2,4-pyrimidinediamine 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 the formula:
or a salt thereof, wherein:
R 2 is phenyl tri-substituted with the same or different R 8 groups;
R 4 is phenyl substituted with one or more of the same or different R 8 groups;
R 2 and R 4 are different;
R 5 is halogen;
R 6 is hydrogen;
R 8 is selected from the group consisting of R a , R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —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 , —S—(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 , —NH[(CH 2 ) m R b ], —N[(CH 2 ) m R b ] 2 , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ;
each R a is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each R b is a suitable group independently selected from the group consisting of ═O, —OR d , —OH, (C1-C3) haloalkyloxy, halogen, —CF 3 , —NO 2 , ═N 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 , OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c and —[NR a C(NR a )] n NR c R c ;
each R c is independently hydrogen or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-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 hydrogen or R a ;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3,
with the provisos that the compound is not
N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis[(3-chloro-4-methoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine;
N2,N4-Bis(3-chloro-4-methoxy)-5-fluoro-2,4-pyrimidinediamine; or
a compound in which R 2 is 3,4,5-trimethoxyphenyl.
2. The compound of claim 1 , wherein R 4 is mono-substituted with an R 8 group.
3. The compound of claim 2 , wherein R 4 is ortho-substituted with the R 8 group.
4. The compound of claim 2 , wherein R 4 is meta-substituted with the R 8 group.
5. The compound of claim 2 , wherein R 4 is para-substituted with the R 8 group.
6. The compound of claim 1 , wherein R 5 is fluoro.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
8. The composition of claim 7 , wherein the compound is in the form of a pharmaceutically acceptable salt.
9. The compound according to claim 1 , provided R 2 is not 3,4,5-tri(C 1 -C 6 )trialkoxyphenyl.
10. The compound of claim 9 , wherein R 4 is mono-substituted with an R 8 group.
11. The compound of claim 10 , wherein R 4 is ortho-substituted with the R 8 group.
12. The compound of claim 10 , wherein R 4 is meta-substituted with the R 8 group.
13. The compound of claim 10 , wherein R 4 is para-substituted with the R 8 group.
14. The compound of claim 9 , wherein R 5 is fluoro.
15. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier, diluent or excipient.
16. The composition of claim 15 , wherein the compound is in the form of a pharmaceutically acceptable salt.