Claims for Patent: 9,266,912

Summary for Patent: 9,266,912

Title:	Prodrugs of 2,4-pyrimidinediamine compounds and their uses
Abstract:	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.
Inventor(s):	Rajinder Singh, Somasekhar Bhamidipati, Esteban Masuda, Thomas Sun, Valentino J. Stella
Assignee:	Rigel Pharmaceuticals Inc
Application Number:	US14/310,312
Patent Claims:	1. A method of treating immune thrombocytopenic purpura 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 O; Z1 and Z2 are each, independently of one another, CH or N; R2 is lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, or a heteroaryl group, each of which is optionally substituted; R5 is halo, cyano, nitro, or trihalomethyl; R17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R17 taken together with R18 are an oxo (═O) group; R18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R18 taken together with R17 are an oxo (═O) group; R19 hydrogen or lower alkyl, or, alternatively, R19 taken together with R20 are an oxo (═O) group; R20 is hydrogen or lower alkyl, or, alternatively, R20 taken together with R19 are an oxo (═O) group; 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; and each RP is, independently of the others, —(CRdRd)y—O—P(O)(ORi)(ORi), —(CRdRd)y—O—P(O)(ORi)(OH), —(CRdRd)y—O—P(ORi)(ORi) or —(CRdRd)y—O—P(ORi)(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; and y is 1, 2, or 3. 2. The method of claim 1 in which R5 is fluoro. 3. The method of claim 1 in which R2 is a phenyl optionally substituted with one or more of the same or different R8 groups. 4. The method of claim 3 in which R2 is 3,4,5 tri(lower alkoxy)phenyl. 5. The method of claim 4 in which R2 is 3,4,5-(trimethoxy)phenyl. 6. The method of claim 1 in which R17 and R18 are each methyl and R19 and R20 are taken together to form an oxo group. 7. The method of claim 6 in which R2 is a phenyl optionally substituted with one or more of the same or different R8 groups. 8. The method of claim 7 in which R2 is 3,4,5-tri(lower alkoxy)phenyl. 9. The method of claim 8 in which R2 is 3,4,5-(trimethoxy)phenyl. 10. The method of claim 9 in which only R21 is RP. 11. The method of claim 10 in which RP is selected from the group consisting of an ester, a thioester, an ether, a thioether, a silyl ether, a thiosilyl ether, a carbonate, a thiourea, an amide, a thioamide, a carbamate and a urea linkage. 12. The method of claim 11 in which R3, together with the heteroatom, A, to which it is bonded, is a phosphate group. 13. The method of claim 12 in which RP has the formula —(CRdRd)—O—P(O)(OH)2, or a salt thereof, where each Rd is, independently of the others, selected from the group consisting of optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two Rd bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms. 14. The method of claim 10 in which RP comprises a phosphate ester group. 15. The method of claim 13 in which RP is selected from the group consisting of —(CRdRd)—O—P(O)(ORe)(OH), —(CRdRd)—O—P(O)(ORe)(ORe), and salts thereof, wherein each Re is, independently of the others, selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl, —(CRdRd)y—ORf, —(CRdRd)y—O—C(O)Rf, —(CRdRd)y—O—C(O)ORf, —(CRdRd)y—S—C(O)Rf, —(CRdRd)y—S—C(O)ORf, —(CRdRd)y—NH—C(O)Rf, —(CRdRd)y—NH—C(O)ORf and —Si(Rd)3, wherein each Rf is, independently of the others, selected from the group consisting of unsubstituted or substituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, and substituted or unsubstituted (C7-C20) arylalkyl; each Rg is, independently of the others, selected from the group consisting of hydrogen and lower alkyl; each Rh is, independently of the others, selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; y is an integer ranging from 1 to 3; z is an integer ranging from 0 to 2; and each Rd is independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two Rd bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms. 16. The method according to claim 1, wherein the compound is or a pharmaceutically acceptable salt and/or hydrate thereof. 17. The method of claim 16, wherein the compound or the pharmaceutically acceptable salt thereof is in the form of a hydrate. 18. The method of claim 17, wherein the compound is a free acid. 19. The method of claim 17, wherein the compound is a pharmaceutically acceptable salt. 20. The method of claim 19, wherein the pharmaceutically acceptable salt is an alkali metal salt. 21. The method of claim 20, wherein the pharmaceutically acceptable salt is a sodium salt. 22. The method of claim 21, wherein the pharmaceutically acceptable salt is a disodium salt. 23. The method of claim 19, wherein the pharmaceutically acceptable salt is an alkaline earth metal salt. 24. The method of claim 23, wherein the pharmaceutically acceptable salt is a calcium salt.