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 prodrug, salt, hydrate, solvate or N-oxides 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

R 5 is selected from the group consisting of halo, 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)O R 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 c 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, methoxy, —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 cycloakyl 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 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,

with the provisos that:

(i) when R 2 is

 then R 9 and R 10 are not both simultaneously lower alkoxy or methoxy;

(ii) R 2 is not 3,4,5-trimethoxyphenyl or 3,4,5-tri(loweralkoxy)phenyl;

(iii) R 2 is not lower alkyl;

(iv) when R 4 is

 where R 15 is t-butyl and R 2 is

 then at least two of R 8 , R 9 and R 10 or R 8 , R 9 and R 13 are other than hydrogen;

and (v) when R 4 is

 where R 15 is t-butyl and R 2 is

 where R 8 and R 9 are each hydrogen, then R 10 is other than —(CH 2 ) n —OH or —O(CH 2 ) n —R b where R b is selected from —NR c R c , —C(O)R a , —C(O)NR c R c and —C(O)NR a R d .

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 4 is

8. The method of claim 7 in which R a is hydrogen and R 15 is selected from lower branched alkyl and lower cycloalkyl.

9. The method of claim 7 in which R 15 is t-butyl or cyclopropyl.

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

11. The method of claim 10 in which R 8 is hydrogen; R 9 is selected from

and R 10 is other than

12. The method of claim 10 in which R 10 is selected from methyl, trifluoromethyl and chloro.

13. The method of claim 10 in which R 12 of R 9 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)CH 2 CH 3 .

14. The method of claim 13 in which R 9 is selected from hydrogen, methyl, trifluoromethyl and chloro.

15. The method of claim 13 in which R 12 of R 10 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)CH 2 CH 3 .

16. The method of claim 10 in which R 8 is hydrogen; R 9 is other than

and R 10 is selected from

17. The method of claim 1 wherein the compound is

or a pharmaceutically acceptable salt of any of the foregoing.