of claim 34 , wherein the subject is a domestic animal.

36. The method of claim 34 , wherein the subject is a human.