2,4-pyridinediamine compounds and their uses
View Patent ↗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-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 ;
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 H, (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;
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 fluoro or (C1-C3) haloalkyl.
3. The compound of claim 2 , wherein each R b is independently —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 or —C(O)NR c R c .
4. The compound of claim 3 , wherein R 5 is fluoro or —CF 3 .
5. The compound of claim 4 , wherein each m is 2.
6. The compound of claim 5 , wherein R 5 is fluoro.
7. The compound of claim 1 , wherein R 2 is phenyl monosubstituted with —O—(CH 2 ) m —NR c R c .
8. A method for treating human allergic asthma comprising administering to a human subject an effective amount of a compound having Formula (I)
or a salt thereof, wherein:
one of R 2 and 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 ;
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 H, (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;
each R d is independently R a ; and
each m is independently an integer from 1 to 2.
9. The method according to claim 8 wherein the compound is administered with a second therapeutic.
10. The method according to claim 9 wherein the second therapeutic is an anti-inflammatory.
11. The method according to claim 8 comprising administering the compound prophylactically.
12. The compound of claim 4 , wherein R 2 is substituted with two R b groups.
13. The compound of claim 12 , wherein at least one R a is unsaturated (C1-C6) alkyl.
14. The compound of claim 12 , wherein at least one R b group is —OR a .