Prodrugs of 2,4-pyrimidinediamine compounds and their uses

摘要

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.

主权项

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 CH2, NR24, O, S, S(O) or S(O)2;Z1 and Z2 are each, independently of one another, CH or N;R2 is an optionally substituted lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, phenyl, or heteroaryl group;R5 is an electronegative group;R17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R17 taken together with R18 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;R18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R18 taken together with R17 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;R19 hydrogen or lower alkyl, or, alternatively, R19 taken together with R20 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;R20 is hydrogen or lower alkyl, or, alternatively, R20 taken together with R19 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;R21, R22 and R23 are each, independently of one another, hydrogen or RP;R24 is hydrogen, lower alkyl or RP, with the proviso that at least one of R21, R22, R23 and R24 is RP; andeach RP is, independently of the others, —(CRdRd)y—O—P(O)(OR1)(OR1), —(CRdRd)y—O—P(O)(OR1)(OH), —(CRdRd)y—O—P(OR1)(OR1) or —(CRdRd)y—O—P(OR1)(OH), where each Ri is, independently of the others, lower unsubstituted alkanyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;each Rd is, independently of the other, hydrogen, cyano, optionally substituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionally substituted (C7-C30) 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 Rd taken together with the carbon atom to which they are bonded are a (C3-C8) cycloalkyl; andy is 1, 2, or 3.