Details for Patent: 7,557,210

Title:	2,4-pyrimidinediamine compounds and their uses
Abstract:	The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
Inventor(s):	Singh; Rajinder (Belmont, CA), Argade; Ankush (Foster City, CA), Payan; Donald (Hillsborough, CA), Molineaux; Susan (San Mateo, CA), Holland; Sacha J. (San Francisco, CA), Clough; Jeffrey (Redwood City, CA), Keim; Holger (Menlo Park, CA), Bhamidipati; Somasekhar (Foster City, CA), Sylvain; Catherine (Burlingame, CA), Li; Hui (Millbrae, CA), Rossi; Alexander B. (San Francisco, CA)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Jan 31, 2003
Application Number:	10/355,543
Claims:	1. A compound according to structuial formula (I): ##STR00065## or a salt or N-oxide thereof, wherein: R.sup.2 is selected from the group consisting of phenyl mono substituted at the 3- or 5-position with an R.sup.8 group, phenyl di- or tri-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.4 is selected from the group consisting of phenyl substituted with one or two 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.8 is selected from the group consisting of R.sup.a, R.sup.b, R.sup.c 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 R.sup.a or R.sup.b, --B(OR.sup.a).sub.2, --B(NR.sup.cCR.sup.c).sub.2, --(CH.sub.2).sub.mR.sup.b, --(CHR.sup.a).sub.m--R.sup.b; --O--(CH.sub.2).sub.mR.sup.b, --S--(CH.sub.2).sub.mR.sup.bk, --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.mR.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.mR.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.mR.sup.b, --NH--(CH.sub.2).sub.mR.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.mR.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.mR.sup.b; each R.sup.a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C1-C10) aryl, (C6-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 suitable group independently selected from the group consisting of .dbd.O, --OR.sup.d, (C1-C3) haloalkyloxy, .dbd.S, --SR.sup.d, .dbd.NR.sup.d, .dbd.NOR.sup.d, --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.d, --S(O).sub.2R.sup.d, --S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c, --S(O).sub.1NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d, --C(O)OR.sup.d, --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).sup.R.sup.d, --OC(O)OR.sup.d, --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.d, --[NR.sup.aC(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d, --[NR.sup.aC(O)].sub.nOR.sup.d--[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.aC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and --[NR.sup.aC(NR.sup.a)].sub.nNR.sup.cR.sup.c; each R.sup.c is R.sup.a, or, alternatively, two R.sup.c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R.sup.a or suitable R.sup.b groups; each R.sup.d is R.sup.a; each R.sup.c is independently selected from the group consisting of(C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3; wherein: one or both of R.sup.2 and R.sup.4 are, independently of one another, a heteroaryl selected from the group consisting of: ##STR00066## ##STR00067## wherein: R.sup.35 is hydrogen or R.sup.8; X is selected from the group consisting of CH, N and N--O; each Y is independently selected from the group consisting of O, S and NH; each Y.sup.1 is independently selected from the group consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH and NR.sup.37; each Y.sup.2 is independently selected from the group consisting of CH, CH.sub.2, O, S, N, NH and NR.sup.37; R.sup.36 is hydrogen or alkyl; R.sup.37 is hydrogen, R.sup.38 is selected from the group consisting of alkyl and aryl; A is selected from the group consisting of O, NH and NR.sup.38; R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R.sup.9 and R.sup.10 or R.sup.11 and R.sup.12, or R.sup.9 and R.sup.10 and R.sup.11 and R.sup.12 are taken together form an oxo group; each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl; Q is selected from the group consisting of --OH, OR.sup.8, --NR.sup.cR.sup.c, --NHR.sup.39--C(O)R.sup.8, --NHR.sup.39--C(O)OR.sup.8, --NR.sup.39CHR.sup.40--R.sup.b, --NR.sup.39--(CH.sub.2).sub.m--R.sup.b and --NR.sup.39--C(O)-CHR.sup.40--NR.sup.cR.sup.c; and R.sup.39 and R.sup.40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR.sup.8. 2. The compound of claim 1 in which R.sup.2 and R.sup.4 are the same. 3. The compound of claim `in which each R.sup.35 is independently selected from the group consisting of hydrogen, --OR.sup.d, --NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --C(O)OR.sup.d, and --OR.sup.d, and --C(O)OR.sup.d, where R.sup.c and R.sup.d are as defined in claim . 4. The compound of claim 1 in which R.sup.4 is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 5. The compound of claim 1 which R.sup.4 is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 6. The compound of claim 1 in which one of R.sup.2 and R.sup.4 is, a phenyl mono substituted at the 3- or 5-position with an R.sup.8 group for R.sup.2, a phenyl di- or tri-substituted with one or more of the same or different R.sup.8 groups for R.sup.2 or a phenyl substituted with one or two of the same or different R.sup.8 groups for R.sup.4. 7. The compound of claim 6 in which the substituted R.sup.4 phenyl group is mono substituted with R.sup.8. 8. The compound of claim 7 in which R.sup.8 is selected from the group consisting of (C1-C6) alkyl, OR.sup.d, --O--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --C(O)OR.sup.d, and --(NH)R.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.d, --O--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cNR.sup.c, and --[NHC(O)].sub.nNR.sup.cR.sup.c. 9. The compound of claim 6 in which the substituted R.sup.2 or R.sup.4 phenyl group is disubstituted with R.sup.8. 10. The compound of claim 9 in which each R.sup.8 is independently selected from the group consisting of (C1-C6) alkyl, --OR.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b, --O--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cR.sup.c, --C(O)NR.sup.c,R.sup.c, --C(O)OR.sup.d, and --(NH)R.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.d, --O--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cNR.sup.c, and --[NHC(O)].sub.nNR.sup.cR.sup.c. 11. The compound of claim 1 in which the R.sup.2 phenyl group is trisubstituted with R.sup.8. 12. The compound of claim 11 in which each R.sup.8 is independently selected from the group consisting of (C1-C6) alkyl, --OR.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b, --O--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --C(O)OR.sup.d, and --(NH)R.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.d, --O--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.mR.sup.b where R.sup.b is selected from the group consisting of --NR.sup.cNR.sup.c, and --[NHC(O)].sub.nNR.sup.cR.sup.c. 13. The, compound of claim 11 in which the phenyl has the formula: ##STR00068## wherein: R.sup.31 is methyl or (C1-C6) alkyl; R.sup.32 is hydrogen or (C1-C6) alkyl; and R.sup.33 is a halo group. 14. The compound of claim 1 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay. 15. The compound of claim 14 which has an IC.sub.50 of about 20 .mu.M or less. 16. A pharmaceutical composition comprising a pyrimidinediamine compound and a pharmaceutically acceptable excipient, carrier or dilutent, said pyrimidinediamine compound being a compound according to structural formula (I): ##STR00069## or a salt or N-oxide thereof, wherein: R.sup.2 is selected from the group consisting of phenyl mono substituted at the 3- or 5-position with an R.sup.8 group, phenyl di- or tn-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.4 is selected from the group consisting of phenyl substituted with one or two 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.8 is selected from the group consisting of R.sup.a, R.sup.b, R.sup.c 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 R.sup.a or R.sup.b, --B(OR.sup.a).sub.2, --B(NR.sup.cCR.sup.c).sub.2, --(CH.sub.2).sub.mR.sup.b, --(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.mR.sup.b, --S--(CH.sub.2).sub.mR.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.mR.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.mR.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.mR.sup.b, --NH--(CH.sub.2).sub.mR.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.mR.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.mR.sup.b; each R.sup.a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C1-C10) aryl, (C6-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 suitable group independently selected from the group consisting of .alpha.O, --OR.sup.d, (C1-C3) haloalkyloxy, .dbd.S, --SR.sup.d, .dbd.NR.sup.d, .dbd.NOR.sup.d, --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.d, --S(O).sub.2R.sup.d, --S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c, --S(O).sub.1NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d, --C(O)OR.sup.d, --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).sup.R.sup.d, --OC(O)OR.sup.d, --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.d, --[NR.sup.aC(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d, --[NR.sup.aC(O)].sub.nOR.sup.d--[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.aC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and --[NR.sup.aC(NR.sup.a)].sub.nNR.sup.cR.sup.c; each R.sup.c is R.sup.a, or, alternatively, two R.sup.c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R.sup.a or suitable R.sup.b groups; each R.sup.d is R.sup.a; each R.sup.c is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3; wherein: one or both of R.sup.2 and R.sup.4 are, independently of one another, a heteroaryl selected from the group consisting of: ##STR00070## ##STR00071## wherein: R.sup.35 is hydrogen or R.sup.8; X is selected from the group consisting of CH, N and N-O; each Y is independently selected from the group consisting of O, S and NH; each Y.sup.1 is independently selected from the group consisting of O, S, SO, SO.sub.2, SONR.sup.36, ,NH and NR.sup.37; each Y.sup.2 is independently selected from the group consisting of CH, CH.sub.2, O, S, N, NH and NR.sup.37; R.sup.36 is hydrogen or alkyl; R.sup.37 is hydrogen, R.sup.38 is selected from the group consisting of alkyl and aryl; A is selected from the group consisting of O, NH and NR.sup.38; R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R.sup.9 and R.sup.10 or R.sup.11 and R.sup.12, or R.sup.9 and R.sup.10 and R.sup.11 and R.sup.12 are taken together form an oxo group; each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl; Q is selected from the group consisting of --OH, OR.sup.8, --NR.sup.cR.sup.c, --NHR.sup.39--C(O)R.sup.8, --NHR.sup.39--C(O)OR.sup.8, --NR.sup.39CHR.sup.40--R.sup.b, --NR.sup.39--(CH.sub.2).sub.m--R.sup.b and --NR.sup.39--C(O)-CHR.sup.40--NR.sup.cR.sup.c; and R.sup.39 and R.sup.40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR.sup.8.