Details for Patent: 9,532,998

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):	Singh; Rajinder (Belmont, CA), Bhamidipati; Somasekhar (Foster City, CA), Masuda; Esteban (Menlo Park, CA), Sun; Thomas (Palo Alto, CA), Stella; Valentino J. (Lawrence, KS)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Jan 13, 2016
Application Number:	14/995,027
Claims:	1. A method of treating autoimmune hemolytic anemia comprising administering to a subject in need thereof an effective amount of a compound according to structural formula (I): ##STR00031## or a salt, solvate, hydrate or N-oxide thereof, wherein: Y is O; Z.sup.1 and Z.sup.2 are each, independently of one another, CH or N; R.sup.2 is lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, or a heteroaryl group, each of which is optionally substituted; R.sup.5 is halo, cyano, nitro, or trihalomethyl; R.sup.17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R.sup.17 taken together with R.sup.18 are an oxo (.dbd.O) group; R.sup.18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R.sup.18 taken together with R.sup.17 are an oxo (.dbd.O) group; R.sup.19 hydrogen or lower alkyl, or, alternatively, R.sup.19 taken together with R.sup.20 are an oxo (.dbd.O) group; R.sup.20 is hydrogen or lower alkyl, or, alternatively, R.sup.20 taken together with R.sup.19 are an oxo (.dbd.O) group; R.sup.21 , R.sup.22 and R.sup.23 are each, independently of one another, hydrogen or R.sup.P; R.sup.24 is hydrogen, lower alkyl or R.sup.P, with the proviso that at least one of R.sup.21, R.sup.22, R.sup.23 and R.sup.24 is R.sup.P; and each R.sup.P is, independently of the others, --(CR.sup.dR.sup.d).sub.y--O--P(O)(OR.sup.i)(OR.sup.i), --(CR.sup.dR.sup.d).sub.y--O--P(O)(OR.sup.i)(OH), --(CR.sup.dR.sup.d).sub.y--O--P(OR.sup.i)(OR.sup.i) or --(CR.sup.dR.sup.d).sub.y--O--P(OR.sup.i)(OH), where each R.sup.i is, independently of the others, lower unsubstituted alkanyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl; each R.sup.d is, independently of the other, hydrogen, cyano, optionally substituted (C.sub.1-C.sub.20) alkyl, (C.sub.1-C.sub.20) perfluoroalkyl, optionally substituted (C.sub.7-C.sub.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.sup.d taken together with the carbon atom to which they are bonded are a (C.sub.3-C.sub.8) cycloalkyl; and y is 1, 2, or 3. 2. The method of claim 1 in which R.sup.5 is fluoro. 3. The method of claim 1 in which R.sup.2 is a phenyl optionally substituted with one or more of the same or different R.sup.8 groups. 4. The method of claim 3 in which R.sup.2 is 3,4,5 tri(lower alkoxy)phenyl. 5. The method of claim 4 in which R.sup.2 is 3,4,5-(trimethoxy)phenyl. 6. The method of claim 1 in which R.sup.17 and R.sup.18 are each methyl and R.sup.19 and R.sup.20 are taken together to form an oxo group. 7. The method of claim 6 in which R.sup.2 is a phenyl optionally substituted with one or more of the same or different R.sup.8 groups. 8. The method of claim 7 in which R.sup.2 is 3,4,5-tri(lower alkoxy)phenyl. 9. The method of claim 8 in which R.sup.2 is 3,4,5-(trimethoxy)phenyl. 10. The method of claim 9 in which only R.sup.21 is R.sup.P. 11. The method of claim 10 in which R.sup.P 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 R.sup.3, together with the heteroatom, A, to which it is bonded, is a phosphate group. 13. The method of claim 12 in which R.sup.P has the formula --(CR.sup.dR.sup.d)--O--P(O)(OH).sub.2, or a salt thereof, where each R.sup.d is, independently of the others, selected from the group consisting of optionally substituted lower alkyl, optionally substituted (C.sub.6-C.sub.14) aryl and optionally substituted (C.sub.7-C.sub.20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C.sub.6-C.sub.14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R.sup.d 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 R.sup.P comprises a phosphate ester group. 15. The method of claim 14 in which R.sup.P is selected from the group consisting of --(CR.sup.dR.sup.d)--O--P(O)(OR.sup.e)(OH), --(CR.sup.dR.sup.d)--O--P(O)(OR.sup.e)(OR.sup.e), ##STR00032## and salts thereof, wherein each R.sup.e is, independently of the others, selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted (C.sub.6-C.sub.14) aryl, substituted or unsubstituted (C.sub.7-C.sub.20) arylalkyl, --(CR.sup.dR.sup.d).sub.y--OR.sup.f, --(CR.sup.dR.sup.d).sub.y--O--C(O)R.sup.f, --(CR.sup.dR.sup.d).sub.y--O--C(O)OR.sup.f, --(CR.sup.dR.sup.d).sub.y--S--C(O)R.sup.f, --(CR.sup.dR.sup.d).sub.y--S--C(O)OR.sup.f, --(CR.sup.dR.sup.d).sub.y--NH--C(O)R.sup.f, --(CR.sup.dR.sup.d).sub.y--NH--C(O)OR.sup.f and --Si(R.sup.d).sub.3, wherein each R.sup.f is, independently of the others, selected from the group consisting of unsubstituted or substituted lower alkyl, substituted or unsubstituted (C.sub.6-C.sub.14) aryl, and substituted or unsubstituted (C.sub.7-C.sub.20) arylalkyl; each R.sup.g is, independently of the others, selected from the group consisting of hydrogen and lower alkyl; each R.sup.h 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 (C.sub.6-C.sub.14) aryl, substituted or unsubstituted (C.sub.7-C.sub.20) 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 R.sup.d is independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C.sub.6-C.sub.14) aryl and optionally substituted (C.sub.7-C.sub.20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C.sub.6-C.sub.14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R.sup.d 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 ##STR00033## 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.