Details for Patent: 7,642,351

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:	Rogel Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Oct 05, 2006
Application Number:	11/539,029
Claims:	1. A compound of formula I: ##STR00062## wherein: each of R.sup.2 and R.sup.4 independently is a phenyl substituted with one or more R.sup.8 groups or a heteroaryl selected from the group consisting of: ##STR00063## wherein the heteroaryl is optionally substituted with one or more R.sup.8 groups and at least one of R.sup.2 and R.sup.4 is the heteroaryl; R.sup.5 is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R.sup.8 groups, --OR.sup.d, --SR.sup.d, fluoro, (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, --NR.sup.cR.sup.c, (C1-C3) haloalkyl, --CN, --NC, --OCN, --SCN, --NO, --NO.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.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O)NR.sup.cR.sup.c, --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, --OC(O)R.sup.d, --SC(O)R.sup.d, --OC(O)OR.sup.d, --SC(O)OR.sup.d, --OC(O)NR.sup.cR.sup.c; --SC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c, --SC(NH)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d, --[NHC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c, (C5-C10) aryl optionally substituted with one or more of the same or different R.sup.8 groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R.sup.8 groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R.sup.8 groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R.sup.8 groups; each R.sup.35 is independently hydrogen or R.sup.8; R.sup.8 is R.sup.e, R.sup.b, R.sup.e 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.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, --NH[(CH.sub.2).sub.mR.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; each R.sup.a is independently selected from the group consisting of hydrogen, (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 R.sup.b is a suitable group independently selected from the group consisting of .dbd.O, --OR.sup.d, (C1-C3) haloalkyloxy, --OCF.sub.3, .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, --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)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 independently 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 independently R.sup.a; each R.sup.e is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroatyl and 6-16 membered heteroarylalkyl; each m independently is an integer from 1 to 3; and each n independently is an integer from 0 to 3. 2. The compound of claim 1, wherein R.sup.2 and R.sup.4 are the same. 3. The compound of claim 1, wherein each R.sup.35 independently is selected from the group consisting of hydrogen, --NR.sup.cR.sup.c, --(CH.sub.2).sub.m--NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --C(O)OR.sup.d, --(CH.sub.2).sub.m--C(O)OR.sup.d and --(CH.sub.2).sub.mR.sup.d. 4. The compound of claim 1, wherein R.sup.2 is a phenyl optionally substituted with one, two or three R.sup.8 groups. 5. The compound of claim 1, wherein R.sup.2 is a phenyl optionally substituted with one or two R.sup.8 groups. 6. The compound of claim 4, wherein R.sup.2 is a phenyl substituted with one R.sup.8 substituent selected from the group consisting of (C1-C6) alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 7. The compound of claim 4, wherein R.sup.2 is a phenyl substituted with two R.sup.8 substituents selected from the group consisting of (C1-C6) alkyl --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 8. The compound of claim 4, wherein R.sup.2 is a phenyl substituted with three R.sup.8 substituents selected from the group consisting of (C1-C6) alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 9. The compound of claim 1, wherein R.sup.4 is a phenyl optionally substituted with one, two or three R.sup.8 groups. 10. The compound of claim 9, wherein the R.sup.4 phenyl is substituted at the 3-, 4- and/or 5-position. 11. The compound of claim 9, wherein R.sup.4 is a phenyl substituted with one R.sup.8 substituent selected from the group consisting of (C1-C6) alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 12. The compound of claim 9, wherein R.sup.4 is a phenyl substituted with two R.sup.8 substituents selected from the group consisting of (C1-C6) alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 13. The compound of claim 9, wherein R.sup.4 is a phenyl substituted with three R.sup.8 substituents selected from the group consisting of (C1-C6) alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 14. The compound of claim 1, wherein one of R.sup.2 and R.sup.4 is a phenyl substituted with one or more R.sup.8 groups and the other of R.sup.2 and R.sup.4 is ##STR00064## optionally substituted with one or more R.sup.8 groups.