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:
R 2 and R 4 are different and independently are each phenyl substituted with one or more of the same or different R 8 groups;
R 5 is fluoro;
R 8 is selected from R a , R b , R a substituted with one or more of the same or different R a or R b , OR a substituted with one or more of the same or different R a , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —O—(CHR a ) 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 (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl, or 6-16 membered heteroarylalkyl;
each R b is independently selected from OR a , (C1-C3) haloalkyloxy, —NR c R c , halogen, —CF 3 , —CN, —OCN, —SCN, —NO, NO 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c , —[NHC(O)]R a , —[NHC(O)]OR a , —[NHC(O)]NR c R c or —[NHC(NH)]NR c R c ;
each R c is independently H or R a ;
at least one R 8 is R b ; and
each m is independently an integer from 1 to 3.
2. The compound of claim 1 , wherein R 2 is monosubstituted with an R 8 group.
3. The compound of claim 2 , wherein the R 8 group is at the para position of R 2 .
4. The compound of claim 2 , wherein the R 8 group on R 2 is selected from (C1-C6) alkyl, (C1-C6) branched alkyl, O—C(O)OR a , —O—(CH 2 ) m —C(O)OR a , —O—(CH 2 ) m —R b , —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 .
5. The compound of claim 4 , wherein the R 8 group on R 2 is O—(CH 2 ) m —R b .
6. The compound of claim 5 , wherein the R 8 group on R 2 is O—(CH 2 ) m —OR a .
7. The compound of claim 1 , wherein R 4 is substituted with at least one R b group.
8. The compound of claim 7 , wherein the at least one R b group is selected from —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c , —[NHC(O)]R a , —[NHC(O)]NR c R c , or —[NHC(NH)] n NR c R c .
9. The compound of claim 1 , wherein the R 4 phenyl is monosubstituted.
10. The compound of claim 9 , wherein the R 4 phenyl is monosubstituted with an R b group at the meta or para position.