Details for Patent: 7,812,029

Title:	Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
Abstract:	The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.
Inventor(s):	Singh; Rajinder (Belmont, CA), Argade; Ankush (Foster City, CA), Payan; Donald G. (Hillsborough, CA), Clough; Jeffrey (Redwood City, CA), Keim; Holger (Menlo Park, CA), Bhamidipati; Somasekhar (Foster City, CA), Sylvain; Catherine (Burlingame, CA), Li; Hui (Santa Clara, CA)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Feb 08, 2008
Application Number:	12/028,581
Claims:	1. A method of treating Glomerulonephritis, and/or one or more symptoms associated therewith, comprising the step of administering to a subject suffering from Glomerulonephritis an effective amount of a 2,4-pyrimidinediamine compound according to structural formula (I): ##STR00052## or a salt, hydrate, solvate and/or N-oxide thereof, wherein: L.sup.1 and L.sup.2 are each a direct bond; 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 group, 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 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 --CN, --NC, --NO.sub.2, fluoro, (C1-C3) haloalkyl, C1-C3 perhalo alkyl, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)CF.sub.3 and --C(O)OCF.sub.3; R.sup.6 is hydrogen; R.sup.8 is selected from the group consisting of 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 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, --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, .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.2NR.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)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.cC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and --[NR.sup.cC(NR.sup.a)].sub.nNR.sup.cR.sup.c; each R.sup.c is independently a protecting group or R.sup.a, or, alternatively, each R.sup.c is taken together with the nitrogen atom to which it is bonded to faun a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional hetero atoms 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 an 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, (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, independently of one another, is an optionally substituted heteroaryl selected from the group consisting of: ##STR00053## ##STR00054## ##STR00055## wherein: p is an integer from one to three; each - - - independently represents a single bond or a double bond; R.sup.35 is hydrogen or R.sup.8, where R.sup.8 is as previously defined; 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 selected from the group consisting of hydrogen or a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, R.sup.a, R.sup.b--CR.sup.aR.sup.b--O--C(O)R.sup.8, --CR.sup.aR.sup.b--O--PO(OR.sup.8).sub.2, --CH.sub.2--O--PO(OR.sup.8).sub.2, --CH.sub.7--PO(OR.sup.8).sub.2, --C(O)--CR.sup.aR.sup.b--N(CH.sub.3).sub.2, --CR.sup.aR.sup.b--O--C(O)--CR.sup.aR.sup.b--N(CH.sub.3).sub.2, --C(O)R.sup.8, --C(O)CF.sub.3 and --C(O)--NR.sup.8--C(O)R.sup.8; 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 and/or 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, and carbamate; 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.39--CHR.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; R.sup.39 and R.sup.40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl. 2. The method of claim 1 in which R.sup.2 is selected from the group consisting of phenyl, benzodioxanyl, benzodioxolyl, benzoxazinyl, benzoxazolyl, benzopyranyl, benzotriazolyl, 1,4-benzoxazinyl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one, 2H-1,3-benzoxazinyl-2,4(3H)-dione, benzoxazolyl-2-one, dihydrocournarinyl, 1,2-benzopyronyl, benzofuranyl, benzo[b]furanyl, indolyl, and pyrrolyl each of which may be optionally substituted with one or more of the same or different R.sup.8 groups. 3. The method of claim 1 in which R.sup.2 and R.sup.4 are the same. 4. The method of claim 1 in which each R.sup.35 is independently selected from the group consisting of hydrogen, R.sup.d, --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.m--OR.sup.d. 5. The method of claim 4 in which each in is one. 6. The method of claim 1 in which R.sup.2 is an optionally substituted 5-15 membered heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 7. The method of claim 1 in which R.sup.4 is an optionally substituted 5-15 membered heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 8. The method of claim 1 in which one of R.sup.2 or R.sup.4 is phenyl substituted with one, two or three R.sup.8 groups. 9. The method of claim 8 in which the substituted phenyl is mono substituted. 10. The method of claim 9 in which the R.sup.4 phenyl is substituted at the ortho, meta or para position. 11. The method of claim 10 in which R.sup.8 is selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched 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 method of claim 8 in which the substituted phenyl is disubstituted. 13. The method of claim 12 in which the R.sup.8 substituents are positioned 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; or 3,5-. 14. The method of claim 12 in which each R.sup.8 is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, --OR.sup.a optionally substituted with one or more of the same or different R.sup.a or R.sup.b groups, --O--(CH.sub.2),n-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. 15. The method of claim 8 in which the substituted phenyl is trisubstituted. 16. The method of claim 15 in which the R.sup.8 substituents are positioned 2,3,4-; 2,3,5-; 2,3,6-; 2,4,5-; 2,4,6-; 2,5,6-; or 3,4,5-. 17. The method of claim 16 in which each R.sup.8 is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, OR.sup.a optionally substituted with one or more of the same or different R.sup.a or R.sup.b groups, --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--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --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. 18. The method of claim 15 in which the trisubstituted phenyl has the formula: ##STR00056## wherein: R.sup.31 is methyl or (C1-C6) alkyl; R.sup.32 is hydrogen, methyl or (C1-C6) alkyl; and R.sup.33 is a halo group. 19. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ic): ##STR00057## or a salt, hydrate, solvate and/or N-oxide thereof, wherein: R.sup.4 is an optionally substituted heteroaryl; and R.sup.18 is --O(CH.sub.2).sub.m--R.sup.b, where m and R.sup.b are as defined in claim 1. 20. The method of claim 19 in which --R.sup.18 is --O--CH.sub.2--C(O)--NHCH.sub.3. 21. The method of claim 1 in which the 2,4-pyrimidinediamine compound is selected from the group consisting of compounds N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl- aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R940323), N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-meth- ylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R940347) and N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl- aminocarbonylmethyleneoxy)phenyl]-2,4,pyrimidinediamine (R921303). 22. The method of claim 1 in which the 2,4-pyrimidinediamine compound is administered in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, diluent or excipient. 23. The method of claim 1, wherein the 2,4-pyrimidinediamine compound is selected from the group consisting of: 7.4.35 N4-(2-Aminopyrid-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxy- phenyl]-2,4-pyrimidinediamine 7.4.36 N4-[2-(N-Acetylamino)pyrid-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylme- thyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.39 N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxaz- in-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.40 N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxaz- in-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.44 N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxaz- in-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.45 N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxaz- in-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.46 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-6-yl- )-5-fluoro-2,4-pyrimidinediamine 7.4.50 N4-[2-Aminopyrid-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinedi- amine 7.4.51 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine 7.4.52 N4-[2-(N-Acetylamino)pyrid-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro- -2,4-pyrimidinediamine 7.4.53 N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5- -fluoro-2,4-pyrimidinediamine 7.4.54 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy-5-- trifluoromethylphenyl)-2,4-pyrimidinediamine 7.4.55 N2-(2,6-Dimethoxypyrid-3-yl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-- yl)-5-fluoro-2,4-pyrimidinediamine 7.4.61 N4-[2-(N-Acetylamino)pyrid-6-yl]-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyr- imidinediamine 7.4.62 N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylaminopyrid-- 6-yl]-2,4-pyrimidinediamine 7.4.64 N4-(2-Aminopyrid-6-yl)-N2-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,- 4-pyrimidinediamine 7.4.65 N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-flu- oro-2,4-pyrimidinediamine 7.4.66 N4-(2-Aminopyrid-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimid- inediamine 7.4.67 N2-(3-Chloro-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-p- yrimidinediamine 7.4.68 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediam- ine 7.4.70 N4-(2-Aminopyrid-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimi- dinediamine 7.4.72 N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6- -yl)-5-fluoro-2,4-pyrimidinediamine 7.4.73 N4-(3,4-Dichlorophenyl)-N2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5- -fluoro-2,4-pyrimidinediamine 7.4.74 N2-(4-Chloro-3,5-dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,- 4-pyrimidinediamine 7.4.75 N2-(4-Chloro-3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazi- n-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.76 (+)-N-4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N-methylamino- carbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.77 (+)-N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminocarbonyl- )-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.78 (+)-N-4-(3-Chloro-4-trifluoromethoxyphenyl)-N2-[2-(N,N-dimethylaminocarbo- nyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.79 (+)-N-4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N-methylaminomethylene)-2,3-dih- ydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.80 5-Fluoro-N2-[2(R)-{(1R,2S,5R)-menthyloxycarbonyl}-2,3-dihydrobenzofuran-5- -yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.4.81 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2(R)-{(1R,2S,5R)-ment- hyloxycarbonyl}-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.82 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin- -6-yl)-5-fluoro-2,4-pyrimidinediamine p-Toluenesulfonic Acid Salt 7.4.83 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-- 5-fluoro-2,4-pyrimidinediamine.sub.-Methanesulfonic Acid Salt 7.4.84 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-- 5-fluoro-2,4-pyrimidinediamine.sub.-Benzenesulfonic Acid Salt 7.4.85 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-- 5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.4.86 N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-- 5-fluoro-2,4-pyrimidinediamine DL-Camphoursulfonic Acid Salt 7.4.87 N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5- -fluoro-2,4-pyrimidinediamine p-Toluenesulfonic Acid Salt 7.4.88 N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5- -fluoro-2,4-pyrimidinediamine Benzenesulfonic Acid Salt 7.4.89 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediam- ine p-Toluenesulfonic Acid Salt 7.4.90 N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyle- neoxyphenyl]-2,4-pyrimidinediamine p-Toluenesulfonic Acid Salt 7.4.101 (+) N2-(2-Carboxyl-2,3-dihydrobenzofuran-5-yl)-N4-(3-chloro-4-trifluoromethox- yphenyl)-5-fluoro-2,4-pyrimidinediamine 7.4.102 (+) N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2,3-dihydroxypro- pylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine 7.4.103 (+) N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylam- ino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine 7.4.104 (+) N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethyl-N- -methylamino]carbonyl-2,3-dihydrobenzo-furan-5-yl]-2,4-pyrimidinediamine 7.4.105 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-isopropy- lamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine 7.4.106 5-Fluoro-N4-(2-isopropoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethy- leneoxyphenyl]-2,4-pyrimidinediamine 7.4.114 N4-(2,2-Difluoro-3-oxo-4H-benz [1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.4.115 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-difluoro-3-oxo-4H-- benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.119 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine 7.4.120 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimi- dinediamine 7.4.121 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-- 2,4-pyrimidinediamine 7.4.122 N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5- -yl]-5-fluoro-2,4-pyrimidinediamine 7.4.123 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminom- ethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.124 N4-(3,4-Dichlorophenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5- -fluoro-2,4-pyrimidinediamine 7.4.125 N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6- -yl)-5-fluoro-2,4-pyrimidinediamine 7.4.126 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-- 2,4-pyrimidinediamine 7.4.127 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminoc- arbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.128 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-me- thoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.4.129 N2-(3,5-Dichlorophenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5- -fluoro-2,4-pyrimidinediamine 7.4.137 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimet- hylphenyl)-2,4-pyrimidinediamine 7.4.147 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4- ]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.148 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4- ]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.149 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-- yl)-2,4-pyrimidinediamine 7.4.150 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-- yl)-2,4-pyrimidinediamine 7.4.153 5-Fluoro-N4-[2-methyl-2-(N-methylaminocarbonyl)-3-oxo-4H-benz[1,4]oxazin-- 6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediami- ne 7.4.154 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1- -methylindazolin-6-yl)-2,4-pyrimidinediamine 7.4.155 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(2,2-dimethyl-3-oxo-4H- -benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.156 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methylinda- zolin-6-yl)-2,4-pyrimidinediamine 7.4.157 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-chloro-4-methoxy- phenyl)-5-fluoro-2,4-pyrimidinediamine 7.4.158 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxypheny- l)-5-fluoro-2,4-pyrimidinediamine 7.4.159 N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine 7.4.160 N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indazoli- n-6-yl)-2,4-pyrimidinediamine 7.4.161 N2-(3-tert-Butylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine 7.4.162 N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-hydrox- yphenyl)-2,4-pyrimidinediamine 7.4.163 N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-fluoro-4-methoxy- phenyl)-5-fluoro-2,4-pyrimidinediamine 7.4.164 N2-(3-Chlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-- fluoro-2,4-pyrimidinediamine 7.4.165 N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine 7.4.166 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methyli- ndazolin-6-yl)-2,4-pyrimidinediamine 7.4.167 N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.168 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.169 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy- carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.4.170 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-flu- oro-2,4-pyrimidinediamine 7.4.171 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.172 N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]o- xazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.173 N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2- ,4-pyrimidinediamine 7.4.174 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-flu- oro-2,4-pyrimidinediamine 7.4.183 (+) N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-m- ethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.186 (+) 5-Fluoro-N-4-[4-(N-methyl)amino-1-benzopyran-6-yl[-N2-[3-(N-methylamino)c- arbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.187 (+) N4-[4-(N-tert-Butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-5-fluoro-N- 2-[3-(N-methylamino)carbonyl-methyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.194 (S)--N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro- -N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.195 (R)--N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro- -N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.196 (S)--N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino- )carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.197 (R)--N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbony- lmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.198 (+) N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-(indazo- l-6-yl)-2,4-pyrimidinediamine 7.4.199 (+) N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidined- iamine 7.4.200 (+) N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro- -2,4-pyrimidinediamine 7.4.201 (+) N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,5-dimethoxyph- enyl)-5-fluoro-2,4-pyrimidinediamine 7.4.202 (+) N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyri- midinediamine 7.4.203 (+) N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3-chloro-4-meth- oxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.4.204 (+) N4-(4-Amino-1-benzopyran-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4- -pyrimidinediamine 7.4.205 (+) N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,4-dichlorophe- nyl)-5-fluoro 2,4-pyrimidinediamine 7.4.206 (+) N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrim- idinediamine 7.4.207 (+) N2-[4-(N-tert-Butoxycarbonylamino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphe- nyl)-5-fluoro-2,4-pyrimidinediamine 7.4.208 (+) N2-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N4-(3,4-dichlorophe- nyl)-5-fluoro-2,4-pyrimidinediamine 7.4.209 N2-[4(R,S)--(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N4-[- 2-(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.4.210 (+) N2-(4-Amino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-- pyrimidinediamine 7.4.211 (+) N2-(4-Amino-1-benzopyran-6-yl)-N4-(3,4-dichlorophenyl)-5-fluoro 2,4-pyrimidinediamine 7.4.213 N2-[4(R,S)-Amino-1-benzopyran-6-yl)-5-fluoro-N4-(2(S)-methyl-3-oxo-4H-ben- z[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.4.245 (+)-5-Fluoro-N2-[3-(N-methylamino)carbonyl-methyleneoxyphenyl]-N4-[4-(N-p- -toluenesulfonyl)amino-1-benzopyran-6-yl)-2,4-pyrimidinediamine 7.4.247 (+)-5-Fluoro N4-[4-(N-methanesulfonyl)amino-1-benzopyran-6-yl)-N2-[3-(N-methylamino)ca- rbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.4.248 (+)-N4-[4-N--(N,N-Dimethylaminomethylencarbonyl)amino-1-benzopyran-6-yl]-- 5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinedi- amine 7.4.249 (+)-N4-[4-N--(N,N-Dimethylaminomethylencarbonyl)-N-methylamino-1-benzopyr- an-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyr- imidinediamine 7.4.281 N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-ox- o-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.282 N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-o- xo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.290 N2-(3,4-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 7.4.291 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin- -6-yl)-2,4-pyrimidinediamine 7.4.292 N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]ox- azin-6-yl)-2,4-pyrimidinediamine 7.4.293 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-2,4-pyrimidinediamine 7.4.294 5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin- -6-yl)-2,4-pyrimidinediamine 7.4.297 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-- 6-yl)-2,4-pyrimidinediamine 7.4.306 N4-(2,2-Difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(Nmethy- lamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine p-Toluenesulfonic Acid Salt 7.4.307 N4-(2,2-Difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(N-meth- ylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine Benzenesulfonic Acid Salt 7.4.314 N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-2,4-pyrimidinediamine 7.4.316 N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl-2H-- 3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.319 N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 7.4.320 N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6- -yl)-5-fluoro-2,4-pyrimidinediamine 7.4.321 5-Fluoro-N2-(3-isopropylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-- 2,4-pyrimidinediamine 7.4.322 N2-(3-Chloro-4-methylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-- 6-yl)-2,4-pyrimidinediamine 7.4.323 5-Fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1- ,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.324 5-Fluoro-N2-(indol-6-yl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyr- imidinediamine 7.4.325 N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-- 6-yl)-2,4-pyrimidinediamine 7.4.326 N2-(3,5-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 7.4.327 N2-(3-Bromophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-- pyrimidinediamine 7.4.328 N2-(3-tert-Butylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 7.4.329 N2-(3,4-Difluorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 7.4.342 (S)-5-Fluoro-N2-[3-(N-methylamino)carbonyl-methyleneoxyphenyl]-N4-(2-meth- yl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.343 N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[3-(N-meth- ylamino)carbonylmethylenedioxyphenyl]-2,4-pyrimidine diamine 7.4.344 (R)-5-Fluoro-N2-[3-(N-methylamino)carbonyl-methyleneoxyphenyl]-N4-(2-meth- yl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.345 N2-(3-Chloro-4-hydroxy-5-methylyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-- isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.346 (S)--N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,- 4]oxazin[6-yl)-2,4-pyrimidinediamine 7.4.347 (R)--N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,- 4]oxazin-6-yl)-2,4-pyrimidinediamine 7.4.348 N2-(3,5-Dimethoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-y- l)-5-fluoro-2,4-pyrimidinediamine 7.4.349 (S)--N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-ben- z[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine 7.4.350 (R)--N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-ben- z[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine 7.4.351 (+)-N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[2-(2-hydroxy-ethyl)-3-oxo-4H-be- nz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.4.352 (+)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-[2-(2-hydroxy-ethyl)-3-oxo-- 4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.4.353 (S,S)--N2,N4-Bis-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-py- rimidinediamine 7.4.354 (S)--N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxa- zin-6-yl)-2,4-pyrimidinediamine 7.4.355 (R)--N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxa- zin-6-yl)-2,4-pyrimidinediamine 7.4.356 N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoqui- nolin-7-yl)-5-fluoro-2,4-pyrimidinediamine 7.4.357 N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-N2-(indazol-6-yl)-5-fl- uoro-2,4-pyrimidinediamine 7.4.358 N4-(3,3-Dimethyl-4H-benz[1,4]oxazin-6-yl)-N2-(3,5-dimethylphenyl)-5-fluor- o-2,4-pyrimidinediamine 7.4.359 N2-(3-Chloro-4-methoxyphenyl)-N4-(3,3-dimethyl-4H-benzo[1,4]oxazin-6-yl)-- 5-fluoro-2,4-pyrimidinediamine 7.4.360 N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyri- midinediamine 7.4.361 N4-(3,3-Dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1-methylindazol-6- -yl)-2,4-pyrimidinediamine 7.4.362 (R)--N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,- 4]oxazin-6-yl)-2,4-pyrimidinediamine Toluenesulfonic Acid Salt 7.4.372 N4-(2,6-Dimethoxypyrid-3-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]- -5-fluoro-2,4-pyrimidinediamine 7.4.373 N4-(4-Chlorophenyl)-5-fluoro-N2-{1-[2-(N-methylamino)carbonylethyl]indazo- lin-5-yl}-2,4-pyrimidinediamine 7.4.374 N4-(4-Chlorophenyl)-5-fluoro-N2-[1-(3-hydroxy-propyl)indazolin-5-yl]-2,4-- pyrimidinediamine 7.4.375 N4-(3,4-Difluorophenyl)-N2-[1-(2-ethoxycarbonyl-ethyl)indazolin-5-yl]-5-f- luoro-2,4-pyrimidinediamine 7.4.376 N4-(3,4-Difluorophenyl)-5-fluoro-N2-{1-[2-(N-- methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine 7.4.377 N4-(3,4-Difluorophenyl)-5-fluoro-N2-[1-(3-hydroxy-propyl)indazolin-5-yl]-- 2,4-pyrimidinediamine 7.4.378 N4-(3,4-Dichlorophenyl)-N2-[1-(2-ethoxycarbonyl-ethyl)indazolin-5-yl]-5-f- luoro-2,4-pyrimidinediamine 7.4.379 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]ind- azolin-5-yl}-2,4-pyrimidinediamine 7.4.380 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxy-propyl)indazolin-5-yl]-- 2,4-pyrimidinediamine 7.4.381 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyr- imidinediamine 7.4.382 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidi- nediamine 7.4.384 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-y- l)-2,4-pyrimidinediamine 7.4.385 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonylbenzyl- )indazolin-6-yl]-2,4-pyrimidinediamine 7.4.386 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonyl- benzyl)indazolin-6-yl]-2,4-pyrimidinediamine 7.4.387 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-{1-[2-methoxy-4-(N-methylaminoca- rbonyl)benzyl]indazolin-6-yl}-2,4-pyrimidinediamine 7.4.388 N4-(3,4-Difluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamin- e 7.4.389 N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4- -pyrimidinediamine 7.4.390 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-py- rimidinediamine 7.4.391 N4-(3,4-Dichlorophenyl)-N2-[1-(2-ethoxy-carbonylethyl)indazolin-6-yl]-5-f- luoro-2,4-pyrimidinediamine 7.4.392 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylamino)carbonylethyl]ind- azolin-6-yl}-2,4-pyrimidinediamine 7.4.393 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-(3-hydroxypropyl)indazolin-6-yl]-2- ,4-pyrimidinediamine 7.4.394 N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl- ]-5-fluoro-2,4-pyrimidinediamine 7.4.395 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-6- -yl]-2,4-pyrimidinediamine 7.4.396 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidine- diamine 7.4.397 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)et- hyl]indazolin-6-yl}-2,4-pyrimidinediamine 7.4.398 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-y- l)-2,4-pyrimidinediamine 7.4.399 N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyr- imidinediamine 7.4.400 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-1-methylindazolin-5-yl)-2,4-pyrimidi- nediamine 7.4.401 N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-p- yrimidinediamine 7.4.402 N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidined- iamine 7.4.403 N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidined- iamine 7.4.404 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidine- diamine 7.4.405 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-5-yl)-2,4-pyrimidine- diamine 7.4.406 N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N-4-{4H-imidazo[2,1-c]-be- nz [1,4]oxazin-8-yl}-2,4-pyrimidinediamine 7.4.407 N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-y- l)-2,4-pyrimidinediamine 7.4.408 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimid- inediamine 7.4.410 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediami- ne 7.4.411 N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazine-6-yl)-5-fluoro-N4-(1- -methylindazolin-6-yl)-2,4-pyrimidinediamine 7.4.412 N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyr- imidinediamine 7.4.413 N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyr- imidinediamine 7.4.414 N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidined- iamine 7.4.415 N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidined- iamine 7.4.416 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-- yl)-2,4-pyrimidinediamine Benzenesulfonic Acid Salt 7.4.417 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-- yl)-2,4-pyrimidinediamine p-Toluenesulfonic Acid Salt 7.4.418 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylet- hyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.419 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(3-hydroxy- propyl)indazolin-5-yl]-2,4-pyrimidinediamine 7.4.420 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2(N-methy- laminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine 7.4.421 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylet- hyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.422 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2-(N-meth- ylaminocarbonyl)ethyl]indazolin-6-yl}-2,4-pyrimidinediamine 7.4.423 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(methoxycarbonyl)me- thyl-indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.424 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(N-methyla- minocarbonyl)methylindazolin-5-yl}-2,4-pyrimidinediamine 7.4.425 N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-5-- yl)-2,4-pyrimidinediamine 7.4.426 N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(1-methylinda- zolin-5-yl)-2,4-pyrimidinediamine 7.4.427 N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-6-- yl)-2,4-pyrimidinediamine 7.4.428 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4 pyrimidinediamine 7.4.429 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(2-methoxy- -4-methoxycarbonylbenzyl)indazolin-6-yl]2,4-pyrimidinediamine 7.4.430 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidi- nediamine p-Toluenesulfonic Acid Salt 7.4.431 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4 pyrimidinediamine 7.4.432 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(2-methylinda- zolin-6-yl)-2,4-pyrimidinediamine 7.4.433 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-py- rimidinediamine 7.4.434 N4-(3,4-Dichlorophenyl)-N2-[2-(2-ethoxy-carbonylethyl)indazolin-5-yl]-5-f- luoro-2,4-pyrimidinediamine 7.4.435 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(2-ethoxycarbonylet- hyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.4.436 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(1-methylindazolin-6-yl)-2,4-py- rimidinediamine 7.4.437 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(2-methylindazolin-6-yl)-2,4-py- rimidinediamine 7.4.438 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2- ,4-pyrimidinediamine Bis(p-Toluenesulfonic Acid Salt 7.4.439 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{2-[2-(N-- methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine 7.4.440 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{2-[2(N-- methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine 7.4.441 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-py- rimidinediamine 7.4.442 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidine- diamine 7.4.443 N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl- ]-5-fluoro-2,4-pyrimidinediamine 7.4.444 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5- -yl]-2,4-pyrimidinediamine 7.4.445 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)et- hyl]indazolin-5-yl}-2,4-pyrimidinediamine, and salts, hydrates, solvates or N-oxides thereof.