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 (C1-C10) alkyl, —OR a optionally substituted with one R b group, —O—C(O)OR a , —O—(CH 2 ) m —C(O)OR a , —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 or —NH—(CH 2 ) m —NR c R c ;
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-C6) alkyl optionally substituted with one or more halogen;
each R 8 is independently selected from the group consisting of R b , R a substituted with one or more of the same or different R a or R b and —OR a substituted with one or more of the same or different R a or R b ;
each R a is independently selected from the group consisting of H, (C1-C6) alkyl and (C3-C8) cycloalkyl;
each R b is independently selected from the group consisting of ═O, —OR d , —OCF 3 , —SR d , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —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 , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d and —OC(O)NR c R c ;
each R c is independently R a or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl;
each R d is independently R a ; and
each m is independently an integer from 1 to 3.
2. The compound of claim 1 , wherein R 5 is fluoro or (C1-C4) alkanyl optionally substituted with one or more of the same or different R 8 groups.
3. The compound of claim 1 , wherein each R 8 is independently selected from the group consisting of R b .
4. The compound of claim 1 , wherein R 2 is monosubstituted with R 8 .
5. The compound of claim 1 , wherein R 4 is monosubstituted with R 8 .
6. The compound of claim 1 , wherein each R b is independently —OR a , —OCF 3 , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —N 3 , —S(O) 2 NR c R c , —C(O)R a , —C(O)OR a or —C(O)NR c R c .
7. The compound of claim 1 , wherein R 5 is (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups.
8. The compound of claim 1 , wherein R 5 is fluoro, (C1-C6) alkanyl or —CF 3 .
9. The compound of claim 1 , wherein R 5 is fluoro.
10. The compound of claim 1 , wherein R 5 is —CF 3 .
11. The compound of claim 1 , wherein each m is 2.
12. The compound of claim 1 , wherein R 2 is phenyl monosubstituted with —O—(CH 2 ) m —NR c R c .
13. The compound of claim 1 , wherein each R a is independently selected from the group consisting of (C1-C6) alkyl and (C3-C8) cycloalkyl.