2,4-pyrimidinediamine compounds and their uses
The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
1. A compound according to the formula:
or a salt thereof, wherein:
R 2 is selected from phenyl mono-substituted at the 3- or 5-position with an R 8 group and phenyl di- or tri-substituted with the same or different R 8 groups, provided R 2 is not 3,4,5-trimethoxyphenyl;
R 4 is phenyl substituted with one or more of the same or different R 8 groups;
R 2 and R 4 are different;
R 5 is halogen;
R 6 is hydrogen;
each R 8 is selected from the group consisting of R a , R b , —O—(CH 2 ) m —R b C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , -;
each R a is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, phenyl, (C6-C16) arylalkyl, benzyl, 3-8 membered cycloheteroalkyl, morpholinyl, 4-11 membered cycloheteroalkylalkyl and 5-10 membered heteroaryl;
each R b is independently selected from the group consisting of —OR d , (C1-C3) haloalkyloxy, halogen, —CF 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c ;
each R c is independently hydrogen or R a ;
each R d is independently hydrogen or R a ; and
each m is independently an integer from 1 to 3.
2. The compound of claim 1 , wherein R 2 is phenyl di-substituted with the same or different R 8 groups.
3. The compound of claim 1 , wherein R 2 is 3,4-disubstituted.
4. The compound of claim 1 , wherein R 4 is mono-substituted with an R 8 group.
5. The compound of claim 4 , wherein R 4 is ortho-substituted with the R 8 group.
6. The compound of claim 4 , wherein R 4 is meta-substituted with the R 8 group.
7. The compound of claim 4 , wherein R 4 is para-substituted with the R 8 group.
8. The compound of claim 1 , wherein R 5 is fluoro.
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
10. The composition of claim 9 , wherein the compound is in the form of a pharmaceutically acceptable salt.
11. The compound of claim 5 , wherein R 5 is fluoro.
12. The compound of claim 5 , wherein R 5 is chloro.
13. The compound of claim 1 , wherein R 2 is phenyl tri-substituted with the same or different R 8 groups.
14. The compound of claim 13 , wherein R 4 is mono-substituted with an R 8 group.
15. The compound of claim 14 , wherein R 4 is mono-substituted with an R 8 group.
16. The compound of claim 14 , wherein R 4 is ortho-substituted with the R 8 group.
17. The compound of claim 14 , wherein R 4 is meta-substituted with the R 8 group.
18. The compound of claim 14 , wherein R 4 is para-substituted with the R 8 group.
19. The compound of claim 15 , wherein R 5 is fluoro.
20. The compound of claim 15 , wherein R 5 is chloro.