2,4-pyrimidinediamine compounds and uses as anti-proliferative agents

1. A method of inhibiting proliferation of a cancer cell, comprising contacting the cancer cell with an effective amount of a 2,4-pyrimidinediamine compound according to structural formula (I):

or a salt or N-oxide thereof, wherein:

L 1 and L 2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower alkylene linker and a covalent bond;

R 2 is selected from the group consisting of lower alkyl optionally substituted with an R b group,

where Y is NH, O or CH 2 ;

R 2′ is hydrogen, methyl or lower alkyl;

R 4′ is hydrogen, methyl or lower alkyl;

R 4 is

where Z 1 is N and Z 2 is O;

R 5 is selected from the group consisting of chloro, iodo, bromo, fluoro and —CF 3 ;

R 6 is hydrogen;

each R 8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —(CH 2 ) n —NR c R c , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)OR a , —C(S)OR a, halo, —CF 3 and —OCF 3 ;

each R 9 is independently selected from the group consisting of hydrogen, lower alkyl, —OR a , —(CH 2 ) n —NR c R c , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)—NR c R c , —C(S)—NR c R c , —S(O) 2 —NR′R c , —NHC(O)R a , —NHC(S)R a , —C(O)—NH—(CH 2 ) n —NR c R c , —C(S)—NH—(CH 2 ) n —NR c R c , halo, —CF 3 , —OCF 3 ,

each R 10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —NR c R c , —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , halo, —CF 3 , —OCF 3 ,

each R 11 is independently selected from the group consisting of —OR a , —NR c R c and —NR a R d ;

each R 12 is independently selected from the group consisting of lower alkyl, arylalkyl, —OR a , —NR c R c , —C(O)R a , —C(O)OR a and —C(O)NR c R c ;

each R 13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, —C(O)NR c R c and —C(O)NH 2 ;

each R 15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl and phenyl;

each R 16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;

each R 17 is independently selected from the group consisting of hydrogen, lower alkyl, and R d ;

each R 18 is independently selected from the group consisting of hydrogen, and lower alkyl;

each R 19 is independently selected form the group consisting of hydrogen, lower alkyl, and R d ;

each R 20 is independently selected from the group consisting of hydrogen, lower alkyl, and R d ;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3;

each R a is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;

each R b is independently selected from the group consisting of −OR a , —CF 3 , —OCF 3 , —NR c R c , —C(O)R a , —C(S)R a , —C(O)OR a , —C(S)OR a , —C(O)NR c R c , —C(S)NR c R c , —S(O) 2 NR c R c , —C(O)NR a R d , —C(S)NR a R d and —S(O) 2 NR a R d ;

each R c is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two R c s may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NR a , NR a —C(O)R a , NR a —C(O)OR a and NR a —C(O)NR a ; and

each R d is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl.

2. The method of claim 1 in which L 1 and L 2 are each a covalent bond.

3. The method of claim 2 in which R 5 is fluoro.

4. The method of claim 3 in which R 2′ and R 4′ are each hydrogen.

5. The method of claim 3 in which R 2′ is hydrogen and R 4′ is methyl.

6. The method of claim 3 in which R 2 is

7. The method of claim 3 in which R 2 is

8. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ig):

or a salt or N-oxide thereof, wherein:

R 28 is hydrogen or methyl;

R 16 is hydrogen or methyl;

R 21 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halogen and chloro;

R 22 is selected from hydrogen, lower alkoxy, fluoro, chloro, bromo, iodo,

R 23 is selected from hydrogen, methyl, lower alkyl, lower alkoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, —OCH 2 C(O)NHR a ,

and

R 24 is selected from hydrogen and methyl.

9. The method of claim 1 in which the cancer cell is a tumor cell.

10. The method of claim 9 in which the tumor cell is a bladder, lung, colon, breast, prostate, pancreatic, ovarian or hepatic tumor cell.

11. The method of claim 1 which is practiced in vivo as a therapeutic approach towards the treatment of a cell proliferative disorder.

12. The method of claim 11 in which the cell proliferative disorder is a metastatic tumor.

13. The method of claim 12 in which the cell proliferative disorder is selected from the group consisting of a renal carcinoma, a lung carcinoma, a colon carcinoma, a liver carcinoma, a breast carcinoma, a prostate carcinoma, a pancreatic carcinoma, an ovarian carcinoma, a melanoma, and an osteosarcoma.

14. The method of claim 11 in which the compound is administered in the form of a pharmaceutical composition.

15. The method of claim 14 in which the compound is administered to a subject orally or intravenously.

16. The method of claim 15 in which the subject is a human.

17. The method of claim 1 , wherein the cancer cell is associated with a cancer selected from the group consisting of lymphomas, leukemias, renal, and urinary tract cancer.

18. The method of claim 1 , wherein the leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or hairy cell leukemia.

19. The method of claim 18 , wherein the leukemia is acute myeloid leukemia.

20. The method of claim 18 , wherein the leukemia is chronic lymphocytic leukemia.

21. The method of claim 1 , wherein the lymphoma is T cell or B cell lymphomas, non-Hodgkins lymphoma, cutaneous T cell lymphoma, Hodgkins disease, or lymphoma of the central nervous system.

22. The method of claim 1 , wherein the cancer cell is a renal carcinoma cell.

23. The method of claim 1 , wherein the cancer cell is a lung cancer cell.

24. The method of claim 1 , wherein the cancer cell is a colon cancer cell.

25. The method of claim 11 , wherein the cell proliferative disorder is lung cancer.

26. The method of claim 11 , wherein the cell proliferative disorder is colon cancer.