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

1. A method of reducing 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 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 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, methyl and R d ;

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

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

each R 20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl 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,

wherein the cancer cell is a lung carcinoma cell.

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 selected from hydrogen and methyl; and

R 21 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, fluoro, chloro, bromo, and iodo;

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

R 23 is selected from hydrogen, methyl, lower alkyl, lower alkoxy, methoxy, 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 which is practiced in vivo as a therapeutic approach towards the treatment of lung cell carcinoma.

10. The method of claim 9 in which the compound is administered in the form of a pharmaceutical composition.

11. The method of claim 10 in which the compound is administered to a subject orally or intravenously.

12. The method of claim 11 in which the subject is a human.