Claims for Patent: 7,989,448

Summary for Patent: 7,989,448

Title:	Prodrugs of 2,4-pyrimidinediamine compounds and their uses
Abstract:	The present disclosure provides compounds of the following formula, ##STR00001## and methods of using the compounds to inhibit cellular degranulation and to treat diseases associated therewith.
Inventor(s):	Singh; Rajinder (Belmont, CA), Bhamidipati; Somasekhar (Foster City, CA), Masuda; Esteban (Menlo Park, CA)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Application Number:	12/268,218
Patent Claims:	1. A compound according to structural formula (I): ##STR00031## or a pharmaceutically acceptable salt and/or N-oxide thereof, wherein: Y is O; Z.sup.1 is CH; Z.sup.2 is N; R.sup.2 is selected from (C1-C6) alkyl optionally substituted with one or more of the same or different R.sup.8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R.sup.8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R.sup.8 groups, (C6-C14) aryl optionally substituted with one or more of the same or different R.sup.8 groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R.sup.8 groups; R.sup.5 is selected from the group consisting of halo, cyano, nitro, and trihalomethyl; R.sup.8 is selected from R.sup.a, R.sup.b, R.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b, --OR.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b, --B(OR.sup.a).sub.2, --B(NR.sup.cR.sup.c).sub.2, --(CH.sub.2).sub.m--R.sup.b, --(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--R.sup.b, --S--(CH.sub.2).sub.m--R.sup.b, --O--CHR.sup.aR.sup.b, --O--CR.sup.a(R.sup.b).sub.2, --O--(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--CH[(CH.sub.2).sub.mR.sup.b]R.sup.b, --S--(CHR.sup.a).sub.m--R.sup.b, --C(O)NH--(CH.sub.2).sub.m--R.sup.b, --C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.m--R.sup.b, --S--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.m--R.sup.b, --O--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --S--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --NH--(CH.sub.2).sub.m--R.sup.b, --NH--(CHR.sup.a).sub.m--R.sup.b, --N[(CH.sub.2).sub.mR.sup.b].sub.2, --NH--C(O)--NH--(CH.sub.2).sub.m--R.sup.b, --NH--C(O)--(CH.sub.2).sub.m--CHR.sup.bR.sup.b and --NH--(CH.sub.2).sub.m--C(O)--NH--(CH.sub.2).sub.m--R.sup.b; R.sup.17 is selected from hydrogen, halogen, and lower alkyl or, alternatively, R.sup.17 may be taken together with R.sup.18 to form an oxo (.dbd.O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R.sup.18 is selected from hydrogen, halogen, and lower alkyl or, alternatively, R.sup.18 may be taken together with R.sup.17 to form an oxo (.dbd.O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R.sup.19 is selected from hydrogen and lower alkyl or, alternatively, R.sup.19 may be taken together with R.sup.20 to form an oxo (.dbd.O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R.sup.20 is selected from hydrogen and lower alkyl or, alternatively, R.sup.20 may be taken together with R.sup.19 to form an oxo (.dbd.O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; each R.sup.a is, independently of the others, selected from hydrogen, lower alkyl, lower cycloalkyl, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, (C7-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.sup.b is a group independently selected from .dbd.O, --OR.sup.a, (C1-C3) haloalkyloxy, .dbd.S, --SR.sup.a, .dbd.NR.sup.a, .dbd.NOR.sup.a, --NR.sup.cR.sup.c halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O)R.sup.a, --S(O).sub.2R.sup.a, --S(O).sub.2OR.sup.a, --S(O)NR.sup.cR.sup.c, --S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a, --OS(O).sub.2OR.sup.a, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.cR.sup.c, --C(NH)NR.sup.cR.sup.c, --C(NR.sup.a)NR.sup.cR.sup.c, --C(NOH)R.sup.a, --C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.a, --OC(O)OR.sup.a, --OC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c, --OC(NR.sup.a)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.a, --[NR.sup.aC(O)].sub.nR.sup.a, --[NHC(O)].sub.nOR.sup.a, --[NR.sup.aC(O)].sub.nOR.sup.a, --[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.aC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.n--NR.sup.cR.sup.c and --[NR.sup.aC(NR.sup.a)].sub.nNR.sup.cR.sup.c; each R.sup.c is, independently of the others, R.sup.a, or, alternatively, the two R.sup.c bonded to the same nitrogen atom are taken together with that nitrogen atom to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally be substituted with one or more of the same or different R.sup.a groups; R.sup.21, R.sup.22 and R.sup.23 are each, independently of one another, selected from hydrogen and R.sup.P; R.sup.P is --(CR.sup.dR.sup.d).sub.y-A-R.sup.3, where A is O or S; each R.sup.d is, independently of the others, selected from 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 the group consisting of hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl and halogen, or, alternatively, two R.sup.d bonded to the same carbon atom, taken together with the carbon atom to which they are bonded, form a cycloalkyl group containing from 3 to 8 carbon atoms; R.sup.3 together with the heteroatom, A, to which it is bonded, is a moiety selected from the group consisting of an alcohol, an ether, a thioether, an ester, a thioester, an amide, a carbonate, a thiocarbonate, a carbamate, a thiocarbamate, a urea, a phosphate, a phosphate salt or a phosphate ester; y is 1 or 2; R.sup.24 is selected from hydrogen, lower alkyl and R.sup.P; each m is, independently of the others, an integer from 1 to 3; and each n is, independently of the others, an integer from 0 to 3, with the proviso that at least one of R.sup.21, R.sup.22 and R.sup.23 is R.sup.P. 2. The compound of claim 1 in which R.sup.5 is fluoro. 3. The compound 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 compound of claim 3 in which R.sup.2 is 3,4,5 tri(lower alkoxy)phenyl. 5. The compound of claim 4 in which R.sup.2 is 3,4,5-(trimethoxy)phenyl. 6. The compound of claim 1 in which Y is O, Z.sup.1 is CH, Z.sup.2 is N, 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 compound 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 compound of claim 7 in which R.sup.2 is 3,4,5-tri(lower alkoxy)phenyl. 9. The compound of claim 8 in which R.sup.2 is 3,4,5-(trimethoxy)phenyl. 10. The compound of claim 9 in which only R.sup.21 is R.sup.P. 11. The compound of claim 10 in which R.sup.P comprises a group selected from the group consisting of an ester, a thioester, an ether, a thioether, a carbonate, an amide, and a carbamate. 12. The compound of claim 9 in which R.sup.3, together with the heteroatom, A, to which it is bonded, is a phosphate group. 13. The compound of claim 12 in which R.sup.P has the formula --(CR.sup.dR.sup.d).sub.y--O--P(O)(OH).sub.2, or a salt thereof, where y is 1 or 2; each R.sup.d is, independently of the others, selected from 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 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 compound of claim 12 in which R.sup.P is selected from --CH.sub.2--O--P(O)(OH).sub.2, --CH.sub.2CH.sub.2--O--P(O)(OH).sub.2 and salts thereof. 15. The compound of claim 10 in which R.sup.P comprises a phosphate ester group. 16. The compound of claim 15 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 substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) 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 hydrogen, unsubstituted or substituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, and substituted or unsubstituted (C7-C20) arylalkyl; each R.sup.g is, independently of the others, selected from hydrogen and lower alkyl; each R.sup.h is, independently of the others, selected from 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; z is an integer ranging from 0 to 2; y is 1 or 2; each R.sup.d is, independently of the others, selected from 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 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. 17. The compound of claim 10 in which R.sup.P is selected from the group consisting of --CH.sub.2--O--P(O)(OH).sub.2, --CH.sub.2CH.sub.2--O--P(O)(OH).sub.2, and --CH.sub.2OH or a salt thereof. 18. A method of treating an autoimmune disease in a subject, and/or one or more symptoms associated therewith, comprising administering to the subject an amount of a compound according to claim 1 effective to treat or prevent the autoimmune disease, wherein the autoimmune disease is selected from Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. 19. A method of treating rheumatoid arthritis in a subject, comprising administering to a subject suffering from rheumatoid arthritis an amount of a compound according to claim 1 effective to provide therapeutic benefit. 20. The method of claim 19 in which the amount of the compound administered is effective to achieve a serum concentration of the corresponding drug that is at or above the IC.sub.50 of Syk inhibition of the drug, as measured in an in vitro assay.