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 2,4-pyrimidinediamine compound according to structural formula (II):
wherein:
R 5 is selected from the group consisting of fluoro, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, —C(O)R a , —C(O)OR a , C(O)CF 3 and —C(O)OCF 3 ;
each R 11 R 12 , R 13 and R 14 , independently of the others, is selected from the group consisting of hydrogen, hydroxy, (C1-C6) perhaloalkyl, (C1-C6) perhaloalkoxy, —NR c R c , (C1-C10) alkyl optionally substituted with one or more of the same or different R a , (C1-C6) alkoxy optionally substituted with one or more of the same or different R a or R b ; —OR a optionally substituted with one or more of the same or different R a or R b groups, —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(O)OR a , —O—(CH 2 ) m —C(O)OR a , —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 , —NH—C(O)NR c R c and —NH—(CH 2 ) m —C(O)NR c R c , where m is independently an integer from 1 to 3;
each R a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 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, (C1-C3) haloalkyloxy, ═S, —SR d , ═NR d , ═NOR d , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —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 , —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 , —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 , where n is independently an integer from 0 to 3;
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 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 ;
wherein at least one of R 11 and R 12 and one of R 13 and R 14 is non-hydrogen;
with the proviso that:
(1) R 11 and R 12 are not both methoxy; and
(2) the 2,4-pyrimidinediamine compound is not:
N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);
N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);
N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788); or
N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964).
2. The compound of claim 1 , wherein R 11 and R 12 are not both optionally substituted alkoxy.
3. The compound of claim 1 , wherein R 11 , R 12 , R 13 and R 14 , independently, are selected from (C1-C10) alkyl optionally substituted with one or more of the same or different R a or R b , —OR a optionally substituted with one or more of the same or different R a or R b groups, —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(O)OR a , —O—(CH 2 ) m —C(O)OR a , —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 , —NH—C(O)NR c R c and —NH—(CH 2 ) m —C(O)NR c R c , where m is independently an integer from 1 to 3.
4. The compound of claim 1 , wherein R 11 , R 12 , R 13 and R 14 , independently of one another, are selected from the group consisting of hydrogen, hydroxy, (C1-C6) alkoxy and —NR c R c .
5. The compound of claim 1 , wherein R 11 and R 14 are the same.
6. The compound of claim 5 , wherein R 12 and R 13 are the same.
7. The compound of claim 1 , wherein R 12 and R 13 are the same.
8. The compound of claim 7 , wherein R 12 and R 13 are hydrogen.
9. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen.
10. The compound of claim 1 , wherein one of R 13 and R 14 is hydrogen.
11. The compound of claim 1 , wherein R 12 is hydrogen and R 11 is —O—(CH 2 ) m —R b , wherein m is an integer from 1 to 3.
12. The compound of claim 11 , wherein R 5 is fluoro or CF 3 .
13. The compound of claim 11 , wherein R 11 is —O—CH 2 —C(O)—NHCH 3 .
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
15. A method of inhibiting cell degranulation, comprising contacting a cell with an amount of a compound according to claim 1 effective to inhibit cell degranulation.
16. The method of claim 15 , wherein the cell is a human mast cell, basophil cell, neutrophil cell or eosinophil cell.
17. The method of claim 15 , wherein the cell is in a human.