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 Formula (I)
or a salt thereof, wherein:
one of R 2 and R 4 is a phenyl monosubstituted with —OH, —OR a , —O—C(O)OR a , —O—(CH 2 ) m —C(O)OR a , —O—(CH 2 ) m —NR c R c , —O—C(O)NR c R c , —O—(CH 2 ) m —C(O)NR c R c , —O—C(NH)NR c R c , —O—(CH 2 ) m —C(NH)NR c R c , —NH—(CH 2 ) m —NR c R c or —[NHC(O)]R d ;
the other of R 2 and R 4 is a phenyl monosubstituted or disubstituted with R 8 ;
R 2 and R 4 are different;
R 5 is fluoro, —CN, or (C1-C3) haloalkyl;
each R 8 is independently R a , R b , or R a substituted with one R a or R b ;
each R a is independently (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each R b is independently —OH, —OR a , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —N 3 , —SO 2 NR c R c , —C(O)R a , —C(O)NR c R c , or —C(NH)NR c R c ;
each R c is independently H or R a ;
each R d is independently R a ; and
each m is independently an integer from 1 to 2.
2. The compound of claim 1 , wherein R 5 is (C1-C3) haloalkyl.
3. The compound of claim 1 , wherein R 5 is —CF 3 .
4. The compound of claim 2 , wherein at least one R 8 is R b and each R b is independently —OH, —OR a , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —N 3 , —SO 2 NR c R c , —C(O)R a , or —C(O)NR c R c .
5. The compound of claim 1 , wherein R 4 is a phenyl monosubstituted with OH, —OR a , —O—C(O)OR a , —O—(CH 2 ) m —C(O)OR a , —O—(CH 2 ) m —NR c R c , —O—C(O)NR c R c , —O—(CH 2 ) m —C(O)NR c R c , —O—C(NH)NR c R c , —O—(CH 2 ) m —C(NH)NR c R c , —NH—(CH 2 ) m —NR c R c or —[NHC(O)]R d .
6. The compound of claim 5 , wherein R 4 is a phenyl monosubstituted with —[NHC(O)]R d .
7. The compound of claim 6 , wherein R d is (C1-C6)alkyl.
8. The compound of claim 1 , wherein R 2 is a phenyl disubstituted with R 8 .
9. The compound of claim 8 , wherein at least one R 8 is R a substituted with one R a or R b .
10. The compound of claim 9 , wherein at least one R 8 is a 3-8 membered cycloheteroalkyl substituted with one R a or R b .
11. The compound of claim 8 , wherein at least one R 8 is R b .
12. The compound of claim 8 , wherein at least one R 8 is OR a .
13. The compound of claim 12 , wherein R a is (C1-C6)alkyl.
14. The compound of claim 8 , wherein one R 8 comprises piperazinyl.
15. The compound of claim 14 , wherein the piperazinyl is substituted with one R a or R b .
16. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
17. The compound of claim 1 , wherein R 4 is a phenyl monosubstituted with (C1-C6) alkyl.