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 —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 (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each R b is —OR a , NR c R c , halogen, —CF 3 , —CN, —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 R a or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 5 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
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 —OR a , —NR c R c , halogen, —CF 3 , —CN, —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 —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 11 , wherein at least one R 8 is NR c R c .
13. The compound of claim 8 , wherein at least one R 8 is —OR a .
14. The compound of claim 13 , wherein R a is (C1-C6)alkyl.
15. The compound of claim 8 , wherein one R 8 comprises piperazinyl.
16. The compound of claim 15 , wherein the piperazinyl is substituted with one R a or R b .
17. A compound according to Formula (I)
or a salt thereof, wherein:
R 4 is a phenyl monosubstituted with (C1-C6) alkyl, —OR a , —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 , —NH—(CH 2 ) m —NR c R c or —[NHC(O)]R d ;
R 2 is a phenyl disubstituted with R 8 ;
R 5 is (C1-C3) haloalkyl;
one R 8 comprises piperazinyl, and the other R 8 is independently R a , R b , or R a substituted with one R a or R b ;
each R a is (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each R b is —OR a , —OCF 3 , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —N 3 , —SO 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , or —C(NH)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 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R d is independently R a ; and
each m is independently an integer from 1 to 2.
18. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable excipient.