Prodrugs of 2,4-pyrimidinediamine compounds and their uses
The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.
1. A method of treating systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound according to structural formula (I):
or a salt, solvate, hydrate or N-oxide thereof, wherein:
Y is CH 2 , NR 24 , O, S, S(O) or S(O) 2 ;
Z 1 and Z 2 are each, independently of one another, CH or N;
R 2 is an optionally substituted lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, phenyl, or heteroaryl group;
R 5 is an electronegative group;
R 17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R 17 taken together with R 18 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R 18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R 18 taken together with R 17 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R 19 hydrogen or lower alkyl, or, alternatively, R 19 taken together with R 20 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R 20 is hydrogen or lower alkyl, or, alternatively, R 20 taken together with R 19 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R 21 , R 22 and R 23 are each, independently of one another, hydrogen or R P ;
R 24 is hydrogen, lower alkyl or R P , with the proviso that at least one of R 21 , R 22 , R 23 and R 24 is R P ; and
each R P is, independently of the others, —(CR d R d ) y —O—P(O)(OR 1 )(OR 1 ), —(CR d R d ) y —O—P(O)(OR 1 )(OH), —(CR d R d ) y —O—P(OR 1 )(OR 1 ) or —(CR d R d ) y —O—P(OR 1 )(OH), where each R i is, independently of the others, lower unsubstituted alkanyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
each R d is, independently of the other, hydrogen, cyano, optionally substituted (C 1 -C 20 ) alkyl, (C 1 -C 20 ) perfluoroalkyl, optionally substituted (C 7 -C 30 ) arylalkyl or optionally substituted 6-30 membered heteroarylalkyl, where each optional substituent is, independently of the others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroalkyl, or, alternatively, two R d taken together with the carbon atom to which they are bonded are a (C 3 -C 8 ) cycloalkyl; and
y is 1, 2, or 3.
2. The method according to claim 1 wherein the method reduces or ameliorates a symptom of systemic lupus erythematosus.
3. The method according to claim 2 wherein the symptom is fever.
4. The method according to claim 2 wherein the symptom is arthralgias.
5. The method according to claim 2 wherein the symptom is arthritis.
6. The method according to claim 2 wherein the symptom is serositis.
7. The method according to claim 6 wherein the serositis manifests as pleurisy.
8. The method according to claim 6 wherein the serositis manifests as pericarditis.