U.S. patent application number 13/442480 was filed with the patent office on 2012-10-04 for methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds.
This patent application is currently assigned to RIGEL PHARMACEUTICALS, INC.. Invention is credited to Ankush Argade, Somasekhar Bhamidipati, David Carroll, Jeffrey Clough, Holger Keim, Hui Li, Rajinder Singh, Catherine Sylvain.
Application Number | 20120253039 13/442480 |
Document ID | / |
Family ID | 34119815 |
Filed Date | 2012-10-04 |
United States Patent
Application |
20120253039 |
Kind Code |
A1 |
Singh; Rajinder ; et
al. |
October 4, 2012 |
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 lupus erythematosis and/or its associated symptoms and
multiple sclerosis and/or its associated symptoms.
Inventors: |
Singh; Rajinder; (Belmont,
CA) ; Argade; Ankush; (Foster City, CA) ; Li;
Hui; (Santa Clara, CA) ; Bhamidipati; Somasekhar;
(Foster City, CA) ; Carroll; David; (San
Francisco, CA) ; Sylvain; Catherine; (San Mateo,
CA) ; Clough; Jeffrey; (Redwood City, CA) ;
Keim; Holger; (Irvine, CA) |
Assignee: |
RIGEL PHARMACEUTICALS, INC.
South San Francisco
CA
|
Family ID: |
34119815 |
Appl. No.: |
13/442480 |
Filed: |
April 9, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10903263 |
Jul 30, 2004 |
8178671 |
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13442480 |
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60491641 |
Jul 30, 2003 |
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60531598 |
Dec 19, 2003 |
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60572246 |
May 18, 2004 |
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Current U.S.
Class: |
544/51 ; 544/105;
544/320; 544/323; 544/324 |
Current CPC
Class: |
A61K 31/538 20130101;
C07D 498/06 20130101; C07D 417/12 20130101; C07D 413/14 20130101;
C07D 403/14 20130101; C07D 417/14 20130101; C07D 403/12 20130101;
C07D 498/02 20130101; A61K 31/506 20130101; C07D 405/12 20130101;
A61K 31/541 20130101; C07D 413/12 20130101; A61P 19/02 20180101;
C07D 498/04 20130101; C07D 405/14 20130101 |
Class at
Publication: |
544/51 ; 544/105;
544/320; 544/323; 544/324 |
International
Class: |
C07D 498/04 20060101
C07D498/04; C07D 403/12 20060101 C07D403/12; C07D 495/04 20060101
C07D495/04; C07D 491/056 20060101 C07D491/056; C07D 413/12 20060101
C07D413/12; C07D 497/04 20060101 C07D497/04; C07D 513/04 20060101
C07D513/04; C07D 471/04 20060101 C07D471/04 |
Claims
1. A 2,4 pyrimidinediamine compound according to structure:
##STR00088## including salts, hydrates, solvates and N-oxides
thereof, wherein: L.sup.1 is a direct bond or a linker; L.sup.2 is
a direct bond or a linker; R.sup.2 is ##STR00089## R.sup.4 is
##STR00090## X is selected from the group consisting of N and CH; Y
is selected from the group consisting of O, S, SO, SO.sub.2,
SONR.sup.36, NH, NR.sup.35 and NR.sup.37; Z is selected from the
group consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH, NR.sup.35
and NR.sup.37; R.sup.5 is selected from the group consisting of
R.sup.6, (C1-C6)alkyl optionally substituted with one or more of
the same or different R.sup.8 groups, (C1-C4)alkanyl optionally
substituted with one or more of the same or different R.sup.8
groups, (C2-C4)alkenyl optionally substituted with one or more of
the same or different R.sup.8 groups and (C2-C4)alkynyl optionally
substituted with one or more of the same or different R.sup.8
groups; each R.sup.6 independently is selected from the group
consisting of hydrogen, an electronegative group, --OR.sup.d,
--SR.sup.d, (C1-C3)haloalkyloxy, (C1-C3)perhaloalkyloxy,
--NR.sup.cR.sup.c, halogen, (C1-C3)haloalkyl, (C1-C3)perhaloalkyl,
--CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --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 and
--[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, phenyl 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; R.sup.8 is selected from the group
consisting of 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,
--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.31, independently of the others, is methyl or (C1-C6)alkyl;
each R.sup.35 is, independently of the others, selected from the
group consisting of hydrogen and R.sup.8, or, alternatively, two
R.sup.35 bonded to the same carbon atom are taken together to form
an oxo (.dbd.O), NH or NR.sup.38 group and the other two R.sup.35
are each, independently of one another, selected from the group
consisting of hydrogen and R.sup.8; each R.sup.36 is independently
selected from the group consisting of hydrogen and (C1-C6)alkyl;
each R.sup.37 is independently selected from the group consisting
of hydrogen and a progroup; R.sup.38 is selected from the group
consisting of (C1-C6)alkyl and (C5-C14)aryl; each R.sup.a is
independently selected from the group consisting of hydrogen,
(C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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 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 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 a protecting group or
R.sup.a; each m is independently an integer from 1 to 3; each n is
independently an integer from 0 to 3; and yy is 1 through 6.
2. The compound of claim 1 in which R.sup.5 is fluoro.
3. The compound of claim 2 in which R.sup.6 is hydrogen.
4. The compound of claim 1 in which Y and Z are each, independently
of one another, selected from the group consisting of O and NH.
5. The compound of claim 4 in which X is CH.
6. The compound of claim 5 in which Y and Z are each O.
7. The compound of claim 6 in which each R.sup.35 is hydrogen.
8. The compound of claim 5 in which Y is O and Z is NH.
9. A 2,4 pyrimidinediamine compound according to structure:
##STR00091## including salts, hydrates, solvates and N-oxides
thereof, wherein: L.sup.1 is a direct bond or a linker; L.sup.2 is
a direct bond or a linker; R.sup.2 is a disubstituted phenyl group
with two R.sup.b groups or R.sup.2 is a trisubstituted phenyl group
with three R.sup.b groups; R.sup.4 is ##STR00092## X is selected
from the group consisting of N and CH; Y is selected from the group
consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH, NR.sup.35 and
NR.sup.37; Z is selected from the group consisting of O, S, SO,
SO.sub.2, SONR.sup.36, NH, NR.sup.35 and NR.sup.37; R.sup.5 is
selected from the group consisting of R.sup.6, (C1-C6)alkyl
optionally substituted with one or more of the same or different
R.sup.8 groups, (C1-C4)alkanyl optionally substituted with one or
more of the same or different R.sup.8 groups, (C2-C4)alkenyl
optionally substituted with one or more of the same or different
R.sup.8 groups and (C2-C4)alkynyl optionally substituted with one
or more of the same or different R.sup.8 groups; each R.sup.6
independently is selected from the group consisting of hydrogen, an
electronegative group, --OR.sup.d, --SR.sup.d, (C1-C3)haloalkyloxy,
(C1-C3)perhaloalkyloxy, --NR.sup.cR.sup.c, halogen,
(C1-C3)haloalkyl, (C1-C3)perhaloalkyl, --CF.sub.3,
--CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --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 and
--[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, phenyl 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; R.sup.8 is selected from the group
consisting of 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,
--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.35 is, independently of the others, selected from the group
consisting of hydrogen and R.sup.8, or, alternatively, two R.sup.35
bonded to the same carbon atom are taken together to form an oxo
(.dbd.O), NH or NR.sup.38 group and the other two R.sup.35 are
each, independently of one another, selected from the group
consisting of hydrogen and R.sup.8; each R.sup.36 is independently
selected from the group consisting of hydrogen and (C1-C6)alkyl;
each R.sup.37 is independently selected from the group consisting
of hydrogen and a progroup; R.sup.38 is selected from the group
consisting of (C1-C6)alkyl and (C5-C14)aryl; each R.sup.a is
independently selected from the group consisting of hydrogen,
(C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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 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 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 a protecting group or
R.sup.a; each m is independently an integer from 1 to 3; and each n
is independently an integer from 0 to 3; with the proviso that
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;
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxypheny-
l)-5-fluoro-2,4-pyrimidinediamine;
N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl-
)-5-fluoro-2,4-pyrimidinediamine;
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;
N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl-
)-5-fluoro-2,4-pyrimidinediamine;
N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[-
1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
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;
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; and
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 are not included.
10. A compound according to the structural formula: ##STR00093##
and salts, hydrates, solvates, N-oxides and prodrugs thereof,
wherein: R.sup.2 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, (C3-C8)cycloalkyl optionally substituted
with one or more of the same or different R.sup.8 groups,
cyclohexyl 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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.4 is ##STR00094## R.sup.6a
is (C5-C10)aryl optionally substituted with one or more of the same
or different R.sup.8 groups or phenyl 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.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,
--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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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, each R.sup.c is taken
together with the nitrogen atom to which it is 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 is optionally 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 m is independently an integer from 1 to
3; each n is independently an integer from 0 to 3; R.sup.35 is a
hydrogen or a suitable R.sup.8; and R.sup.45 is a (C3-C8)cycloalkyl
optionally substituted with one or more of the same or different
R.sup.8 groups.
11. A compound according to the structural formula: ##STR00095##
and salts, hydrates, solvates and N-oxides thereof, wherein:
R.sup.2 is selected from the group consisting of ##STR00096##
wherein each R.sup.21 is independently a halogen atom or an alkyl
optionally substituted with one or more of the same or different
halo groups, R.sup.22 and R.sup.23 are each, independently of one
another, a hydrogen atom, methyl or ethyl optionally substituted
with one or more of the same or different halo groups; R.sup.4 is a
(C3-C8)cycloalkyl optionally substituted with one or more of the
same or different R.sup.8 groups; and R.sup.8 is selected from the
group consisting of 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,
--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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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, each R.sup.c is taken
together with the nitrogen atom to which it is 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 is optionally 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 m is independently an integer from 1 to
3; and each n is independently an integer from 0 to 3.
12. A compound according to the structural formula: ##STR00097##
and salts, hydrates, solvates and N-oxides thereof, wherein:
R.sup.2 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, (C3-C8)cycloalkyl optionally substituted with one
or more of the same or different R.sup.8 groups, cyclohexyl
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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.4 is selected from the
group consisting of hydrogen, (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, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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; and R.sup.8 is selected from the group consisting of
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,
--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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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, each R.sup.c is taken
together with the nitrogen atom to which it is 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 is optionally 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 m is independently an integer from 1 to
3; each n is independently an integer from 0 to 3; and R.sup.55 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, (C3-C8)cycloalkyl optionally substituted with one or more
of the same or different R.sup.8 groups, cyclohexyl 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, (C5-C15)aryl
optionally substituted with one or more of the same or different
R.sup.8 groups, 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.
13. A compound according to the structural formula: ##STR00098##
and salts, hydrates, solvates and N-oxides thereof, wherein:
R.sup.2 is ##STR00099## R.sup.4 is selected from the group
consisting of hydrogen, (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, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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; and R.sup.8 is selected from the group consisting of
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.nR.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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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, --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.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, each R.sup.c is taken
together with the nitrogen atom to which it is 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 is optionally 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 m is independently an integer from 1 to
3; each n is independently an integer from 0 to 3; and each
R.sup.35 individually is a hydrogen or R.sup.8.
14. A 2,4-pyrimidinediamine compound according to structure:
##STR00100## and salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.2 is a phenyl group or indazole group, substituted
with one or more of the same R.sup.8 groups; R.sup.4 is
##STR00101## R.sup.5 is a fluorine atom; R.sup.6 is a hydrogen
atom; R.sup.8 is selected from the group consisting of 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,
--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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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.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 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 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 an R.sup.a; each m is
independently an integer from 1 to 3; and each n is independently
an integer from 0 to 3.
15. The compound of claim 14 in which R.sup.2 is a di or tri
substituted phenyl group.
16. The compound of claim 15 in which one or more of the R.sup.8
groups are selected from the group consisting of halogens and
alkoxy groups.
17. The compound of claim 16 in which the 2,4-pyrimidinediamine
compound is 1256, 1257, 1258, 1259 or 1260.
18. A 2,4-pyrimidinediamine compound according to structure:
##STR00102## and salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.2 is ##STR00103## or phenyl substituted with one or
more R.sup.8 groups; R.sup.4 is ##STR00104## R.sup.5 is a fluorine
atom; R.sup.6 is a hydrogen atom; R.sup.11 and R.sup.12 are each,
independently of one another, selected from the group consisting of
hydrogen, alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and
hydroxyalkyl; R.sup.35 is hydrogen or R.sup.8; and R.sup.8 is
selected from the group consisting of 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,
--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, cyclohexyl,
(C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl,
benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,
morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 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.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 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 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 an R.sup.a; each m is
independently an integer from 1 to 3; and each n is independently
an integer from 0 to 3.
19. The compound of claim 18 in which R.sup.35 is not a methyl
group.
20. The compound of claim 18 in which the 2,4-pyrimidinediamine
compound is 1000, 1001 or 1002.
21-50. (canceled)
Description
1. CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit under 35 U.S.C. .sctn.119(e)
to application Ser. No. 60/491,641, filed Jul. 30, 2003 (attorney
docket No. 28575/US/US/2), Ser. No. 60/531,598, filed Dec. 19, 2003
(attorney docket No. 28575/US/8) and Ser. No. 60/572,246, filed May
18, 2004 (attorney docket No. 28575/US/9).
2. FIELD OF THE INVENTION
[0002] The present invention relates generally to
2,4-pyrimidinediamine compounds, pharmaceutical compositions
comprising the compounds, intermediates and synthetic methods of
making the compounds and methods of using the compounds and
compositions in a variety of contexts, such as in the treatment or
prevention of autoimmune diseases and/or the symptoms associated
therewith.
3. BACKGROUND OF THE INVENTION
[0003] Crosslinking of Fc receptors, such as the high affinity
receptor for IgE (Fc.epsilon.RI) and/or the high affinity receptor
for IgG (Fc.gamma.RI) activates a signaling cascade in mast,
basophil and other immune cells that results in the release of
chemical mediators responsible for numerous adverse events. For
example, such crosslinking leads to the release of preformed
mediators of Type I (immediate) anaphylactic hypersensitivity
reactions, such as histamine, from storage sites in granules via
degranulation. It also leads to the synthesis and release of other
mediators, including leukotrienes, prostaglandins and
platelet-activating factors (PAFs), that play important roles in
inflammatory reactions. Additional mediators that are synthesized
and released upon crosslinking Fc receptors include cytokines and
nitric oxide.
[0004] The signaling cascade(s) activated by crosslinking Fc
receptors such as Fc.epsilon.RI and/or Fc.gamma.RI comprises an
array of cellular proteins. Among the most important intracellular
signal propagators are the tyrosine kinases. And, an important
tyrosine kinase involved in the signal transduction pathways
associated with crosslinking the Fc.epsilon.RI and/or Fc.gamma.RI
receptors, as well as other signal transduction cascades, is Syk
kinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362
for review).
[0005] As the mediators released as a result of Fc.epsilon.RI and
Fc.gamma.RI receptor cross-linking are responsible for, or play
important roles in, the manifestation of numerous adverse events,
the availability of compounds capable of inhibiting the signaling
cascade(s) responsible for their release would be highly desirable.
Moreover, owing to the critical role that Syk kinase plays these
and other receptor signaling cascade(s), the availability of
compounds capable of inhibiting Syk kinase would also be highly
desirable.
4. SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides novel
2,4-pyrimidinediamine compounds that, as will be discussed in more
detail below, have myriad biological activities. The compounds
generally comprise a 2,4-pyrimidinediamine "core" having the
following structure and numbering convention:
##STR00001##
[0007] The compounds of the invention are substituted at the C2
nitrogen (N2) to form a secondary amine and are optionally further
substituted at one or more of the following positions: the C4
nitrogen (N4), the C5 position and/or the C6 position. When
substituted at N4, the substituent forms a secondary amine. The
substituent at N2, as well as the optional substituents at the
other positions, may range broadly in character and
physico-chemical properties. For example, the substituent(s) may be
a branched, straight-chained or cyclic alkyl, a branched,
straight-chained or cyclic heteroalkyl, a mono- or polycyclic aryl
a mono- or polycyclic heteroaryl or combinations of these groups.
These substituent groups may be further substituted, as will be
described in more detail below.
[0008] The N2 and/or N4 substituents may be attached directly to
their respective nitrogen atoms, or they may be spaced away from
their respective nitrogen atoms via linkers, which may be the same
or different. The nature of the linkers can vary widely, and can
include virtually any combination of atoms or groups useful for
spacing one molecular moiety from another. For example, the linker
may be an acyclic hydrocarbon bridge (e.g, a saturated or
unsaturated alkyleno such as methano, ethano, etheno, propano,
prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the
like), a monocyclic or polycyclic hydrocarbon bridge (e.g.,
[1,2]benzeno, [2,3]naphthaleno, and the like), a simple acyclic
heteroatomic or heteroalkyldiyl bridge (e.g., --O--, --S--,
--S--O--, --NH--, --PH--, --C(O)--, --C(O)NH--, --S(O)--,
--S(O).sub.2--, --S(O)NH--, --S(O).sub.2NH--, --O--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --O--CH.dbd.CH--CH.sub.2--, and the
like), a monocyclic or polycyclic heteroaryl bridge (e.g.,
[3,4]furano, pyridino, thiopheno, piperidino, piperazino,
pyrazidino, pyrrolidino, and the like) or combinations of such
bridges.
[0009] The substituents at the N2, N4, C5 and/or C6 positions, as
well as the optional linkers, may be further substituted with one
or more of the same or different substituent groups. The nature of
these substituent groups may vary broadly. Non-limiting examples of
suitable substituent groups include branched, straight-chain or
cyclic alkyls, mono- or polycyclic aryls, branched, straight-chain
or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos,
branched, straight-chain or cyclic haloalkyls, hydroxyls, oxos,
thioxos, branched, straight-chain or cyclic alkoxys, branched,
straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or
polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers,
alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos,
azides, amines (primary, secondary and tertiary), nitriles (any
isomer), cyanates (any isomer), thiocyanates (any isomer),
nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids,
sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones,
carboxylic acids, esters, amides, amidines, formadines, amino
acids, acetylenes, carbamates, lactones, lactams, glucosides,
gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic
acids, oxamic esters, etc., and combinations of these groups.
Substituent groups bearing reactive functionalities may be
protected or unprotected, as is well-known in the art.
[0010] In one illustrative embodiment, the 2,4-pyrimidinediamine
compounds of the invention are compounds according to structural
formula (I):
##STR00002##
[0011] including salts, hydrates, solvates and N-oxides thereof,
wherein:
[0012] L.sup.1 and L.sup.2 are each, independently of one another,
selected from the group consisting of a direct bond and a
linker;
[0013] R.sup.2 and R.sup.4 are described infra;
[0014] R.sup.5 is selected from the group consisting of R.sup.6,
(C1-C6)alkyl optionally substituted with one or more of the same or
different R.sup.8 groups, (C1-C4)alkanyl optionally substituted
with one or more of the same or different R.sup.8 groups,
(C2-C4)alkenyl optionally substituted with one or more of the same
or different R.sup.8 groups and (C2-C4)alkynyl optionally
substituted with one or more of the same or different R.sup.8
groups;
[0015] each R.sup.6 is independently selected from the group
consisting of hydrogen, an electronegative group, --OR.sup.d,
--SR.sup.d, (C1-C3)haloalkyloxy, (C1-C3)perhaloalkyloxy,
--NR.sup.cR.sup.c, halogen, (C1-C3)haloalkyl, (C1-C3)perhaloalkyl,
--CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --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 and
--[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, phenyl 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;
[0016] R.sup.8 is selected from the group consisting of 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,
--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;
[0017] each R.sup.a is independently selected from the group
consisting of hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl,
cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl,
(C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered
cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl,
piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered
heteroaryl and 6-16 membered heteroarylalkyl;
[0018] 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, --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.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;
[0019] 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 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;
[0020] each R.sup.d is independently a protecting group or
R.sup.a;
[0021] each m is independently an integer from 1 to 3; and
[0022] each n is independently an integer from 0 to 3.
[0023] In one embodiment, R.sup.5 is F and R.sup.6 is hydrogen.
[0024] In another aspect, the present invention provides prodrugs
of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active
in their prodrug form, or may be inactive until converted under
physiological or other conditions of use to an active drug form. In
the prodrugs of the invention, one or more functional groups of the
2,4-pyrimidinediamine compounds are included in promoieties that
cleave from the molecule under the conditions of use, typically by
way of hydrolysis, enzymatic cleavage or some other cleavage
mechanism, to yield the functional groups. For example, primary or
secondary amino groups may be included in an amide promoiety that
cleaves under conditions of use to generate the primary or
secondary amino group. Thus, the prodrugs of the invention include
special types of protecting groups, termed "progroups," masking one
or more functional groups of the 2,4-pyrimidinediamine compounds
that cleave under the conditions of use to yield an active
2,4-pyrimidinediamine drug compound. Functional groups within the
2,4-pyrimidinediamine compounds that may be masked with progroups
for inclusion in a promoiety include, but are not limited to,
amines (primary and secondary), hydroxyls, sulfanyls (thiols),
carboxyls, carbonyls, phenols, catechols, diols, alkynes,
phosphates, etc. Myriad progroups suitable for masking such
functional groups to yield promoieties that are cleavable under the
desired conditions of use are known in the art. All of these
progroups, alone or in combinations, may be included in the
prodrugs of the invention. Specific examples of promoieties that
yield primary or secondary amine groups that can be included in the
prodrugs of the invention include, but are not limited to amides,
carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls.
Specific examples of promoieties that yield sulfanyl groups that
can be included in the prodrugs of the invention include, but are
not limited to, thioethers, for example S-methyl derivatives
(monothio, dithio, oxythio, aminothio acetals), silyl thioethers,
thioesters, thiocarbonates, thiocarbamates, asymmetrical
disulfides, etc. Specific examples of promoieties that cleave to
yield hydroxyl groups that can be included in the prodrugs of the
invention include, but are not limited to, sulfonates, esters and
carbonates. Specific examples of promoieties that yield carboxyl
groups that can be included in the prodrugs of the invention
included, but are not limited to, esters (including silyl esters,
oxamic acid esters and thioesters), amides and hydrazides.
[0025] In one illustrative embodiment, the prodrugs of the
invention are compounds according to structural formula (I) in
which the protecting group of R.sup.c and R.sup.d is a
progroup.
[0026] In another illustrative embodiment, the prodrugs of the
invention are compounds according to structural formula (II):
##STR00003##
[0027] including salts, hydrates, solvates and N-oxides thereof,
wherein:
[0028] R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1 and L.sup.2 are
as previously defined for structural formula (I);
[0029] R.sup.2b is a progroup;
[0030] R.sup.4b is progroup or an alkyl group, e.g., methyl, and as
further defined by the examples.
[0031] In another aspect, the present invention provides
compositions comprising one or more compounds and/or prodrugs of
the invention and an appropriate carrier, excipient or diluent. The
exact nature of the carrier, excipient or diluent will depend upon
the desired use for the composition, and may range from being
suitable or acceptable for veterinary uses to being suitable or
acceptable for human use.
[0032] In still another aspect, the present invention provides
intermediates useful for synthesizing the 2,4-pyrimidinediamine
compounds and prodrugs of the invention. In one embodiment, the
intermediates are 4-pyrimidineamines according to structural
formula (III):
##STR00004##
[0033] including salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.4, R.sup.5, R.sup.6 and L.sup.2 are as previously
defined for structural formula (I); LG is a leaving group such as,
for example, --S(O).sub.2Me, --SMe or halo (e.g., F, Cl, Br, I);
and R.sup.4c is hydrogen, a progroup, an alkyl group or as
described herein.
[0034] In another embodiment, the intermediates are
2-pyrimidineamines according to structural formula (IV):
##STR00005##
[0035] including salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.2, R.sup.5, R.sup.6 and L.sup.1 are as previously
defined for structural formula (I); LG is a leaving group, such as,
for example, --S(O).sub.2Me, --SMe or halo (e.g., F, Cl, Br, I)
and.
[0036] In yet another embodiment, the intermediates are 4-amino- or
4-hydroxy-2-pyrimidineamines according to structural formula
(V):
##STR00006##
[0037] including salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.2, R.sup.5, R.sup.6 and L.sup.1 are as previously
defined for structural formula (I), R.sup.7 is an amino or hydroxyl
group and R.sup.2c is hydrogen or a progroup.
[0038] In another embodiment, the intermediates are N4-substituted
cytosines according to structural formula (VI):
##STR00007##
[0039] including salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.4, R.sup.5, R.sup.6 and L.sup.2 are as previously
defined for structural formula (I) and R.sup.4c is as previously
defined in formula (III).
[0040] In yet another aspect, the present invention provides
methods of synthesizing the 2,4-pyrimidinediamine compounds and
prodrugs of the invention. In one embodiment, the method involves
reacting a 4-pyrimidineamine according to structural formula (III)
with an amine of the formula HR.sup.2cN-L.sup.1-R.sup.2, where
L.sup.1, R.sup.2 and R.sup.2 are as previously defined for
structural formula (IV) to yield a 2,4-pyrimidinediamine according
to structural formula (I) or a prodrug according to structural
formula (II).
[0041] In another embodiment, the method involves reacting a
2-pyrimidineamine according to structural formula (IV) with an
amine of the formula R.sup.4-L.sup.2-NHR.sup.4c where L.sup.4,
R.sup.4 and R.sup.4c are as previously defined for structural
formula (III) to yield a 2,4-pyrimidinediamine according to
structural formula (I) or a prodrug according to structural formula
(II).
[0042] In yet another embodiment, the method involves reacting a
4-amino-2-pyrimidineamine according to structural formula (V) (in
which R.sup.7 is an amino group) with an amine of the formula
R.sup.4-L.sup.2-NHR.sup.4c, where L.sup.2, R.sup.4 and R.sup.4c are
as defined for structural formula (III), to yield a
2,4-pyrimidinediamine according to structural formula (I) or a
prodrug according to structural formula (II). Alternatively, the
4-amino-2-pyrimidineamine may be reacted with a compound of the
formula R.sup.4-L.sup.2-LG, where R.sup.4 and L.sup.2 are as
previously defined for structural formula (I) and LG is a leaving
group.
[0043] In still another embodiment, the method involves
halogenating a 4-hydroxy-2-pyrimidineamine according to structural
formula (V) (R.sup.7 is a hydroxyl group) to yield a
2-pyrimidineamine according to structural formula (IV) and reacting
this pyrimidineamine with an appropriate amine, as described
above.
[0044] In yet another embodiment, the method involves halogenating
an N4-substituted cytosine according to structural formula (VI) to
yield a 4-pyrimidineamine according to structural formula (III) and
reacting this pyrimidineamine with an appropriate amine, as
described above.
[0045] The 2,4-pyrimidinediamine compounds of the invention are
potent inhibitors of degranulation of immune cells, such as mast,
basophil, neutrophil and/or eosinophil cells. Thus, in still
another aspect, the present invention provides methods of
regulating, and in particular inhibiting, degranulation of such
cells. The method generally involves contacting a cell that
degranulates with an amount of a 2,4-pyrimidinediamine compound or
prodrug of the invention, or an acceptable salt, hydrate, solvate,
N-oxide and/or composition thereof, effective to regulate or
inhibit degranulation of the cell. The method may be practiced in
in vitro contexts or in in vivo contexts as a therapeutic approach
towards the treatment or prevention of diseases characterized by,
caused by or associated with cellular degranulation.
[0046] While not intending to be bound by any theory of operation,
biochemical data confirm that the 2,4-pyrimidinediamine compounds
exert their degranulation inhibitory effect, at least in part, by
blocking or inhibiting the signal transduction cascade(s) initiated
by crosslinking of the high affinity Fc receptors for IgE
("Fc.epsilon.RI") and/or IgG ("Fc.gamma.RI"). Indeed, the
2,4-pyrimidinediamine compounds are potent inhibitors of both
Fc.epsilon.RI-mediated and Fc.gamma.RI-mediated degranulation. As a
consequence, the 2,4-pyrimidine compounds may be used to inhibit
these Fc receptor signalling cascades in any cell type expressing
such Fc.epsilon.RI and/or Fc.gamma.RI receptors including but not
limited to macrophages, mast, basophil, neutrophil and/or
eosinophil cells.
[0047] The methods also permit the regulation of, and in particular
the inhibition of, downstream processes that result as a
consequence of activating such Fc receptor signaling cascade(s).
Such downstream processes include, but are not limited to,
Fc.epsilon.RI-mediated and/or Fc.gamma.RI-mediated degranulation,
cytokine production and/or the production and/or release of lipid
mediators such as leukotrienes and prostaglandins. The method
generally involves contacting a cell expressing an Fc receptor,
such as one of the cell types discussed above, with an amount of a
2,4-pyrimidinediamine compound or prodrug of the invention, or an
acceptable salt, hydrate, solvent, N-oxide and/or composition
thereof, effective to regulate or inhibit the Fc receptor signaling
cascade and/or a downstream process effected by the activation of
this signaling cascade. The method may be practiced in in vitro
contexts or in in vivo contexts as a therapeutic approach towards
the treatment or prevention of diseases characterized by, caused by
or associated with the Fc receptor signaling cascade, such as
diseases effected by the release of granule specific chemical
mediators upon degranulation, the release and/or synthesis of
cytokines and/or the release and/or synthesis of lipid mediators
such as leukotrienes and prostaglandins.
[0048] In yet another aspect, the present invention provides
methods of treating and/or preventing diseases characterized by,
caused by or associated with the release of chemical mediators as a
consequence of activating Fc receptor signaling cascades, such as
Fc.epsilon.RI and/or Fc.gamma.RI-signaling cascades. The methods
may be practiced in animals in veterinary contexts or in humans.
The methods generally involve administering to an animal subject or
human an amount of a 2,4-pyrimidinediamine compound or prodrug of
the invention, or an acceptable salt, hydrate, solvate, N-oxide
and/or composition thereof, effective to treat or prevent the
disease. As discussed previously, activation of the Fc.epsilon.RI
or Fc.gamma.RI receptor signaling cascade in certain immune cells
leads to the release and/or synthesis of a variety of chemical
substances that are pharmacological mediators of a wide variety of
diseases. Any of these diseases may be treated or prevented
according to the methods of the invention.
[0049] For example, in mast cells and basophil cells, activation of
the Fc.epsilon.RI or Fc.gamma.RI signaling cascade leads to the
immediate (i.e., within 1-3 min. of receptor activation) release of
preformed mediators of atopic and/or Type I hypersensitivity
reactions (e.g., histamine, proteases such as tryptase, etc.) via
the degranulation process. Such atopic or Type I hypersensitivity
reactions include, but are not limited to, anaphylactic reactions
to environmental and other allergens (e.g., pollens, insect and/or
animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoid
reactions, hay fever, allergic conjunctivitis, allergic rhinitis,
allergic asthma, atopic dermatitis, eczema, urticaria, mucosal
disorders, tissue disorders and certain gastrointestinal
disorders.
[0050] The immediate release of the preformed mediators via
degranulation is followed by the release and/or synthesis of a
variety of other chemical mediators, including, among other things,
platelet activating factor (PAF), prostaglandins and leukotrienes
(e.g., LTC4) and the de novo synthesis and release of cytokines
such as TNF.alpha., IL-4, IL-5, IL-6, IL-13, etc. The first of
these two processes occurs approximately 3-30 min. following
receptor activation; the latter approximately 30 min.-7 hrs.
following receptor activation. These "late stage" mediators are
thought to be in part responsible for the chronic symptoms of the
above-listed atopic and Type I hypersensitivity reactions, and in
addition are chemical mediators of inflammation and inflammatory
diseases (e.g., osteoarthritis, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel
disease, irritable bowel syndrome, spastic colon, etc.), low grade
scarring (e.g., scleroderma, increased fibrosis, keloids,
post-surgical scars, pulmonary fibrosis, vascular spasms, migraine,
reperfusion injury and post myocardial infarction), and sicca
complex or syndrome. All of these diseases may be treated or
prevented according to the methods of the invention.
[0051] Additional diseases which can be treated or prevented
according to the methods of the invention include diseases
associated with basophil cell and/or mast cell pathology. Examples
of such diseases include, but are not limited to, diseases of the
skin such as scleroderma, cardiac diseases such as post myocardial
infarction, pulmonary diseases such as pulmonary muscle changes or
remodeling and chronic obstructive pulmonary disease (COPD) and
diseases of the gut such as inflammatory bowel syndrome (spastic
colon).
[0052] The 2,4-pyrimidinediamine compounds of the invention are
also potent inhibitors of the tyrosine kinase Syk kinase. Thus, in
still another aspect, the present invention provides methods of
regulating, and in particular inhibiting, Syk kinase activity. The
method generally involves contacting a Syk kinase or a cell
comprising a Syk kinase with an amount of a 2,4-pyrimidinediamine
compound or prodrug of the invention, or an acceptable salt,
hydrate, solvate, N-oxide and/or composition thereof, effective to
regulate or inhibit Syk kinase activity. In one embodiment, the Syk
kinase is an isolated or recombinant Syk kinase. In another
embodiment, the Syk kinase is an endogenous or recombinant Syk
kinase expressed by a cell, for example a mast cell or a basophil
cell. The method may be practiced in in vitro contexts or in in
vivo contexts as a therapeutic approach towards the treatment or
prevention of diseases characterized by, caused by or associated
with Syk kinase activity.
[0053] While not intending to be bound by any particular theory of
operation, it is believed that the 2,4-pyrimidinediamine compounds
of the invention inhibit cellular degranulation and/or the release
of other chemical mediators primarily by inhibiting Syk kinase that
gets activated through the gamma chain homodimer of Fc.epsilon.RI
(see, e.g., FIG. 2). This gamma chain homodimer is shared by other
Fc receptors, including Fc.gamma.RI, Fc.gamma.RIII and Fc.alpha.RI.
For all of these receptors, intracellular signal transduction is
mediated by the common gamma chain homodimer. Binding and
aggregation of those receptors results in the recruitment and
activation of tyrosine kinases such as Syk kinase. As a consequence
of these common signaling activities, the 2,4-pyrimidinediamine
compounds described herein may be used to regulate, and in
particular inhibit, the signaling cascades of Fc receptors having
this gamma chain homodimer, such as Fc.epsilon.RI, Fc.gamma.RI,
Fc.gamma.RIII and Fc.alpha.RI, as well as the cellular responses
elicited through these receptors.
[0054] Syk kinase is known to play a critical role in other
signaling cascades. For example, Syk kinase is an effector of
B-cell receptor (BCR) signaling (Turner et al., 2000, Immunology
Today 21:148-154) and is an essential component of integrin
beta(1), beta(2) and beta(3) signaling in neutrophils (Mocsai et
al., 2002, Immunity 16:547-558). As the 2,4-pyrimidinediamine
compounds described herein are potent inhibitors of Syk kinase,
they can be used to regulate, and in particular inhibit, any
signaling cascade where Syk plays a role, such as, fore example,
the Fc receptor, BCR and integrin signaling cascades, as well as
the cellular responses elicited through these signaling cascades.
The particular cellular response regulated or inhibited will
depend, in part, on the specific cell type and receptor signaling
cascade, as is well known in the art. Non-limiting examples of
cellular responses that may be regulated or inhibited with the
2,4-pyrimidinediamine compounds include a respiratory burst,
cellular adhesion, cellular degranulation, cell spreading, cell
migration, phagocytosis (e.g., in macrophages), calcium ion flux
(e.g., in mast, basophil, neutrophil, eosinophil and B-cells),
platelet aggregation, and cell maturation (e.g., in B-cells).
[0055] Thus, in another aspect, the present invention provides
methods of regulating, and in particular inhibiting, signal
transduction cascades in which Syk plays a role. The method
generally involves contacting a Syk-dependent receptor or a cell
expressing a Syk-dependent receptor with an amount of a
2,4-pyrimidinediamine compound or prodrug of the invention, or an
acceptable salt, hydrate, solvate, N-oxide and/or composition
thereof, effective to regulate or inhibit the signal transduction
cascade. The methods may also be used to regulate, and in
particular inhibit, downstream processes or cellular responses
elicited by activation of the particular Syk-dependent signal
transduction cascade. The methods may be practiced to regulate any
signal transduction cascade where Syk is not known or later
discovered to play a role. The methods may be practiced in in vitro
contexts or in in vivo contexts as a therapeutic approach towards
the treatment or prevention of diseases characterized by, caused by
or associated with activation of the Syk-dependent signal
transduction cascade. Non-limited examples of such diseases include
those previously discussed.
[0056] Cellular and animal data also confirm that the
2,4-pyrimidinediamine compounds of the invention may also be used
to treat or prevent autoimmune diseases and/or symptoms of such
diseases. The methods generally involve administering to a subject
suffering from an autoimmune disease or at risk of developing an
autoimmune disease an amount of a 2,4-pyrimidinediamine method or
prodrug of the invention, or an acceptable salt, N-oxide, hydrate,
solvate or composition thereof, effective to treat or prevent the
autoimmune disease and/or its associated symptoms. Autoimmune
diseases that can be treated or prevented with the
2,4-pyrimidinediamine compounds include those diseases that are
commonly associated with nonanaphylactic hypersensitivity reactions
(Type II, Type III and/or Type IV hypersensitivity reactions)
and/or those diseases that are mediated, at least in part, by
activation of the Fc.gamma.R signaling cascade in monocyte cells.
Such autoimmune disease include, but are not limited to, those
autoimmune diseases that are frequently designated as single organ
or single cell-type autoimmune disorders and those autoimmune
disease that are frequently designated as involving systemic
autoimmune disorder. Non-limiting examples of diseases frequently
designated as single organ or single cell-type autoimmune disorders
include: 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 and membranous
glomerulopathy. Non-limiting examples of diseases often designated
as involving systemic autoimmune disorder include: systemic lupus
erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's
syndrome, polymyositis-dermatomyositis, systemic sclerosis,
polyarteritis nodosa, multiple sclerosis and bullous
pemphigoid.
5. BRIEF DESCRIPTION OF THE FIGURES
[0057] FIG. 1 provides a cartoon illustrating allergen-induced
production of IgE and consequent release of preformed and other
chemical mediators from mast cells;
[0058] FIG. 2 provides a cartoon illustrating the Fc.epsilon.R1
signal transduction cascade leading to degranulation of mast and/or
basophil cells; and
[0059] FIG. 3 provides a cartoon illustrating the putative points
of action of compounds that selectively inhibit upstream
Fc.epsilon.RI-mediated degranulation and compounds that inhibit
both Fc.epsilon.RI-mediated and ionomycin-induced
degranulation.
6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
6.1 Definitions
[0060] As used herein, the following terms are intended to have the
following meanings:
[0061] "Alkyl" by itself or as part of another substituent refers
to a saturated or unsaturated branched, straight-chain or cyclic
monovalent hydrocarbon radical having the stated number of carbon
atoms (i.e., C1-C6 means one to six carbon atoms) that is derived
by the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl,
cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature "alkanyl," "alkenyl"
and/or "alkynyl" is used, as defined below. In preferred
embodiments, the alkyl groups are (C1-C6) alkyl.
[0062] "Alkanyl" by itself or as part of another substituent refers
to a saturated branched, straight-chain or cyclic alkyl derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane. Typical alkanyl groups include, but are not limited
to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl
(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,
butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),
2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the
like. In preferred embodiments, the alkanyl groups are
(C1-C6)alkanyl.
[0063] "Alkenyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl having
at least one carbon-carbon double bond derived by the removal of
one hydrogen atom from a single carbon atom of a parent alkene. The
group may be in either the cis or trans conformation about the
double bond(s). Typical alkenyl groups include, but are not limited
to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,
2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,
buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,
cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. In
preferred embodiments, the alkenyl group is (C2-C6)alkenyl.
[0064] "Alkenyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl having
at least one carbon-carbon triple bond derived by the removal of
one hydrogen atom from a single carbon atom of a parent alkyne.
Typical alkynyl groups include, but are not limited to, ethynyl;
propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls
such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like. In preferred embodiments, the alkynyl group is
(C2-C6)alkynyl.
[0065] "Alkyldiyl" by itself or as part of another substituent
refers to a saturated or unsaturated, branched, straight-chain or
cyclic divalent hydrocarbon group having the stated number of
carbon atoms (i.e., C1-C6 means from one to six carbon atoms)
derived by the removal of one hydrogen atom from each of two
different carbon atoms of a parent alkane, alkene or alkyne, or by
the removal of two hydrogen atoms from a single carbon atom of a
parent alkane, alkene or alkyne. The two monovalent radical centers
or each valency of the divalent radical center can form bonds with
the same or different atoms. Typical alkyldiyl groups include, but
are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl,
ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as
propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl,
cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl,
prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl,
cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,
cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such
as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,
butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,
cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,
but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,
but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,
2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,
buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl,
buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl,
cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,
cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,
but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.;
and the like. Where specific levels of saturation are intended, the
nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used.
Where it is specifically intended that the two valencies are on the
same carbon atom, the nomenclature "alkylidene" is used. In
preferred embodiments, the alkyldiyl group is (C1-C6)alkyldiyl.
Also preferred are saturated acyclic alkanyldiyl groups in which
the radical centers are at the terminal carbons, e.g., methandiyl
(methano); ethan-1,2-diyl(ethano); propan-1,3-diyl (propano);
butan-1,4-diyl (butano); and the like (also referred to as
alkylenos, defined infra).
[0066] "Alkyleno" by itself or as part of another substituent
refers to a straight-chain saturated or unsaturated alkyldiyl group
having two terminal monovalent radical centers derived by the
removal of one hydrogen atom from each of the two terminal carbon
atoms of straight-chain parent alkane, alkene or alkyne. The locant
of a double bond or triple bond, if present, in a particular
alkyleno is indicated in square brackets. Typical alkyleno groups
include, but are not limited to, methano; ethylenos such as ethano,
etheno, ethyno; propylenos such as propano, prop[1]eno,
propa[1,2]dieno, prop[1]yno, etc.; butylenos such as butano,
but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno,
buta[1,3]diyno, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature alkano, alkeno and/or
alkyno is used. In preferred embodiments, the alkyleno group is
(C1-C6) or (C1-C3)alkyleno. Also preferred are straight-chain
saturated alkano groups, e.g., methano, ethano, propano, butano,
and the like.
[0067] "Heteroalkyl," Heteroalkanyl," Heteroalkenyl,"
Heteroalkynyl," Heteroalkyldiyl" and "Heteroalkyleno" by themselves
or as part of another substituent refer to alkyl, alkanyl, alkenyl,
alkynyl, alkyldiyl and alkyleno groups, respectively, in which one
or more of the carbon atoms are each independently replaced with
the same or different heteratoms or heteroatomic groups. Typical
heteroatoms and/or heteroatomic groups which can replace the carbon
atoms include, but are not limited to, --O--, --S--, --S--O--,
--NR'--, --PH--, --S(O)--, --S(O).sub.2--, --S(O)NR'--,
--S(O).sub.2NR'--, and the like, including combinations thereof,
where each R' is independently hydrogen or (C1-C6)alkyl.
[0068] "Cycloalkyl" and "Heterocycloalkyl" by themselves or as part
of another substituent refer to cyclic versions of "alkyl" and
"heteroalkyl" groups, respectively. For heteroalkyl groups, a
heteroatom can occupy the position that is attached to the
remainder of the molecule. Typical cycloalkyl groups include, but
are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl
and cyclobutenyl; cyclopentyls such as cyclopentanyl and
cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl;
and the like. Typical heterocycloalkyl groups include, but are not
limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl,
piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl,
morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl,
piperazin-2-yl, etc.), and the like.
[0069] "Acyclic Heteroatomic Bridge" refers to a divalent bridge in
which the backbone atoms are exclusively heteroatoms and/or
heteroatomic groups. Typical acyclic heteroatomic bridges include,
but are not limited to, --O--, --S--, --S--O--, --NR'--, --PH--,
--S(O)--, --S(O).sub.2--, --S(O)NR'--, --S(O).sub.2NR'--, and the
like, including combinations thereof, where each R' is
independently hydrogen or (C1-C6)alkyl.
[0070] "Parent Aromatic Ring System" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
of the rings are aromatic and one or more of the rings are
saturated or unsaturated, such as, for example, fluorene, indane,
indene, phenalene, tetrahydronaphthalene, etc. Typical parent
aromatic ring systems include, but are not limited to,
aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexylene, indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and
the like, as well as the various hydro isomers thereof.
[0071] "Aryl" by itself or as part of another substituent refers to
a monovalent aromatic hydrocarbon group having the stated number of
carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived
by the removal of one hydrogen atom from a single carbon atom of a
parent aromatic ring system. Typical aryl groups include, but are
not limited to, groups derived from aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene,
as-indacene, s-indacene, indane, indene, naphthalene, octacene,
octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like, as well as the various hydro isomers
thereof. In preferred embodiments, the aryl group is (C5-C15)aryl,
with (C5-C10) being even more preferred. Particularly preferred
aryls are cyclopentadienyl, phenyl and naphthyl.
[0072] "Arylaryl" by itself or as part of another substituent
refers to a monovalent hydrocarbon group derived by the removal of
one hydrogen atom from a single carbon atom of a ring system in
which two or more identical or non-identical parent aromatic ring
systems are joined directly together by a single bond, where the
number of such direct ring junctions is one less than the number of
parent aromatic ring systems involved. Typical arylaryl groups
include, but are not limited to, biphenyl, triphenyl,
phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, and the like. Where
the number of carbon atoms in an arylaryl group are specified, the
numbers refer to the carbon atoms comprising each parent aromatic
ring. For example, (C5-C15)arylaryl is an arylaryl group in which
each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl,
triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parent
aromatic ring system of an arylaryl group is independently a
(C5-C15) aromatic, more preferably a (C5-C10) aromatic. Also
preferred are arylaryl groups in which all of the parent aromatic
ring systems are identical, e.g., biphenyl, triphenyl, binaphthyl,
trinaphthyl, etc.
[0073] "Biaryl" by itself or as part of another substituent refers
to an arylaryl group having two identical parent aromatic systems
joined directly together by a single bond. Typical biaryl groups
include, but are not limited to, biphenyl, binaphthyl, bianthracyl,
and the like. Preferably, the aromatic ring systems are (C5-C15)
aromatic rings, more preferably (C5-C10) aromatic rings. A
particularly preferred biaryl group is biphenyl.
[0074] "Arylalkyl" by itself or as part of another substituent
refers to an acyclic alkyl group in which one of the hydrogen atoms
bonded to a carbon atom, typically a terminal or sp.sup.3 carbon
atom, is replaced with an aryl group. Typical arylalkyl groups
include, but are not limited to, benzyl, 2-phenylethan-1-yl,
2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and
the like. Where specific alkyl moieties are intended, the
nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used. In
preferred embodiments, the arylalkyl group is (C6-C21)arylalkyl,
e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group
is (C1-C6) and the aryl moiety is (C5-C15). In particularly
preferred embodiments the arylalkyl group is (C6-C13), e.g., the
alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is
(C1-C3) and the aryl moiety is (C5-C10).
[0075] "Parent Heteroaromatic Ring System" refers to a parent
aromatic ring system in which one or more carbon atoms are each
independently replaced with the same or different heteroatoms or
heteroatomic groups. Typical heteroatoms or heteroatomic groups to
replace the carbon atoms include, but are not limited to, N, NH, P,
O, S, S(O), S(O).sub.2, Si, etc. Specifically included within the
definition of "parent heteroaromatic ring systems" are fused ring
systems in which one or more of the rings are aromatic and one or
more of the rings are saturated or unsaturated, such as, for
example, benzodioxan, benzofuran, chromane, chromene, indole,
indoline, xanthene, etc. Also included in the definition of "parent
heteroaromatic ring system" are those recognized rings that include
common substituents, such as, for example, benzopyrone and
1-methyl-1,2,3,4-tetrazole. Specifically excluded from the
definition of "parent heteroaromatic ring system" are benzene rings
fused to cyclic polyalkylene glycols such as cyclic polyethylene
glycols. Typical parent heteroaromatic ring systems include, but
are not limited to, acridine, benzimidazole, benzisoxazole,
benzodioxan, benzodioxole, benzofuran, benzopyrone,
benzothiadiazole, benzothiazole, benzotriazole, benzoxaxine,
benzoxazole, benzoxazoline, carbazole, .beta.-carboline, chromane,
chromene, cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, perimidine, phenanthridine, phenanthroline, phenazine,
phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the
like.
[0076] "Heteroaryl" by itself or as part of another substituent
refers to a monovalent heteroaromatic group having the stated
number of ring atoms (e.g., "5-14 membered" means from 5 to 14 ring
atoms) derived by the removal of one hydrogen atom from a single
atom of a parent heteroaromatic ring system. Typical heteroaryl
groups include, but are not limited to, groups derived from
acridine, benzimidazole, benzisoxazole, benzodioxan, benzodiaxole,
benzofuran, benzopyrone, benzothiadiazole, benzothiazole,
benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole,
.beta.-carboline, chromane, chromene, cinnoline, furan, imidazole,
indazole, indole, indoline, indolizine, isobenzofuran, isochromene,
isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,
tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,
and the like, as well as the various hydro isomers thereof. In
preferred embodiments, the heteroaryl group is a 5-14 membered
heteroaryl, with 5-10 membered heteroaryl being particularly
preferred.
[0077] "Heteroaryl-Heteroaryl" by itself or as part of another
substituent refers to a monovalent heteroaromatic group derived by
the removal of one hydrogen atom from a single atom of a ring
system in which two or more identical or non-identical parent
heteroaromatic ring systems are joined directly together by a
single bond, where the number of such direct ring junctions is one
less than the number of parent heteroaromatic ring systems
involved. Typical heteroaryl-heteroaryl groups include, but are not
limited to, bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, etc.
Where the number of atoms are specified, the numbers refer to the
number of atoms comprising each parent heteroaromatic ring systems.
For example, 5-15 membered heteroaryl-heteroaryl is a
heteroaryl-heteroaryl group in which each parent heteroaromatic
ring system comprises from 5 to 15 atoms, e.g., bipyridyl,
tripuridyl, etc. Preferably, each parent heteroaromatic ring system
is independently a 5-15 membered heteroaromatic, more preferably a
5-10 membered heteroaromatic. Also preferred are
heteroaryl-heteroaryl groups in which all of the parent
heteroaromatic ring systems are identical.
[0078] "Biheteroaryl" by itself or as part of another substituent
refers to a heteroaryl-heteroaryl group having two identical parent
heteroaromatic ring systems joined directly together by a single
bond. Typical biheteroaryl groups include, but are not limited to,
bipyridyl, bipurinyl, biquinolinyl, and the like. Preferably, the
heteroaromatic ring systems are 5-15 membered heteroaromatic rings,
more preferably 5-10 membered heteroaromatic rings.
[0079] "Heteroarylalkyl" by itself or as part of another
substituent refers to an acyclic alkyl group in which one of the
hydrogen atoms bonded to a carbon atom, typically a terminal or
sp.sup.a carbon atom, is replaced with a heteroaryl group. Where
specific alkyl moieties are intended, the nomenclature
heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is
used. In preferred embodiments, the heteroarylalkyl group is a 6-21
membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the heteroarylalkyl is (C1-C6)alkyl and the heteroaryl
moiety is a 5-15-membered heteroaryl. In particularly preferred
embodiments, the heteroarylalkyl is a 6-13 membered
heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is
(C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered
heteroaryl.
[0080] "Halogen" or "Halo" by themselves or as part of another
substituent, unless otherwise stated, refer to fluoro, chloro,
bromo and iodo.
[0081] "Haloalkyl" by itself or as part of another substituent
refers to an alkyl group in which one or more of the hydrogen atoms
is replaced with a halogen. Thus, the term "haloalkyl" is meant to
include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to
perhaloalkyls. For example, the expression "(C1-C2)haloalkyl"
includes fluoromethyl, difluoromethyl, trifluoromethyl,
1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl,
1,1,1-trifluoroethyl, perfluoroethyl, etc.
[0082] The above-defined groups may include prefixes and/or
suffixes that are commonly used in the art to create additional
well-recognized substituent groups. As examples, "alkyloxy" or
"alkoxy" refers to a group of the formula --OR'', "alkylamine"
refers to a group of the formula --NHR'' and "dialkylamine" refers
to a group of the formula --NR''R'', where each R'' is
independently an alkyl. As another example, "haloalkoxy" or
"haloalkyloxy" refers to a group of the formula --OR''', where R'''
is a haloalkyl.
[0083] "Protecting group" refers to a group of atoms that, when
attached to a reactive functional group in a molecule, mask, reduce
or prevent the reactivity of the functional group. Typically, a
protecting group may be selectively removed as desired during the
course of a synthesis. Examples of protecting groups can be found
in Greene and Wuts, Protective Groups in Organic Chemistry,
3.sup.rd Ed., 1999, John Wiley & Sons, NY and Harrison et al.,
Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John
Wiley & Sons, NY. Representative amino protecting groups
include, but are not limited to, formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"),
trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxyl protecting groups
include, but are not limited to, those where the hydroxyl group is
either acylated or alkylated such as benzyl and trityl ethers, as
well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl
ethers (e.g., TMS or TIPPS groups) and allyl ethers.
[0084] "Prodrug" refers to a derivative of an active
2,4-pyrimidinediamine compound (drug) that requires a
transformation under the conditions of use, such as within the
body, to release the active 2,4-pyrimidinediamine drug. Prodrugs
are frequently, but not necessarily, pharmacologically inactive
until converted into the active drug. Prodrugs are typically
obtained by masking a functional group in the 2,4-pyrimidinediamine
drug believed to be in part required for activity with a progroup
(defined below) to form a promoiety which undergoes a
transformation, such as cleavage, under the specified conditions of
use to release the functional group, and hence the active
2,4-pyrimidinediamine drug. The cleavage of the promoiety may
proceed spontaneously, such as by way of a hydrolysis reaction, or
it may be catalyzed or induced by another agent, such as by an
enzyme, by light, by acid or base, or by a change of or exposure to
a physical or environmental parameter, such as a change of
temperature. The agent may be endogenous to the conditions of use,
such as an enzyme present in the cells to which the prodrug is
administered or the acidic conditions of the stomach, or it may be
supplied exogenously.
[0085] A wide variety of progroups, as well as the resultant
promoieties, suitable for masking functional groups in the active
2,4-pyrimidinediamines compounds to yield prodrugs are well-known
in the art. For example, a hydroxyl functional group may be masked
as a sulfonate, ester or carbonate promoiety, which may be
hydrolyzed in vivo to provide the hydroxyl group. An amino
functional group may be masked as an amide, carbamate, imine, urea,
phosphenyl, phosphoryl or sulfenyl promoiety, which may be
hydrolyzed in vivo to provide the amino group. A carboxyl group may
be masked as an ester (including silyl esters and thioesters),
amide or hydrazide promoiety, which may be hydrolyzed in vivo to
provide the carboxyl group. Nitrogen protecting groups and nitrogen
pro-drugs of the invention may include lower alkyl groups as well
as amides, carbamates, etc. Other specific examples of suitable
progroups and their respective promoieties will be apparent to
those of skill in the art.
[0086] "Progroup" refers to a type of protecting group that, when
used to mask a functional group within an active
2,4-pyrimidinediamine drug to form a promoiety, converts the drug
into a prodrug. Progroups are typically attached to the functional
group of the drug via bonds that are cleavable under specified
conditions of use. Thus, a progroup is that portion of a promoiety
that cleaves to release the functional group under the specified
conditions of use. As a specific example, an amide promoiety of the
formula --NH--C(O)CH.sub.3 comprises the progroup
--C(O)CH.sub.3.
[0087] "Fc Receptor" refers to a member of the family of cell
surface molecules that binds the Fc portion (containing the
specific constant region) of an immunoglobulin. Each Fc receptor
binds immunoglobulins of a specific type. For example the Fc.alpha.
receptor ("Fc.alpha.R") binds IgA, the Fc.epsilon.R binds IgE and
the Fc.gamma.R binds IgG.
[0088] The Fc.alpha.R family includes the polymeric Ig receptor
involved in epithelial transport of IgA/IgM, the myeloid specific
receptor Rc.alpha.RI (also called CD89), the Fc.alpha./.mu.R and at
least two alternative IgA receptors (for a recent review see
Monteiro & van de Winkel, 2003, Annu. Rev. Immunol, advanced
e-publication. The Fc.alpha.RI is expressed on neutrophils,
eosinophils, monocytes/macrophages, dendritic cells and kupfer
cells. The Fc.alpha.RI includes one alpha chain and the FcR gamma
homodimer that bears an activation motif (ITAM) in the cytoplasmic
domain and phosphorylates Syk kinase.
[0089] The Fc.epsilon.R family includes two types, designated
Fc.epsilon.RI and Fc.epsilon.RII (also known as CD23).
Fc.epsilon.RI is a high affinity receptor (binds IgE with an
affinity of about 10.sup.10M.sup.-1) found on mast, basophil and
eosinophil cells that anchors monomeric IgE to the cell surface.
The Fc.epsilon.RI possesses one alpha chain, one beta chain and the
gamma chain homodimer discussed above. The Fc.epsilon.RII is a low
affinity receptor expressed on mononuclear phagocytes, B
lymphocytes, eosinophils and platelets. The Fc.epsilon.RII
comprises a single polypeptide chain and does not include the gamma
chain homodimer.
[0090] The Fc.gamma.R family includes three types, designated
Fc.gamma.RI (also known as CD64), Fc.gamma.RII (also known as CD32)
and Fc.gamma.RIII (also known as CD16). Fc.gamma.RI is a high
affinity receptor (binds IgG1 with an affinity of 10.sup.8M.sup.-1)
found on mast, basophil, mononuclear, neutrophil, eosinophil,
deudritic and phagocyte cells that anchors nomomeric IgG to the
cell surface. The Fc.gamma.RI includes one alpha chain and the
gamma chain dimer shared by Fc.alpha.RI and FI.epsilon.RI.
[0091] The Fc.gamma.RII is a low affinity receptor expressed on
neutrophils, monocytes, eosinophils, platelets and B lymphocytes.
The Fc.gamma.RII includes one alpha chain, and does not include the
gamma chain homodimer discussed above.
[0092] The Fc.gamma.RIII is a low affinity (binds IgG1 with an
affinity of 5.times.10.sup.5M.sup.-1) expressed on NK, eosinophil,
macrophage, neutrophil and mast cells. It comprises one alpha chain
and the gamma homodimer shared by Fc.alpha.RI, Fc.epsilon.RI and
Fc.gamma.RI.
[0093] Skilled artisans will recognize that the subunit structure
and binding properties of these various Fc receptors, cell types
expressing them, are not completely characterized. The above
discussion merely reflects the current state-of-the-art regarding
these receptors (see, e.g., Immunobiology: The Immune System in
Health & Disease, 5.sup.th Edition, Janeway et al., Eds, 2001,
ISBN 0-8153-3642-x, FIG. 9.30 at pp. 371), and is not intended to
be limiting with respect to the myriad receptor signaling cascades
that can be regulated with the compounds described herein.
[0094] "Fc Receptor-Mediated Degranulation" or "Fc Receptor-Induced
Degranulation" refers to degranulation that proceeds via an Fc
receptor signal transduction cascade initiated by crosslinking of
an Fc receptor.
[0095] "IgE-Induced Degranulation" or "Fc.epsilon.RI-Mediated
Degranulation" refers to degranulation that proceeds via the IgE
receptor signal transduction cascade initiated by crosslinking of
Fc.epsilon.RI-bound IgE. The crosslinking may be induced by an
IgE-specific allergen or other multivalent binding agent, such as
an anti-IgE antibody. Referring to FIG. 2, in mast and/or basophil
cells, the Fc.epsilon.RI signaling cascade leading to degranulation
may be broken into two stages: upstream and downstream. The
upstream stage includes all of the processes that occur prior to
calcium ion mobilization (illustrated as "Ca.sup.2+" in FIG. 2; see
also FIG. 3). The downstream stage includes calcium ion
mobilization and all processes downstream thereof. Compounds that
inhibit Fc.epsilon.RI-mediated degranulation may act at any point
along the Fc.epsilon.RI-mediated signal transduction cascade.
Compounds that selectively inhibit upstream Fc.epsilon.RI-mediated
degranulation act to inhibit that portion of the Fc.epsilon.RI
signaling cascade upstream of the point at which calcium ion
mobilization is induced. In cell-based assays, compounds that
selectively inhibit upstream Fc.epsilon.RI-mediated degranulation
inhibit degranulation of cells such as mast or basophil cells that
are activated or stimulated with an IgE-specific allergen or
binding agent (such as an anti-IgE antibody) but do not appreciably
inhibit degranulation of cells that are activated or stimulated
with degranulating agents that bypass the Fc.epsilon.RI signaling
pathway, such as, for example the calcium ionophores ionomycin and
A23187.
[0096] "IgG-Induced Degranulation" or "Fc.gamma.RI-Mediated
Degranulation" refers to degranulation that proceeds via the
Fc.gamma.RI signal transduction cascade initiated by crosslinking
of Fc.gamma.RI-bound IgG. The crosslinking may be induced by an
IgG-specific allergen or another multivalent binding agent, such as
an anti-IgG or fragment antibody. Like the Fc.epsilon.RI signaling
cascade, in mast and basophil cells the Fc.gamma.RI signaling
cascade also leads to degranulation which may be broken into the
same two stages: upstream and downstream. Similar to
Fc.epsilon.RI-mediated degranulation, compounds that selectively
inhibit upstream Fc.gamma.RI-mediated degranulation act upstream of
the point at which calcium ion mobilization is induced. In
cell-based assays, compounds that selectively inhibit upstream
Fc.gamma.RI-mediated degranulation inhibit degranulation of cells
such as mast or basophil cells that are activated or stimulated
with an IgG-specific allergen or binding agent (such as an anti-IgG
antibody or fragment) but do not appreciably inhibit degranulation
of cells that are activated or stimulated with degranulating agents
that bypass the Fc.gamma.RI signaling pathway, such as, for example
the calcium ionophores ionomycin and A23187.
[0097] "Ionophore-Induced Degranulation" or "Ionophore-Mediated
Degranulation" refers to degranulation of a cell, such as a mast or
basophil cell, that occurs upon exposure to a calcium ionophore
such as, for example, ionomycin or A23187.
[0098] "Syk Kinsase" refers to the well-known 72 kDa non-receptor
(cytoplasmic) spleen protein tyrosine kinase expressed in B-cells
and other hematopoetic cells. Syk kinase includes two consensus
Src-homology 2 (SH2) domains in tandem that bind to phosphorylated
immunoreceptor tyrosine-based activation motifs ("ITAMs"), a
"linker" domain and a catalytic domain (for a review of the
structure and function of Syk kinase see Sada et al., 2001, J.
Biochem. (Tokyo) 130:177-186); see also Turner et al., 2000,
Immunology Today 21:148-154). Syk kinase has been extensively
studied as an effector of B-cell receptor (BCR) signaling (Turner
et al., 2000, supra). Syk kinase is also critical for tyrosine
phosphorylation of multiple proteins which regulate important
pathways leading from immunoreceptors, such as Ca.sup.2+
mobilization and mitogen-activated protein kinase (MAPK) cascades
(see, e.g., FIG. 2) and degranulation. Syk kinase also plays a
critical role in integrin signaling in neutrophils (see, e.g.,
Mocsai et al. 2002, Immunity 16:547-558).
[0099] As used herein, Syk kinase includes kinases from any species
of animal, including but not limited to, homosapiens, simian,
bovine, porcine, rodent, etc., recognized as belonging to the Syk
family. Specifically included are isoforms, splice variants,
allelic variants, mutants, both naturally occurring and man-made.
The amino acid sequences of such Syk kinases are well known and
available from GENBANK. Specific examples of mRNAs encoding
different isoforms of human Syk kinase can be found at GENBANK
accession no. gi.ident.21361552|ref|NM.sub.--003177.2|,
gi|496899|emb|Z29630.1|HSSYKPTK[496899] and
gi|15030258|gb|BC011399.1|BC011399[15030258], which are
incorporated herein by reference.
[0100] Skilled artisans will appreciate that tyrosine kinases
belonging to other families may have active sites or binding
pockets that are similar in three-dimensional structure to that of
Syk. As a consequence of this structural similarity, such kinases,
referred to herein as "Syk mimics," are expected to catalyze
phosphorylation of substrates phosphorylated by Syk. Thus, it will
be appreciated that such Syk mimics, signal transduction cascades
in which such Syk mimics play a role and biological responses
effected by such Syk mimics and Syk mimic-dependent signaling
cascades may be regulated, and in particular inhibited, with the
2,4-pyrimidinediamine compounds described herein.
[0101] "Syk-Dependent Signaling Cascade" refers to a signal
transduction cascade in which Syk kinase plays a role. Non-limiting
examples of such Syk-dependent signaling cascades include the
Fc.alpha.RI, Fc.epsilon.RI, Fc.gamma.RI, Fc.gamma.RIII, BCR and
integrin signaling cascades.
[0102] "Autoimmune Disease" refers to those diseases which are
commonly associated with the nonanaphylactic hypersensitivity
reactions (Type II, Type III and/or Type IV hypersensitivity
reactions) that generally result as a consequence of the subject's
own humoral and/or cell-mediated immune response to one or more
immunogenic substances of endogenous and/or exogenous origin. Such
autoimmune diseases are distinguished from diseases associated with
the anaphylactic (Type I or IgE-mediated) hypersensitivity
reactions.
6.2 The 2,4-Pyrimidinediamine Compounds
[0103] The compounds of the invention are generally
2,4-pyrimidinediamine compounds according to structural formula
(I):
##STR00008##
[0104] including salts, hydrates, solvates and N-oxides thereof,
wherein:
[0105] L.sup.1 and L.sup.2 are each, independently of one another,
selected from the group consisting of a direct bond and a
linker;
[0106] R.sup.2 and R.sup.4 are as described in the following
embodiments and examples;
[0107] R.sup.5 is selected from the group consisting of R.sup.6,
(C1-C6)alkyl optionally substituted with one or more of the same or
different R.sup.8 groups, (C1-C4)alkanyl optionally substituted
with one or more of the same or different R.sup.8 groups,
(C2-C4)alkenyl optionally substituted with one or more of the same
or different R.sup.8 groups and (C2-C4)alkynyl optionally
substituted with one or more of the same or different R.sup.8
groups;
[0108] each R.sup.6 independently is selected from the group
consisting of hydrogen, an electronegative group, --OR.sup.d,
--SR.sup.d, (C1-C3)haloalkyloxy, (C1-C3)perhaloalkyloxy,
--NR.sup.cR.sup.c, halogen, (C1-C3)haloalkyl, (C1-C3)perhaloalkyl,
--CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --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 and
--[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, phenyl 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;
[0109] R.sup.8 is selected from the group consisting of 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, --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.mCH[(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.mR.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.mR.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.mR.sup.b;
[0110] each R.sup.a is independently selected from the group
consisting of hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl,
cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl,
(C6-C16)arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered
cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl,
piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered
heteroaryl and 6-16 membered heteroarylalkyl;
[0111] 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, --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.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;
[0112] each R.sup.c is independently R.sup.a, or, alternatively,
each R.sup.c is taken together with the nitrogen atom to which it
is 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 is optionally substituted with one
or more of the same or different R.sup.a or suitable R.sup.b
groups;
[0113] each R.sup.d is independently R.sup.a;
[0114] each m is independently an integer from 1 to 3; and
[0115] each n is independently an integer from 0 to 3.
[0116] In the compounds of structural formula (I), L.sup.1 and
L.sup.2 represent, independently of one another, a direct bond or a
linker. Thus, as will be appreciated by skilled artisans, the
substituents R.sup.2 and/or R.sup.4 may be bonded either directly
to their respective nitrogen atoms or, alternatively, spaced away
from their respective nitrogen atoms by way of a linker. The
identity of the linker is not critical and typical suitable linkers
include, but are not limited to, (C1-C6)alkyldiyls, (C1-C6)alkanos
and (C1-C6)heteroalkyldiyls, each of which may be optionally
substituted with one or more of the same or different R.sup.8
groups, where R.sup.8 is as previously defined for structural
formula (I). In a specific embodiment, L.sup.1 and L.sup.2 are
each, independently of one another, selected from the group
consisting of a direct bond, (C1-C3) alkyldiyl optionally
substituted with one or more of the same or different R.sup.a,
suitable R.sup.b or R.sup.9 groups and 1-3 membered heteroalkyldiyl
optionally substituted with one or more of the same or different
R.sup.a, suitable R.sup.b or R.sup.9 groups, wherein R.sup.9 is
selected from the group consisting of (C1-C3)alkyl, --OR.sup.a,
--C(O)OR.sup.a, (C5-C10)aryl optionally substituted with one or
more of the same or different halogens, phenyl optionally
substituted with one or more of the same or different halogens,
5-10 membered heteroaryl optionally substituted with one or more of
the same or different halogens and 6 membered heteroaryl optionally
substituted with one or more of the same or different halogens; and
R.sup.a and R.sup.b are as previously defined for structural
formula (I). Specific R.sup.9 groups that may be used to substitute
L.sup.1 and L.sup.2 include --OR.sup.a, --C(O)OR.sup.a, phenyl,
halophenyl and 4-halophenyl, wherein R.sup.a is as previously
defined for structural formula (I).
[0117] In another specific embodiment, L.sup.1 and L.sup.2 are
each, independently of one another, selected from the group
consisting of methano, ethano and propano, each of which may be
optionally monosubstituted with an R.sup.9 group, where R.sup.9 is
as previously defined above.
[0118] In all of the above embodiments, specific R.sup.a groups
that may be included in R.sup.9 groups are selected from the group
consisting of hydrogen, (C1-C6)alkyl, phenyl and benzyl.
[0119] In still another specific embodiment, L.sup.1 and L.sup.2
are each a direct bond such that the 2,4-pyrimidinediamine
compounds of the invention are compounds according to structural
formula (Ia):
##STR00009##
[0120] including salts, hydrates, solvates and N-oxides thereof,
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as previously
defined for structural formula (I). Additional specific embodiments
of the 2,4-pyrimidinediamine compounds of the invention are
described below.
[0121] In a first embodiment of the compounds of structural formula
(I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, m and n are as previously defined,
R.sup.2 is
##STR00010##
wherein each R.sup.31, independently of the others, is methyl or
(C1-C6)alkyl and R.sup.4 is
##STR00011##
X is selected from the group consisting of N and CH, Y is selected
from the group consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH,
NR.sup.35 and NR.sup.37, Z is selected from the group consisting of
O, S, SO, SO.sub.2, SONR.sup.36, NH, NR.sup.35 and NR.sup.37. Each
R.sup.35 is, independently of the others, selected from the group
consisting of hydrogen and R.sup.8, or, alternatively, two R.sup.35
bonded to the same carbon atom are taken together to form an oxo
(.dbd.O), NH or NR.sup.38 group and the other two R.sup.35 are
each, independently of one another, selected from the group
consisting of hydrogen and R.sup.8. Each R.sup.36 is independently
selected from the group consisting of hydrogen and (C1-C6)alkyl.
Each R.sup.37 is independently selected from the group consisting
of hydrogen and a progroup. R.sup.38 is selected from the group
consisting of (C1-C6)alkyl and (C5-C14)aryl.
[0122] In particular, Y is O, Z is NH and X is N. R.sup.5 can be
halogen and R.sup.6 is a hydrogen.
[0123] In a second embodiment of the compounds of structural
formula (I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8,
R.sup.a, R.sup.b, R.sup.c, R.sup.d, m, n, R.sup.35, R.sup.36,
R.sup.37, R.sup.38, X, Y and Z are as previously defined, R.sup.2
is
##STR00012##
wherein each R.sup.31, independently of the others, is methyl or
(C1-C6)alkyl and R.sup.4 is
##STR00013##
In particular, Y is O, Z is NH and X is N. R.sup.5 can be halogen
and R.sup.6 is a hydrogen. In one particular aspect, Y is O, Z is
NH, X is N and each R.sup.31 is methyl.
[0124] In a third embodiment of the compounds of structural formula
(I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, m, n, R.sup.31, R.sup.35, R.sup.36,
R.sup.37, R.sup.38, X, Y and Z are as previously defined, R.sup.2
is
##STR00014##
[0125] and R.sup.4 is
##STR00015##
and yy is 1-6. In particular, Y is O, Z is NH and X is N. R.sup.5
can be halogen and R.sup.6 is a hydrogen.
[0126] In a fourth embodiment of the compounds of structural
formula (I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8,
R.sup.a, R.sup.b, R.sup.c, R.sup.d, m, n, R.sup.35, R.sup.36,
R.sup.37, R.sup.38, X, Y and Z are as previously defined, R.sup.2
is
##STR00016##
and R.sup.4 is
##STR00017##
[0127] Substitution about the R.sup.2 phenyl ring can be at the 2,
3, 4, 5 or 6 positions. In particular, Y is O, Z is NH and X is N.
R.sup.5 can be halogen and R.sup.6 is a hydrogen.
[0128] In a fifth embodiment of the compounds of structural formula
(I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, m, n, R.sup.35, R.sup.36, R.sup.37,
R.sup.38, X, Y and Z are as previously defined, R.sup.2 is a phenyl
group disubstituted with two R.sup.b groups and R.sup.4 is
##STR00018##
Substitution about the R.sup.2 phenyl ring can be at the 2,3, 2,4,
2,5, 2,6, 3,4, 3,5, 3,6, 4,5, 4,6 or 5,6 positions, with the
proviso that the following compounds are not included: [0129]
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; [0130]
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxypheny-
l)-5-fluoro-2,4-pyrimidinediamine; [0131]
N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl-
)-5-fluoro-2,4-pyrimidinediamine; [0132]
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; [0133]
N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl-
)-5-fluoro-2,4-pyrimidinediamine; and [0134]
N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[-
1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.
[0135] In particular, Y is O, Z is NH and X is N. R.sup.5 can be
halogen and R.sup.6 is a hydrogen. In certain aspects, each R.sup.b
independently is selected from (C1-C6)alkoxy, (C1-16)alkyl, (C1-C6)
perhaloalkyls, halogens, carboxylic acid, carboxylic ester,
carboxamides, sulfonamides and imidazoles.
[0136] In a sixth embodiment of the compounds of structural formula
(I) and (Ia), L.sup.1, L.sup.2, R.sup.5, R.sup.6, R.sup.8, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, m, n, R.sup.35, R.sup.36, R.sup.37,
R.sup.38, X, Y and Z are as previously defined, R.sup.2 is a phenyl
group trisubstituted with three R.sup.b groups and R.sup.4 is
##STR00019##
Substitution about the R.sup.2 phenyl ring can be at the 2,3,4,
2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4,5, 3,4,6, 3,5,6, or 4,5,6
positions, with the proviso that the following compounds are not
included: [0137]
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; [0138]
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; and [0139]
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.
[0140] In particular, Y is O, Z is NH and X is N. R.sup.5 can be
halogen and R.sup.6 is a hydrogen. In certain aspects, each R.sup.b
independently is selected from (C1-C6)alkoxy, (C1-16)alkyl, (C1-C6)
perhaloalkyls, halogens, carboxylic acid, carboxylic esters,
carboxamides, sulfonamides
[0141] In certain embodiments, the compounds disclosed in U.S.
patent application Ser. Nos. 10/631,029, filed on Jul. 29, 2003 and
10/355,543, filed Jan. 31, 2003, respectively, are not included
within the scope of the present application. In a seventh
embodiment of the compounds of structural formula (I) and (Ia),
R.sup.5, R.sup.6, L.sup.1 and L.sup.2 are as previously defined,
R.sup.2 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, (C3-C8)cycloalkyl optionally substituted with one
or more of the same or different R.sup.8 groups, cyclohexyl
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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.4 is
##STR00020##
R.sup.6a is (C5-C10)aryl optionally substituted with one or more of
the same or different R.sup.8 groups or phenyl optionally
substituted with one or more of the same or different R.sup.8
groups and R.sup.8 is as previously defined.
[0142] In an eighth embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 is selected from the
group consisting of
##STR00021##
wherein each R.sup.21 is independently a halogen atom or an alkyl
optionally substituted with one or more of the same or different
halo groups, R.sup.22 and R.sup.23 are each, independently of one
another, a hydrogen atom, methyl or ethyl group optionally
substituted with one or more of the same or different halo groups
and R.sup.4 is a (C3-C8)cycloalkyl optionally substituted with one
or more of the same or different R.sup.8 groups.
[0143] In a ninth embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 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, (C3-C8)cycloalkyl
optionally substituted with one or more of the same or different
R.sup.8 groups, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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.4 is
##STR00022##
[0144] R.sup.35 is a hydrogen or R.sup.8; and
[0145] R.sup.45 is a (C3-C8)cycloalkyl optionally substituted with
one or more of the same or different R.sup.8 groups.
[0146] In a tenth embodiment compounds of structural formulae
##STR00023##
R.sup.2 selected from the group consisting of (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, cyclohexyl
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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.4 is selected from the
group consisting of hydrogen, (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, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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, and R.sup.55 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, (C3-C8)cycloalkyl optionally substituted
with one or more of the same or different R.sup.8 groups,
cyclohexyl 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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.
[0147] In an eleventh embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 is
##STR00024##
and R.sup.4 is selected from the group consisting of hydrogen,
(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,
cyclohexyl 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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.
[0148] In a twelfth embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 is
##STR00025##
R.sup.4 is selected from the group consisting of hydrogen,
(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,
cyclohexyl 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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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 and each R.sup.35 individually is
a hydrogen or a suitable R.sup.8.
[0149] In a thirteenth embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 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, (C3-C8)cycloalkyl
optionally substituted with one or more of the same or different
R.sup.8 groups, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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.4 is
##STR00026##
and R.sup.35 is a hydrogen or a suitable R.sup.8.
[0150] In a fourteenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is a substituted phenyl
group, substituted with the same or different R.sup.8 groups and
R.sup.2 is
##STR00027##
wherein "yy"=1 to 6. In one aspect, the R.sup.4 phenyl group is di
or tri substituted with the same or different R.sup.8 groups, and
in particular, halogen atoms. In particular, R.sup.4 can be
substituted at the 3 and 4 positions relative to attachment to the
N4 amine, particularly with halogen atoms and/or alkoxy groups.
[0151] In a fifteenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is a substituted phenyl
group, substituted with the same or different R.sup.8 groups and
R.sup.2 is
##STR00028##
In one aspect, the R.sup.4 phenyl group is di or tri substituted
with the same or different R.sup.8 groups, and in particular,
halogen atoms. In particular, R.sup.4 can be substituted at the 3
and 4 positions relative to attachment to the N4 amine,
particularly with halogen atoms and/or alkoxy groups.
[0152] In a sixteenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is a substituted phenyl
group, substituted with the same or different R.sup.8 groups and
R.sup.2 is
##STR00029##
In one aspect, the R.sup.4 phenyl group is di or tri substituted
with the same or different R.sup.8 groups, and in particular,
halogen atoms. In particular, R.sup.4 can be substituted at the 3
and 4 positions relative to attachment to the N4 amine,
particularly with halogen atoms and/or alkoxy groups.
[0153] In a seventeenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is a substituted phenyl
group, substituted with the same or different R.sup.8 groups and
R.sup.2 is
##STR00030##
wherein R.sup.35 is an alkylalkoxy group, and in particular is
##STR00031##
In one aspect, the R.sup.4 phenyl group is di or tri substituted
with the same or different R.sup.8 groups, and in particular,
halogen atoms. In particular, R.sup.4 can be substituted at the 3
and 4 positions relative to attachment to the N4 amine,
particularly with halogen atoms and/or alkoxy groups.
[0154] In a eighteenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is a substituted phenyl
group, substituted with the same or different R.sup.8 groups and
R.sup.2 is
##STR00032##
wherein R.sup.35 is an alkyl group, and in particular is
##STR00033##
In one aspect, the R.sup.4 phenyl group is di or tri substituted
with the same or different R.sup.8 groups, and in particular,
halogen atoms. In particular, R.sup.4 can be substituted at the 3
and 4 positions relative to attachment to the N4 amine,
particularly with halogen atoms and/or alkoxy groups.
[0155] In a nineteenth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined R.sup.4 is
##STR00034##
and R.sup.2 is
##STR00035##
[0156] and in particular, is substituted at the 3 or 4 position
with the isoxazole. Y is selected from the group consisting of O,
S, SO, SO.sub.2, SONR.sup.36, NH and NR.sup.37. Z is selected from
the group consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH and
NR.sup.37. Each R.sup.35 is, independently of the others, selected
from the group consisting of hydrogen and R.sup.8, or,
alternatively, two R.sup.35 bonded to the same carbon atom are
taken together to form an oxo (.dbd.O), NH or NR.sup.38 group and
the other two R.sup.35 each, if present, independently of one
another, are selected from the group consisting of hydrogen and
R.sup.8. Each R.sup.36 is independently selected from the group
consisting of hydrogen and (C1-C6)alkyl. Each R.sup.37 is
independently selected from the group consisting of hydrogen and a
progroup. R.sup.38 is selected from the group consisting of
(C1-C6)alkyl and (C5-C14)aryl.
[0157] In certain aspects, R.sup.37 is 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.2--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
[0158] In one aspect, Y is oxygen, Z is NH and one or more of
R.sup.35 is an alkyl group, and in particular, a methyl group. In
certain, two R.sup.35's form a gem dialkyl moiety, in particular, a
gem dimethyl moiety adjacent to the NH depicted as
##STR00036##
[0159] In a twentieth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00037##
wherein each R.sup.35 are as defined above, and in particular are
both halogen atoms, e.g., fluorine, and R.sup.2 is a substituted
phenyl group, substituted with the same or different R.sup.8
groups. In one aspect, the R.sup.2 phenyl group is di or tri
substituted with the same or different R.sup.8 groups, and in
particular, halogen atoms. In particular, R.sup.2 can be
substituted at the 3 and 5 positions relative to attachment to the
N2 amine, particularly with halogen atoms and/or alkoxy groups.
[0160] In a twenty first embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00038##
wherein Y and Z are defined as above and R.sup.2 is
##STR00039##
and in particular is substituted at the 3 or 4 position with the
isoxazole. In one aspect of the thirty ninth embodiment with regard
to R.sup.4, Y is NH and Z is O, e.g.,
##STR00040##
[0161] In a twenty second embodiment the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00041##
wherein R.sup.8 and R.sup.c are as defined above and R.sup.2 is a
phenyl group substituted at the 3 or 4 position with
##STR00042##
In one aspect --OR.sup.8, R.sup.8 is a hydrogen atom.
[0162] In a twenty third embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00043##
and R.sup.2 is a substituted phenyl group, substituted with at
least two of the same or different R.sup.8 groups as defined above.
Suitable examples include compounds 340, 343, 349, 350 and 351.
[0163] In a twenty fourth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00044##
and R.sup.2 is
##STR00045##
[0165] In a twenty fifth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00046##
and R.sup.2 is
##STR00047##
[0166] wherein Y and R.sup.35 are as defined above. Suitable
examples include compounds 368, 381, 382, 383 and 384.
[0167] In a twenty sixth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 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, (C3-C8)cycloalkyl
optionally substituted with one or more of the same or different
R.sup.8 groups, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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 and R.sup.2 is
##STR00048##
wherein R.sup.35 is as defined above. Suitable examples include
compounds 205 and 206.
[0168] In a twenty seventh embodiment the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00049##
and R.sup.2 is a phenyl group substituted with one or more of the
same R.sup.8 groups. Suitable examples include compounds 328, 329,
330, 341, 553, 554, 555, 556, 559 and 560.
[0169] In a twenty eighth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 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, (C3-C8)cycloalkyl
optionally substituted with one or more of the same or different
R.sup.8 groups, cyclohexyl 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, (C5-C15)aryl optionally
substituted with one or more of the same or different R.sup.8
groups, 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 and R.sup.2 is
##STR00050##
wherein Y is as defined above or is NR.sup.35 and R.sup.35 is as
defined above. Suitable examples include compounds 1070, 1071,
1073, 1074, 1075, 1076, 1078, 1080, 1085, 1091 and 1092.
[0170] In a twenty ninth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00051##
wherein R.sup.2 is a substituted phenyl group or an indazole,
substituted with one or more of the same or different R.sup.8
groups as defined above. Suitable examples include compounds 1251,
1252, 1253, 1254 and 1255.
[0171] In a thirtieth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00052##
wherein each R.sup.35 independently is as described above and
R.sup.2 is
##STR00053##
Suitable examples include compounds 217, 218, 219, 220, 221, 222,
223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236,
237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 1281, 1283,
1283, 1284, 1285, 1287, 1288, 1289, 1290 and 1291.
[0172] In a thirty first embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.4 is
##STR00054##
wherein R.sup.z is a hydrogen or lower alkyl group, R.sup.x and
R.sup.y are each independently lower alkyl groups, or taken
together form a cycloalkyl and R.sup.p is a halogen atom or a lower
alkyl group and R.sup.2 is as defined above. Suitable examples
include compounds 402, 403, 407, 408, 409 and 410.
[0173] In a thirty second embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, R.sup.2 is
##STR00055##
and R.sup.4 is
##STR00056##
[0174] 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;
[0175] In a thirty third embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined, 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,
cyclohexyl 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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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,
##STR00057## ##STR00058##
[0176] R.sup.4 is
##STR00059##
[0177] R.sup.5, R.sup.6, R.sup.8, R.sup.a, R.sup.b, R.sup.c,
R.sup.d, m and n are as described above;
[0178] each R.sup.21, R.sup.22 and R.sup.23 are each, independently
of one another, as described above and in particular, an alkyl
group;
[0179] each R.sup.28 individually is a halogen or alkoxy;
[0180] R.sup.29 is a (C1-C6)alkyl or (C3-C9)cycloalkyl;
[0181] R.sup.30 is an alkyl group or a halogen;
[0182] X is selected from the group consisting of N and CH;
[0183] Y, Z, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 are as
described above;
[0184] each R.sup.46, R.sup.47 and R.sup.48 independently is
selected from the group consisting of a hydrogen, alkyl, alkoxy,
hydroxyl, halogen, isoxazole, piperazino, N-alkyl piperazine,
morpholino and CH.sub.3NHC(O)CH.sub.2O--, with the proviso that
R.sup.46, R.sup.47 and R.sup.48 are all not hydrogen and when one
of R.sup.46, R.sup.47 or R.sup.48 is isoxazole, piperazino, N-alkyl
piperazine, morpholino or CH.sub.3NHC(O)CH.sub.2O--, then the
remaining R.sup.46, R.sup.47 or R.sup.48 are hydrogen;
[0185] R.sup.50 is an alkyl group or --(CH.sub.2).sub.qOH;
[0186] q is an integer from 1 to 6;
[0187] R.sup.52 is an alkyl group or a substituted alkyl group
[0188] p is 1, 2 or 3; and
[0189] x=1-8.
[0190] In a thirty fourth embodiment of the compounds of structural
formulae (I) and (Ia), R.sup.2, R.sup.4, R.sup.5, L.sup.1 and
L.sup.2 are as previously described for their respective structures
(I) and (Ia), with the proviso that R.sup.2 is not
3,4,5-trimethoxyphenyl, (C1-C6)alkoxyphenyl or
##STR00060##
[0191] where R.sup.21, R.sup.22 and R.sup.23 are as defined for
R.sup.1, R.sup.2 and R.sup.3, respectively of U.S. Pat. No.
6,235,746, the disclosure of which is incorporated by reference. In
a specific embodiment of this first embodiment, R.sup.21 is
hydrogen, halo, straight-chain or branched (C1-C6)alkyl optionally
substituted with one or more of the same or different R.sup.25
groups, hydroxyl, (C1-C6)alkoxy optionally substituted with one or
more of the same or different phenyl or R.sup.25 groups, thiol
(--SH), (C1-C6)alkylthio optionally substituted with one or more of
the same or different phenyl or R.sup.25 groups, amino
(--NH.sub.2), --NHR.sup.26 or --NR.sup.26R.sup.26; R.sup.22 and
R.sup.23 are each, independently of one another, a (C1-C6)
straight-chain or branched alkyl optionally substituted with one or
more of the same or different R.sup.25 groups; R.sup.25 is selected
from the group consisting of halo, hydroxyl, (C1-C6)alkoxy, thiol,
(C1-C6)alkylthio, (C1-C6)alkylamino and (C1-C6)dialkylamino; and
each R.sup.26 is independently a (C1-C6)alkyl optionally
substituted with one or more of the same or different phenyl or
R.sup.25 groups or a --C(O)R.sup.27, where R.sup.27 is a
(C1-C6)alkyl optionally substituted with one or more of the same or
different phenyl or R.sup.25 groups.
[0192] In another specific embodiment, R.sup.21 is methoxy
optionally substituted with one or more of the same or different
halo groups and/or R.sup.22 and R.sup.23 are each, independently of
one another, a methyl or ethyl optionally substituted with one or
more of the same or different halo groups.
[0193] In a thirty fifth embodiment, the compounds of structural
formulae (I) and (Ia), R.sup.5, R.sup.6, R.sup.8, L.sup.1 and
L.sup.2 are as previously defined:
[0194] R.sup.2 is
##STR00061##
R.sup.4 is
##STR00062##
[0195] R.sup.5, R.sup.6, R.sup.30, R.sup.35 and x are as defined
above. In certain embodiments, x is 2 through 4. In other
embodiments, R.sup.35 is a methyl group. In still additional
embodiments, R.sup.30 is chlorine, methyl or trifluoromethyl. In
still other embodiments, R.sup.5 is fluorine and R.sup.6 is
hydrogen.
[0196] In a thirty sixth embodiment the 2,4-pyrimidinediamine
includes those compounds according to structures I and I(a) wherein
R.sup.2 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, (C3-C8)cycloalkyl optionally substituted with one
or more of the same or different R.sup.8 groups, cyclohexyl
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, (C5-C15)aryl optionally substituted with one or more of the
same or different R.sup.8 groups, 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.4 is
##STR00063##
R.sup.5, R.sup.6 and R.sup.8 are described as above. In certain
embodiments, R.sup.5 is a fluorine atom and R.sup.6 is a hydrogen
atom. In certain embodiments, R.sup.2 is a di or tri-substituted
phenyl group.
[0197] In a thirty seventh embodiment, the invention pertains to
2,4-pyrimidinediamine compounds according to structures I and I(a)
wherein R.sup.2 is
##STR00064##
R.sup.4 is
##STR00065##
[0198] and R.sup.5, R.sup.6, R.sup.22 and R.sup.23, R.sup.46,
R.sup.47 and R.sup.48 are as defined above, each R.sup.21,
independently of one another, is an alkyl group. In certain
embodiments, R.sup.5 is a fluorine atom and R.sup.6 is a hydrogen
atom.
[0199] In a thirty eighth embodiment, the present invention relates
to 2,4-pyrimidinediamine compounds according to structures I and
I(a) wherein R.sup.2 is
##STR00066##
[0200] R.sup.4 is,
##STR00067##
[0201] R.sup.5, R.sup.6, R.sup.8, R.sup.21, R.sup.23, R.sup.28,
R.sup.35, R.sup.36, R.sup.37, R.sup.38, Y, R.sup.a, R.sup.c,
R.sup.d, m and n are as described above, and X is selected from the
group consisting of N and CH. In a particular embodiment, R.sup.28
is a methoxy. In another embodiment, R.sup.23 is methyl. In
particular embodiments, R.sup.21 is a methyl group. In other
embodiments, each R.sup.28 is chlorine. In still additional
embodiments, R.sup.21 is a methyl group and at least one R.sup.28
is a chlorine. In another embodiment, R.sup.28 is a methoxy.
[0202] In a thirty ninth embodiment, the present invention provides
pyrimidinediamine compounds according to structures I and I(a)
wherein R.sup.2 is
##STR00068##
[0203] R.sup.4 is,
##STR00069##
R.sup.5, R.sup.6, R.sup.8, R.sup.21, each R.sup.28, R.sup.29,
R.sup.a, R.sup.b, R.sup.c. R.sup.d, m and n, X, Y, Z, each
R.sup.35, each R.sup.36, each R.sup.37 and R.sup.38 are as
described above.
[0204] In certain embodiments, R.sup.29 is a t-butyl group. In
other embodiments, R.sup.23 is a methyl group. In certain
embodiments, each R.sup.28 is a chlorine. In still another
embodiment, R.sup.21 is a methyl group and at least one of R.sup.28
is a chlorine.
[0205] In a fortieth embodiment, the invention pertains to
2,4-pyrimidinediamine compounds according to structures I and I(a)
wherein R.sup.2 is
##STR00070##
[0206] R.sup.4 is
##STR00071##
R.sup.5, R.sup.6, R.sup.8, R.sup.21, each R.sup.28, R.sup.a,
R.sup.b, R.sup.c. R.sup.d, m, n, p, X, Y, Z, each R.sup.35, each
R.sup.36, each R.sup.37 and R.sup.38 are as described above. In
particular embodiments, R.sup.21 is a methyl group. In other
embodiments, each R.sup.28 is a chlorine. In still other
embodiments, R.sup.21 is a methyl group and at least one of
R.sup.28 is a chlorine. In still another aspect, p is 1 or 2.
[0207] In a forty first embodiment, the invention relates to
2,4-pyrimidinediamine compounds according to structures I and I(a)
wherein R.sup.2 is
##STR00072##
R.sup.4 is
##STR00073##
[0208] R.sup.5, R.sup.6, R.sup.8, R.sup.21, each R.sup.28, R.sup.a,
R.sup.b, R.sup.c. R.sup.d, M, n, q, X, Y, Z, R.sup.35, R.sup.36,
R.sup.37, R.sup.38, R.sup.50, and R.sup.52 are as described
above.
[0209] In certain aspects, R.sup.50 is --CH.sub.2CH.sub.2--OH or
methyl. In another aspect, R.sup.52 is trifluoromethyl. In still
another aspect, at least one R.sup.28 is a chlorine. In yet another
aspect, R.sup.50 is a methyl and at least one R.sup.28 is a
chlorine.
[0210] In a forty second embodiment, applicable to the first
through forty first embodiments, R.sup.5 of the pyrimidine ring is
a halogen atom, such as fluorine, and R.sup.6 of the pyrimidine
ring is a hydrogen atom.
[0211] In a forty third embodiment, L.sup.1 and L.sup.2 are
covalent bonds for the above-identified embodiments.
[0212] Also specifically described are combinations of the above
first through forty third embodiments.
[0213] Those of skill in the art will appreciate that the
2,4-pyrimidinediamine compounds described herein may include
functional groups that can be masked with progroups to create
prodrugs. Such prodrugs are usually, but need not be,
pharmacologically inactive until converted into their active drug
form. Indeed, many of the active 2,4-pyrimidinediamine compounds
described in TABLE 1, include promoieties that are hydrolyzable or
otherwise cleavable under conditions of use. For example, ester
groups commonly undergo acid-catalyzed hydrolysis to yield the
parent carboxylic acid when exposed to the acidic conditions of the
stomach, or base-catalyzed hydrolysis when exposed to the basic
conditions of the intestine or blood. Thus, when administered to a
subject orally, 2,4-pyrimidinediamines that include ester moieties
may be considered prodrugs of their corresponding carboxylic acid,
regardless of whether the ester form is pharmacologically active.
Referring to TABLE 1, numerous ester-containing
2,4-pyrimidinediamines of the invention are active in their ester,
"prodrug" form.
[0214] In the prodrugs of the invention, any available functional
moiety may be masked with a progroup to yield a prodrug. Functional
groups within the 2,4-pyrimidinediamine compounds that may be
masked with progroups for inclusion in a promoiety include, but are
not limited to, amines (primary and secondary), hydroxyls,
sulfanyls (thiols), carboxyls, etc. Myriad progroups suitable for
masking such functional groups to yield promoieties that are
cleavable under the desired conditions of use are known in the art.
All of these progroups, alone or in combinations, may be included
in the prodrugs of the invention.
[0215] In one illustrative embodiment, the prodrugs of the
invention are compounds according to structural formula (I) in
which R.sup.c and R.sup.d may be, in addition to their
previously-defined alternatives, a progroup.
[0216] Those of skill in the art will appreciate that many of the
compounds and prodrugs of the invention, as well as the various
compound species specifically described and/or illustrated herein,
may exhibit the phenomena of tautomerism, conformational isomerism,
geometric isomerism and/or optical isomerism. For example, the
compounds and prodrugs of the invention may include one or more
chiral centers and/or double bonds and as a consequence may exist
as stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers and diasteromers and mixtures thereof, such
as racemic mixtures. As another example, the compounds and prodrugs
of the invention may exist in several tautomeric forms, including
the enol form, the keto form and mixtures thereof. As the various
compound names, formulae and compound drawings within the
specification and claims can represent only one of the possible
tautomeric, conformational isomeric, optical isomeric or geometric
isomeric forms, it should be understood that the invention
encompasses any tautomeric, conformational isomeric, optical
isomeric and/or geometric isomeric forms of the compounds or
prodrugs having one or more of the utilities described herein, as
well as mixtures of these various different isomeric forms. In
cases of limited rotation around the 2,4-pyrimidinediamine core
structure, atropisomers are also possible and are also specifically
included in the compounds of the invention.
[0217] Moreover, skilled artisans will appreciate that when lists
of alternative substituents include members which, owing to valency
requirements or other reasons, cannot be used to substitute a
particular group, the list is intended to be read in context to
include those members of the list that are suitable for
substituting the particular group. For example, skilled artisans
will appreciate that while all of the listed alternatives for
R.sup.b can be used to substitute an alkyl group, certain of the
alternatives, such as .dbd.O, cannot be used to substitute a phenyl
group. It is to be understood that only possible combinations of
substituent-group pairs are intended.
[0218] The compounds and/or prodrugs of the invention may be
identified by either their chemical structure or their chemical
name. When the chemical structure and the chemical name conflict,
the chemical structure is determinative of the identity of the
specific compound.
[0219] Depending upon the nature of the various substituents, the
2,4-pyrimidinediamine compounds and prodrugs of the invention may
be in the form of salts. Such salts include salts suitable for
pharmaceutical uses ("pharmaceutically-acceptable salts"), salts
suitable for veterinary uses, etc. Such salts may be derived from
acids or bases, as is well-known in the art.
[0220] In one embodiment, the salt is a pharmaceutically acceptable
salt. Generally, pharmaceutically acceptable salts are those salts
that retain substantially one or more of the desired
pharmacological activities of the parent compound and which are
suitable for administration to humans. Pharmaceutically acceptable
salts include acid addition salts formed with inorganic acids or
organic acids. Inorganic acids suitable for forming
pharmaceutically acceptable acid addition salts include, by way of
example and not limitation, hydrohalide acids (e.g., hydrochloric
acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric
acid, phosphoric acid, and the like. Organic acids suitable for
forming pharmaceutically acceptable acid addition salts include, by
way of example and not limitation, acetic acid, trifluoroacetic
acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,
glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic
acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, palmitic acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
etc.), arylsulfonic acids (e.g., benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, cycloalkylsulfonic acids (e.g.,
camphorsulfonic acid),
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like.
[0221] Pharmaceutically acceptable salts also include salts formed
when an acidic proton present in the parent compound is either
replaced by a metal ion (e.g., an alkali metal ion, an alkaline
earth metal ion or an aluminum ion), an ammonium ion or coordinates
with an organic base (e.g., ethanolamine, diethanolamine,
triethanolamine, N-methylglucamine, morpholine, piperidine,
dimethylamine, diethylamine, etc.).
[0222] The 2,4-pyrimidinediamine compounds and of the invention, as
well as the salts thereof, may also be in the form of hydrates,
solvates and N-oxides, as are well-known in the art.
6.3 Methods of Synthesis
[0223] The compounds and prodrugs of the invention may be
synthesized via a variety of different synthetic routes using
commercially available starting materials and/or starting materials
prepared by conventional synthetic methods. Suitable exemplary
methods that may be routinely adapted to synthesize the
2,4-pyrimidinediamine compounds and prodrugs of the invention are
found in U.S. Pat. No. 5,958,935, U.S. patent application Ser. No.
10/355,543, filed Jan. 31, 2003 (US Publication US20040029902-A1),
WO 03/063794, published Aug. 1, 2003, U.S. patent application Ser.
No. 10/631,029, filed Jul. 29, 2003 and WO 2004/014382, published
Feb. 19, 2004, the disclosures of which are incorporated herein by
reference. All of the compounds of structural formulae (I), (Ia)
and (II) may be prepared by routine adaptation of these
methods.
[0224] A variety of exemplary synthetic routes that can be used to
synthesize the 2,4-pyrimidinediamine compounds of the invention are
described in Schemes (I)-(XI), below. In Schemes (I)-(XI),
like-numbered compounds have similar structures. These methods may
be routinely adapted to synthesize the prodrugs according to
structural formula (II).
[0225] In one exemplary embodiment, the compounds can be
synthesized from substituted or unsubstituted uracils or
thiouracils as illustrated in Scheme (I), below:
##STR00074##
[0226] In Scheme (I), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1
and L.sup.2 are as previously defined for structural formula (I), X
is a halogen (e.g., F, Cl, Br or I) and Y and Y' are each,
independently of one another, selected from the group consisting of
O and S. Referring to Scheme (I), uracil or thiouracil 2 is
dihalogenated at the 2- and 4-positions using standard halogenating
agent POX.sub.3 (or other standard halogenating agent) under
standard conditions to yield 2,4-bishalo pyrimidine 4. Depending
upon the R.sup.5 substituent, in pyrimidine 4, the halide at the C4
position is more reactive towards nucleophiles than the halide at
the C2 position. This differential reactivity can be exploited to
synthesize 2,4-pyrimidinediamines according structural formula (I)
by first reacting 2,4-bishalopyrimidine 4 with one equivalent of
amine 10, yielding 4N-substituted-2-halo-4-pyrimidineamine 8,
followed by amine 6 to yield a 2,4-pyrimidinediamine according
structural formula (I).
2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be
obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10,
respectively.
[0227] In most situations, the C4 halide is more reactive towards
nucleophiles, as illustrated in the Scheme. However, as will be
recognized by skilled artisans, the identity of the R.sup.5
substituent may alter this reactivity. For example, when R.sup.5 is
trifluoromethyl, a 50:50 mixture of
4N-substituted-4-pyrimidineamine 8 and the corresponding
2N-substituted-2-pyrimidineamine is obtained. Regardless of the
identity of the R.sup.5 substituent, the regioselectivity of the
reaction can be controlled by adjusting the solvent and other
synthetic conditions (such as temperature), as is well-known in the
art.
[0228] The reactions depicted in Scheme (I) may proceed more
quickly when the reaction mixtures are heated via microwave. When
heating in this fashion, the following conditions may be used: heat
to 175.degree. C. in ethanol for 5-20 min. in a Smith Reactor
(Personal Chemistry) in a sealed tube (at 20 bar pressure).
[0229] The uracil or thiouracil 2 starting materials may be
purchased from commercial sources or prepared using standard
techniques of organic chemistry. Commercially available uracils and
thiouracils that can be used as starting materials in Scheme (I)
include, by way of example and not limitation, uracil (Aldrich
#13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4;
CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS
Registry 2001-93-6); 5-acetouracil (Chem. Sources Int'l 2000; CAS
Registry 6214-65-9); 5-azidouracil; 5-aminouracil (Aldrich
#85,528-6; CAS Registry 932-52-5); 5-bromouracil (Aldrich
#85,247-3; CAS Registry 51-20-7); 5-(trans-2-bromovinyl)-uracil
(Aldrich #45,744-2; CAS Registry 69304-49-0);
5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2);
5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid
(2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich
#27,770-3; CAS Registry 23945-44-0); 5-chlorouracil (Aldrich
#22,458-8; CAS Registry 1820-81-1); 5-cyanouracil (Chem. Sources
Int'l 2000; CAS Registry 4425-56-3); 5-ethyluracil (Aldrich
#23,044-8; CAS Registry 4212-49-1); 5-ethenyluracil (CAS Registry
37107-81-6); 5-fluorouracil (Aldrich #85,847-1; CAS Registry
51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1);
5-methyluracil (thymine; Aldrich #13,199-7; CAS Registry 65-71-4);
5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5);
uracil-5-sulfamic acid (Chem. Sources Intl 2000; CAS Registry
5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS
Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry
155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry
60007-38-3); 6-aminouracil (Aldrich #A5060-6; CAS Registry
873-83-6) uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2;
CAS Registry 50887-69-9); 6-methyluracil (Aldrich #D11, 520-7; CAS
Registry 626-48-2); uracil-5-amino-6-carboxylic acid (5-aminoorotic
acid; Aldrich #19,121-3; CAS Registry #7164-43-4);
6-amino-5-nitrosouracil (6-amino-2,4-dihydroxy-5-nitrosopyrimidine;
Aldrich #27,689-8; CAS Registry 5442-24-0);
uracil-5-fluoro-6-carboxylic acid (5-fluoroorotic acid; Aldrich
#42,513-3; CAS Registry 00000-00-0); and
uracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich
#18,528-0; CAS Registry 600779-49-9). Additional 5-, 6- and
5,6-substituted uracils and/or thiouracils are available from
General Intermediates of Canada, Inc., Edmonton, Alberta, CA
(www.generalintermediates.com) and/or Interchim, France
(www.interchim.com), or may be prepared using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0230] Amines 6 and 10 may be purchased from commercial sources or,
alternatively, may be synthesized utilizing standard techniques.
For example, suitable amines may be synthesized from nitro
precursors using standard chemistry. Specific exemplary reactions
are provided in the Examples section. See also Vogel, 1989,
Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John
Wiley & Sons, Inc.
[0231] Skilled artisans will recognize that in some instances,
amines 6 and 10 and/or substituents R.sup.5 and/or R.sup.6 on
uracil or thiouracil 2 may include functional groups that require
protection during synthesis. The exact identity of any protecting
group(s) used will depend upon the identity of the functional group
being protected, and will be apparent to these of skill in the art.
Guidance for selecting appropriate protecting groups, as well as
synthetic strategies for their attachment and removal, may be
found, for example, in Greene & Wuts, Protective Groups in
Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New
York (1999) and the references cited therein (hereinafter "Greene
& Wuts").
[0232] A specific embodiment of Scheme (I) utilizing 5-fluorouracil
(Aldrich #32,937-1) as a starting material is illustrated in Scheme
(Ia), below:
##STR00075##
[0233] In Scheme (Ia), R.sup.2, R.sup.4, L.sup.1 and L.sup.2 are as
previously defined for Scheme (I). According to Scheme (Ia),
5-fluorouracil 3 is halogenated with POCl.sub.3 to yield
2,4-dichloro-5-fluoropyrimidine 5, which is then reacted with
excess amine 6 or 10 to yield N2,N4-bis substituted
5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively.
Alternatively, non-bis
2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be
obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one
equivalent of amine 10 (to yield
2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by
one or more equivalents of amine 6.
[0234] In another exemplary embodiment, the 2,4-pyrimidinediamine
compounds of the invention may be synthesized from substituted or
unsubstituted cytosines as illustrated in Schemes (IIa) and (IIb),
below:
##STR00076##
##STR00077##
[0235] In Schemes (IIa) and (IIb), R.sup.2, R.sup.4, R.sup.5,
R.sup.6, L.sup.1, L.sup.2 and X are as previously defined for
Scheme (I) and PG represents a protecting group. Referring to
Scheme (IIa), the C4 exocyclic amine of cytosine 20 is first
protected with a suitable protecting group PG to yield N4-protected
cytosine 22. For specific guidance regarding protecting groups
useful in this context, see Vorbruggen and Ruh-Pohlenz, 2001,
Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp.
1-631 ("Vorbruggen"). Protected cytosine 22 is halogenated at the
C2 position using a standard halogenation reagent under standard
conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24.
Reaction with amine 6 followed by deprotection of the C4 exocyclic
amine and reaction with amine 10 yields a 2,4-pyrimidinediamine
according to structural formula (I).
[0236] Alternatively, referring to Scheme (IIb), cytosine 20 may be
reacted with amine 10 or protected amine 21 to yield N4-substituted
cytosine 23 or 27, respectively. These substituted cytosines may
then be halogenated as previously described, deprotected (in the
case of N4-substituted cytosine 27) and reacted with amine 6 to
yield a 2,4-pyrimidinediamine according to structural formula
(I).
[0237] Commercially-available cytosines that may be used as
starting materials in Schemes (IIa) and (IIb) include, but are not
limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7);
N.sup.4-acetylcytosine (Aldrich #37,791-0; CAS Registry
14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry
2022-85-7); and 5-(trifluoromethyl)-cytosine. Other suitable
cytosines useful as starting materials in Schemes (IIa) are
available from General Intermediates of Canada, Inc., Edmonton,
Alberta, CA (www.generalintermediates.com) and/or Interchim, France
(www.interchim.com), or may be prepared using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0238] In still another exemplary embodiment, the
2,4-pyrimidinediamine compounds of the invention may be synthesized
from substituted or unsubstituted 2-amino-4-pyrimidinols as
illustrated in Scheme (III), below:
##STR00078##
[0239] In Scheme (III), R.sup.2, R.sup.4, R.sup.5, R.sup.6,
L.sup.1, L.sup.2 and X are as previously defined for Scheme (I) and
Z is a leaving group as discussed in more detail in connection with
Scheme IV, infra. Referring to Scheme (III), 2-amino-4-pyrimidinol
30 is reacted with amine 6 (or optionally protected amine 21) to
yield N2-substituted-4-pyrimidinol 32, which is then halogenated as
previously described to yield
N2-substituted-4-halo-2-pyrimidineamine 34. Optional deprotection
(for example if protected amine 21 was used in the first step)
followed by reaction with amine 10 affords a 2,4-pyrimidinediamine
according to structural formula (I). Alternatively, pyrimidinol 30
can be reacted with acylating agent 31.
[0240] Suitable commercially-available 2-amino-4-pyrimidinols 30
that can be used as starting materials in Scheme (III) include, but
are not limited to, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich
#A4702-8; CAS Registry 00000-00-0) and
2-amino-6-hydroxy-4-pyrimidinol (Aldrich #A5040-1; CAS Registry
56-09-7). Other 2-amino-4-pyrimidinols 30 useful as starting
materials in Scheme (III) are available from General Intermediates
of Canada, Inc., Edmonton, Alberta, CA
(www.generalintermediates.com) and/or Interchim, France
(www.interchim.com), or may be prepared using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0241] Alternatively, the 2,4-pyrimidinediamine compounds of the
invention may be prepared from substituted or unsubstituted
4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:
##STR00079##
[0242] In Scheme (IV), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1
and L.sup.2 are as previously defined for Scheme (I) and Z
represents a leaving group. Referring to Scheme (N), the
C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards
nucleophiles than the C4-amino such that reaction with amine 6
yields N2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction
with compound 44, which includes a good leaving group Z, or amine
10 yields a 2,4-pyrimidinediamine according to structural formula
(I). Compound 44 may include virtually any leaving group that can
be displaced by the C4-amino of
N2-substituted-2,4-pyrimidinediamine 42. Suitable leaving groups Z
include, but are not limited to, halogens, methanesulfonyloxy
(mesyloxy; "OMs"), trifluoromethanesulfonyloxy ("OTf") and
p-toluenesulfonyloxy (tosyloxy; "OTs"), benzene sulfonyloxy
("besylate") and metanitro benzene sulfonyloxy ("nosylate"). Other
suitable leaving groups will be apparent to those of skill in the
art.
[0243] Substituted 4-amino-2-pyrimidinol starting materials may be
obtained commercially or synthesized using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0244] In still another exemplary embodiment, the
2,4-pyrimidinediamine compounds of the invention can be prepared
from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as
illustrated in Scheme (V), below:
##STR00080##
[0245] In Scheme (V), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1,
L.sup.2 and X are as defined for Scheme (I) and Z is as defined for
Scheme (IV). Referring to Scheme (V), 2-amino-4-chloropyrimidine 50
is reacted with amino 10 to yield 4N-substituted-2-pyrimidineamine
52 which, following reaction with compound 31 or amine 6, yields a
2,4-pyrimidinediamine according to structural formula (I).
Alternatively, 2-chloro-4-amino-pyrimidine 54 may be reacted with
compound 44 followed by amine 6 to yield a compound according to
structural formula (I).
[0246] A variety of pyrimidines 50 and 54 suitable for use as
starting materials in Scheme (V) are commercially available,
including by way of example and not limitation,
2-amino-4,6-dichloropyrimidine (Aldrich #A4860-1; CAS Registry
56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine (Aldrich #51,864-6;
CAS Registry 5734-64-5); 2-amino-4-chloro-6-methylpyrimidine
(Aldrich #12,288-2; CAS Registry 5600-21-5); and
2-amino-4-chloro-6-methylthiopyrimidine (Aldrich #A4600-5; CAS
Registry 1005-38-5). Additional pyrimidine starting materials are
available from General Intermediates of Canada, Inc., Edmonton,
Alberta, CA (www.generalintermediates.com) and/or Interchim, France
(www.interchim.com), or may be prepared using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0247] Alternatively, 4-chloro-2-pyrimidineamines 50 may be
prepared as illustrated in Scheme (Va):
##STR00081##
[0248] In Scheme (Va), R.sup.5 and R.sup.6 are as previously
defined for structural formula (I). In Scheme (Va), dicarbonyl 53
is reacted with guanidine to yield 2-pyrimidineamine 51. Reaction
with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid
or urea hydrogen peroxide complex yields N-oxide 55, which is then
halogenated to give 4-chloro-2-pyrimidineamine 50. The
corresponding 4-halo-2-pyrimidineamines may be obtained by using
suitable halogenation reagents.
[0249] In yet another exemplary embodiment, the
2,4-pyrimidinediamine compounds of the invention can be prepared
from substituted or unsubstituted uridines as illustrated in Scheme
(VI), below:
##STR00082##
[0250] In Scheme (VI), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1,
L.sup.2 and X are as previously defined for Scheme (I) and the
superscript PG represents a protecting group, as discussed in
connection with Scheme (IIb). According to Scheme (VI), uridine 60
has a C4 reactive center such that reaction with amine 10 or
protected amine 21 yields N4-substituted cytidine 62 or 64,
respectively. Acid-catalyzed deprotection of N4-substituted 62 or
64 (when "PG" represents an acid-labile protecting group) yields
N4-substituted cytosine 28, which may be subsequently halogenated
at the C2-position and reacted with amine 6 to yield a
2,4-pyrimidinediamine according to structural formula (I).
[0251] Cytidines may also be used as starting materials in an
analogous manner, as illustrated in Scheme (VII), below:
##STR00083##
[0252] In Scheme (VII), R.sup.2, R.sup.4, R.sup.5, R.sup.6,
L.sup.1, L.sup.2 and X are as previously defined in Scheme (I) and
the superscript PG represents a protecting group as discussed
above. Referring to Scheme (VII), like uridine 60, cytidine 70 has
a C4 reactive center such that reaction with amine 10 or protected
amine 21 yields N4-substituted cytidine 62 or 64, respectively.
These cytidines 62 and 64 are then treated as previously described
for Scheme (VI) to yield a 2,4-pyrimidinediamine according to
structural formula (I).
[0253] Although Schemes (VI) and (VII) are exemplified with
ribosylnucleosides, skilled artisans will appreciate that the
corresponding 2'-deoxyribo and 2',3'-dideoxyribo nucleosides, as
well as nucleosides including sugars or sugar analogs other than
ribose, would also work.
[0254] Numerous uridines and cytidines useful as starting materials
in Schemes (VI) and (VII) are known in the art, and include, by way
of example and not limitation, 5-trifluoromethyl-2'-deoxycytidine
(Chem. Sources #ABCR F07669; CAS Registry 66, 384-66-5);
5-bromouridine (Chem. Sources Int'12000; CAS Registry 957-75-5);
5-iodo-2'-deoxyuridine (Aldrich #1-775-6; CAS Registry 54-42-2);
5-fluorouridine (Aldrich #32,937-1; CAS Registry 316-46-1);
5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);
5-(trifluoromethyl)uridine (Chem. Sources Intl 2000; CAS Registry
70-00-8); 5-trifluoromethyl-2'-deoxyuridine (Chem. Sources Int'l
2000; CAS Registry 70-00-8). Additional uridines and cytidines that
can be used as starting materials in Schemes (VI) and (VII) are
available from General Intermediates of Canada, Inc., Edmonton,
Alberta, CA (www.generalintermediates.com) and/or Interchim, France
(www.interchim.com), or may be prepared using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0255] The 2,4-pyrimidinediamine compounds of the invention can
also be synthesized from substituted pyrimidines, such as
chloro-substituted pyrimidines, as illustrated in Schemes (VIII)
and (IX), below:
##STR00084##
##STR00085##
[0256] In Schemes (VIII) and (IX), R.sup.2, R.sup.4, L.sup.1,
L.sup.2 and R.sup.a are as previously defined for structural
formula (I) and "Ar" represents an aryl group. Referring to Scheme
(VIII), reaction of 2,4,6-trichloropyrimidine 80 (Aldrich
#T5,620-0; CAS #3764-01-0) with amine 6 yields a mixture of three
compounds: substituted pyrimidine mono-, di- and triamines 81, 82
and 83, which can be separated and isolated using HPLC or other
conventional techniques. Mono- and diamines 81 and 82 may be
further reacted with amines 6 and/or 10 to yield
N2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85,
respectively.
[0257] N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared
in a manner analogous to Scheme (VIII) by employing
2,4-dichloro-5-methylpyrimidine or 2,4-dichloro-pyrimidine as
starting materials. In this instance, the mono-substituted
pyrimidineamine corresponding to compound 81 is not obtained.
Instead, the reaction proceeds to yield the
N2,N4-bis-substituted-2,4-pyrimidinediamine directly.
[0258] Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90
(Aldrich #24,671-9; CAS #1780-40-1) is reacted with excess amine 6
to yield a mixture of three compounds: 91, 92, and 93, which can be
separated and isolated using HPLC or other conventional techniques.
As illustrated,
N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may be
further reacted at the C6 halide with, for example a nucleophilic
agent 94 to yield compound 95. Alternatively, compound 92 can be
converted into
N2,N4-bis-substituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 via
a Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to
2,4-pyrimidinediamine 99 by reaction with Bn.sub.3SnH.
[0259] As will be recognized by skilled artisans,
2,4-pyrimidinediamines according to the invention, synthesized via
the exemplary methods described above or by other well-known means,
may also be utilized as starting materials and/or intermediates to
synthesize additional 2,4-pyrimidinediamine compounds of the
invention. A specific example is illustrated in Scheme (X),
below:
##STR00086##
[0260] In Scheme (X), R.sup.4, R.sup.5, R.sup.6, L.sup.2 and
R.sup.a are as previously defined for structural formula (I). Each
R.sup.a' is independently an R.sup.a, and may be the same or
different from the illustrated R.sup.a. Referring to Scheme (X),
carboxylic acid or ester 100 may be converted to amide 104 by
reaction with amine 102. In amine 102, R.sup.a' may be the same or
different than R.sup.a of acid or ester 100. Similarly, carbonate
ester 106 may be converted to carbamate 108.
[0261] A second specific example is illustrated in Scheme (XI),
below:
##STR00087##
[0262] In Scheme (XI), R.sup.4, R.sup.5, R.sup.6, L.sup.2 and are
as previously defined for structural formula (I). Referring to
Scheme (XI), amide 110 or 116 may be converted to amine 114 or 118,
respectively, by borane reduction with borane methylsulfide complex
112. Other suitable reactions for synthesizing
2,4-pyrimidinediamine compounds from 2,4-pyrimidinediamine starting
materials will be apparent to those of skill in the art.
[0263] Although many of the synthetic schemes discussed above do
not illustrate the use of protecting groups, skilled artisans will
recognize that in some instances substituents R.sup.2, R.sup.4,
R.sup.5, R.sup.6, L.sup.1 and/or L.sup.2 may include functional
groups requiring protection. The exact identity of the protecting
group used will depend upon, among other things, the identity of
the functional group being protected and the reaction conditions
used in the particular synthetic scheme, and will be apparent to
those of skill in the art. Guidance for selecting protecting groups
and chemistries for their attachment and removal suitable for a
particular application can be found, for example, in Greene &
Wuts, supra.
[0264] Prodrugs according to structural formula (II) may be
prepared by routine modification of the above-described methods.
Alternatively, such prodrugs may be prepared by reacting a suitably
protected 2,4-pyrimidinediamine of structural formula (I) with a
suitable progroup. Conditions for carrying out such reactions and
for deprotecting the product to yield a prodrug of formula (II) are
well-known.
[0265] Myriad references teaching methods useful for synthesizing
pyrimidines generally, as well as starting materials described in
Schemes (I)-(IX), are known in the art. For specific guidance, the
reader is referred to Brown, D. J., "The Pyrimidines", in The
Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A.,
Ed.), 1962, Interscience Publishers, (A Division of John Wiley
& Sons), New York ("Brown I"); Brown, D. J., "The Pyrimidines",
in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I
(Weissberger, A. and Taylor, E. C., Ed.), 1970, Wiley-Interscience,
(A Division of John Wiley & Sons), New York (Brown II'');
Brown, D. J., "The Pyrimidines", in The Chemistry of Heterocyclic
Compounds, Volume 16, Supplement II (Weissberger, A. and Taylor, E.
C., Ed.), 1985, An Interscience Publication (John Wiley &
Sons), New York ("Brown III"); Brown, D. J., "The Pyrimidines" in
The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A.
and Taylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New
York, pp. 1-1509 (Brown IV''); Kenner, G. W. and Todd, A., in
Heterocyclic Compounds, Volume 6, (Elderfield, R. C., Ed.), 1957,
John Wiley, New York, Chapter 7 (pyrimidines); Paquette, L. A.,
Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin,
Inc., New York, pp. 1-401 (uracil synthesis pp. 313, 315;
pyrimidine synthesis pp. 313-316; amino pyrimidine synthesis pp.
315); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic
Chemistry, 3.sup.rd Edition, 1995, Chapman and Hall, London, UK,
pp. 1-516; Vorbruggen, H. and Ruh-Pohlenz, C., Handbook of
Nucleoside Synthesis, John Wiley & Sons, New York, 2001, pp.
1-631 (protection of pyrimidines by acylation pp. 90-91; silylation
of pyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G.
F., Heterocyclic Chemistry, 4.sup.th Edition, 2000, Blackwell
Science, Ltd, Oxford, UK, pp. 1-589; and Comprehensive Organic
Synthesis, Volumes 1-9 (Trost, B. M. and Fleming, I., Ed.), 1991,
Pergamon Press, Oxford, UK.
[0266] It should be understood by the skilled artisan that in
Schemes I through XI, the N4 nitrogen can be substituted by
R.sup.4c as described throughout the specification and in the
examples provided herein.
6.4 Inhibition of Fc Receptor Signal Cascades
[0267] Active 2,4-pyrimidinediamine compounds of the invention
inhibit Fc receptor signalling cascades that lead to, among other
things, degranulation of cells. As a specific example, the
compounds inhibit the Fc.epsilon.RI and/or Fc.gamma.RI signal
cascades that lead to degranulation of immune cells such as
neutrophil, eosinophil, mast and/or basophil cells. Both mast and
basophil cells play a central role in allergen-induced disorders,
including, for example, allergic rhinitis and asthma. Referring to
FIG. 1, upon exposure allergens, which may be, among other things,
pollen or parasites, allergen-specific IgE antibodies are
synthesized by B-cells activated by IL-4 (or IL-13) and other
messengers to switch to IgE class specific antibody synthesis.
These allergen-specific IgEs bind to the high affinity
Fc.epsilon.RI. Upon binding of antigen, the Fc.epsilon.RI-bound
IgEs are cross-linked and the IgE receptor signal transduction
pathway is activated, which leads to degranulation of the cells and
consequent release and/or synthesis of a host of chemical
mediators, including histamine, proteases (e.g., tryptase and
chymase), lipid mediators such as leukotrienes (e.g., LTC4),
platelet-activating factor (PAF) and prostaglandins (e.g., PGD2)
and a series of cytokines, including TNF-.alpha., IL-4, IL-13,
IL-5, IL-6, IL-8, GMCSF, VEGF and TGF-.beta.. The release and/or
synthesis of these mediators from mast and/or basophil cells
accounts for the early and late stage responses induced by
allergens, and is directly linked to downstream events that lead to
a sustained inflammatory state.
[0268] The molecular events in the Fc.epsilon.RI signal
transduction pathway that lead to release of preformed mediators
via degranulation and release and/or synthesis of other chemical
mediators are well-known and are illustrated in FIG. 2. Referring
to FIG. 2, the Fc.epsilon.RI is a heterotetrameric receptor
composed of an IgE-binding alpha-subunit, a beta subunit, and two
gamma subunits (gamma homodimer). Cross-linking of
Fc.epsilon.RI-bound IgE by multivalent binding agents (including,
for example IgE-specific allergens or anti-IgE antibodies or
fragments) induces the rapid association and activation of the
Src-related kinase Lyn. Lyn phosphorylates immunoreceptor
tyrosine-based activation motifs (ITAMS) on the intracellular beta
and gamma subunits, which leads to the recruitment of additional
Lyn to the beta subunit and Syk kinase to the gamma homodimer.
These receptor-associated kinases, which are activated by intra-
and intermolecular phosphorylation, phosphorylate other components
of the pathway, such as the Btk kinase, LAT, and phospholipase
C-gamma PLC-gamma). Activated PLC-gamma initiates pathways that
lead to protein kinase C activation and Ca.sup.2+ mobilization,
both of which are required for degranulation. Fc.epsilon.R1
cross-linking also activates the three major classes of mitogen
activated protein (MAP) kinases, i.e. ERK1/2, JNK1/2, and p38.
Activation of these pathways is important in the transcriptional
regulation of proinflammatory mediators, such as TNF-.alpha. and
IL-6, as well as the lipid mediator leukotriene CA (LTC4).
[0269] Although not illustrated, the Fc.gamma.RI signaling cascade
is believed to share some common elements with the FceRI signaling
cascade. Importantly, like Fc.epsilon.RI, the Fc.gamma.RI includes
a gamma homodimer that is phosphorylated and recruits Syk, and like
Fc.epsilon.RI, activation of the Fc.gamma.RI signaling cascade
leads to, among other things, degranulation. Other Fc receptors
that share the gamma homodimer, and which can be regulated by the
active 2,4-pyrimidinediamine compounds include, but are not limited
to, Fc.alpha.RI and Fc.gamma.RIII.
[0270] The ability of the 2,4-pyrimidinediamine compounds of the
invention to inhibit Fc receptor signaling cascades may be simply
determined or confirmed in in vitro assays. Suitable assays for
confirming inhibition of Fc.epsilon.RI-mediated degranulation are
provided in the Examples section. In one typical assay, cells
capable of undergoing Fc.epsilon.RI-mediated degranulation, such as
mast or basophil cells, are first grown in the presence of IL-4,
Stem Cell Factor (SCF), IL-6 and IgE to increase expression of the
Fc.epsilon.RI, exposed to a 2,4-pyrimidinediamine test compound of
the invention and stimulated with anti-IgE antibodies (or,
alternatively, an IgE-specific allergen). Following incubation, the
amount of a chemical mediator or other chemical agent released
and/or synthesized as a consequence of activating the Fc.epsilon.RI
signaling cascade may be quantified using standard techniques and
compared to the amount of the mediator or agent released from
control cells (i.e., cells that are stimulated but that are not
exposed to test compound). The concentration of test compound that
yields a 50% reduction in the quantity of the mediator or agent
measured as compared to control cells is the IC.sub.50 of the test
compound. The origin of the mast or basophil cells used in the
assay will depend, in part, on the desired use for the compounds
and will be apparent to those of skill in the art. For example, if
the compounds will be used to treat or prevent a particular disease
in humans, a convenient source of mast or basophil cells is a human
or other animal which constitutes an accepted or known clinical
model for the particular disease. Thus, depending upon the
particular application, the mast or basophil cells may be derived
from a wide variety of animal sources, ranging from, for example,
lower mammals such as mice and rats, to dogs, sheep and other
mammals commonly employed in clinical testing, to higher mammals
such as monkeys, chimpanzees and apes, to humans. Specific examples
of cells suitable for carrying out the in vitro assays include, but
are not limited to, rodent or human basophil cells, rat basophil
leukemia cell lines, primary mouse mast cells (such as bone
marrow-derived mouse mast cells "BMMC") and primary human mast
cells isolated from cord blood ("CHMC") or other tissues such as
lung. Methods for isolating and culturing these cell types are
well-known or are provided in the Examples section (see, e.g., Demo
et al., 1999, Cytometry 36(4):340-348 and copending application
Ser. No. 10/053,355, filed Nov. 8, 2001, the disclosures of which
are incorporated herein by reference). Of course, other types of
immune cells that degranulate upon activation of the Fc.epsilon.RI
signaling cascade may also be used, including, for example,
eosinophils.
[0271] As will be recognized by skilled artisans, the mediator or
agent quantified is not critical. The only requirement is that it
be a mediator or agent released and/or synthesized as a consequence
of initiating or activating the Fc receptor signaling cascade. For
example, referring to FIG. 1, activation of the Fc.epsilon.RI
signaling cascade in mast and/or basophil cells leads to numerous
downstream events. For example, activation of the Fc.epsilon.RI
signal cascade leads to the immediate release (i.e., within 1-3
min. following receptor activation) of a variety of preformed
chemical mediators and agents via degranulation. Thus, in one
embodiment, the mediator or agent quantified may be specific to
granules (i.e., present in granules but not in the cell cytoplasm
generally). Examples of granule-specific mediators or agents that
can be quantified to determine and/or confirm the activity of a
2,4-pyrimidinediamine compound of the invention include, but are
not limited to, granule-specific enzymes such as hexosaminidase and
tryptase and granule-specific components such as histamine and
serotonin. Assays for quantifying such factors are well-known, and
in many instances are commercially available. For example, tryptase
and/or hexosaminidase release may be quantified by incubating the
cells with cleavable substrates that fluoresce upon cleavage and
quantifying the amount of fluorescence produced using conventional
techniques. Such cleavable fluorogenic substrates are commercially
available. For example, the fluorogenic substrates
Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl;
AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc.,
Plymouth Meeting, Pa. 19462, Catalog No. P-142) and
Z-Ala-Lys-Arg-AMC (Enzyme Systems Products, a division of ICN
Biomedicals, Inc., Livermore, Calif. 94550, Catalog No. AMC-246)
can be used to quantify the amount of tryptase released. The
fluorogenic substrate
4-methylumbelliferyl-N-acetyl-.beta.-D-glucosaminide (Sigma, St.
Louis, Mo., Catalog #69585) can be used to quantify the amount of
hexosaminidase released. Histamine release may be quantified using
a commercially available enzyme-linked immunosorbent assay (ELISA)
such as Immunotech histamine ELISA assay #IM2015 (Beckman-Coulter,
Inc.). Specific methods of quantifying the release of tryptase,
hexosaminidase and histamine are provided in the Examples section.
Any of these assays may be used to determine or confirm the
activity of the 2,4-pyrimidinediamine compounds of the
invention.
[0272] Referring again to FIG. 1, degranulation is only one of
several responses initiated by the Fc.epsilon.RI signaling cascade.
In addition, activation of this signaling pathway leads to the de
novo synthesis and release of cytokines and chemokines such as
IL-4, IL-5, IL-6, TNF-.alpha., IL-13 and MIP1-.alpha.), and release
of lipid mediators such as leukotrienes (e.g., LTC4), platelet
activating factor (PAF) and prostaglandins. Accordingly, the
2,4-pyrimidinediamine compounds of the invention may also be
assessed for activity by quantifying the amount of one or more of
these mediators released and/or synthesized by activated cells.
[0273] Unlike the granule-specific components discussed above,
these "late stage" mediators are not released immediately following
activation of the Fc.epsilon.RI signaling cascade. Accordingly,
when quantifying these late stage mediators, care should be taken
to insure that the activated cell culture is incubated for a time
sufficient to result in the synthesis (if necessary) and release of
the mediator being quantified. Generally, PAF and lipid mediators
such as leukotriene C4 are released 3-30 min. following
Fc.epsilon.RI activation. The cytokines and other late stage
mediators are released approx. 4-8 hrs. following Fc.epsilon.RI
activation. Incubation times suitable for a specific mediator will
be apparent to those of skill in the art. Specific guidance and
assays are provided in the Examples section.
[0274] The amount of a particular late stage mediator released may
be quantified using any standard technique. In one embodiment, the
amount(s) may be quantified using ELISA assays. ELISA assay kits
suitable for quantifying the amount of TNF.alpha., IL-4, IL-5, IL-6
and/or IL-13 released are available from, for example, Biosource
International, Inc., Camarillo, Calif. 93012 (see, e.g., Catalog
Nos. KHC3011, KHC0042, KHC0052, KHC0061 and KHC0132). ELISA assay
kits suitable for quantifying the amount of leukotriene C4 (LTC4)
released from cells are available from Cayman Chemical Co., Ann
Arbor, Mich. 48108 (see, e.g., Catalog No. 520211).
[0275] Typically, active 2,4-pyrimidinediamine compounds of the
invention will exhibit IC.sub.50s with respect to
Fc.epsilon.RI-mediated degranulation and/or mediator release or
synthesis of about 20 .mu.M or lower, as measured in an in vitro
assay, such as one of the in vitro assays described above or in the
Examples section. Of course, skilled artisans will appreciate that
compounds which exhibit lower IC.sub.50s, for example on the order
of 10 .mu.M, 1 .mu.M, 100 nM, 10 nM, 1 nM, or even lower, are
particularly useful.
[0276] Skilled artisans will also appreciate that the various
mediators discussed above may induce different adverse effects or
exhibit different potencies with respect to the same adverse
effect. For example, the lipid mediator LTC4 is a potent
vasoconstrictor--it is approximately 1000-fold more potent at
inducing vasoconstriction than histamine. As another example, in
addition to mediating atopic or Type I hypersensitivity reactions,
cytokines can also cause tissue remodeling and cell proliferation.
Thus, although compounds that inhibit release and/or synthesis of
any one of the previously discussed chemical mediators are useful,
skilled artisans will appreciate that compounds which inhibit the
release and/or synthesis of a plurality, or even all, of the
previously described mediators find particular use, as such
compounds are useful for ameliorating or avoiding altogether a
plurality, or even all, of the adverse effects induced by the
particular mediators. For example, compounds which inhibit the
release of all three types of mediators--granule-specific, lipid
and cytokine--are useful for treating or preventing immediate Type
I hypersensitivity reactions as well as the chronic symptoms
associated therewith.
[0277] Compounds of the invention capable of inhibiting the release
of more than one type of mediator (e.g., granule-specific or late
stage) may be identified by determining the IC.sub.50 with respect
to a mediator representative of each class using the various in
vitro assays described above (or other equivalent in vitro assays).
Compounds of the invention which are capable of inhibiting the
release of more than one mediator type will typically exhibit an
IC.sub.50 for each mediator type tested of less than about 20
.mu.M. For example, a compound which exhibits an IC.sub.50 of 1
.mu.M with respect to histamine release (IC.sub.50.sup.histamine)
and an IC.sub.50 of 1 nM with respect to leukotriene LTC4 synthesis
and/or release (IC.sub.50.sup.LTC4) inhibits both immediate
(granule-specific) and late stage mediator release. As another
specific example, a compound that exhibits an
IC.sub.50.sup.tryptase of 10 .mu.M, an IC.sub.50.sup.LTC4 of 1
.mu.M and an IC.sub.50.sup.IL-4 of 1 .mu.M inhibits immediate
(granule-specific), lipid and cytokine mediator release. Although
the above specific examples utilize the IC.sub.50s of one
representative mediator of each class, skilled artisans will
appreciate that the IC.sub.50s of a plurality, or even all,
mediators comprising one or more of the classes may be obtained.
The quantity(ies) and identity(ies) of mediators for which
IC.sub.50 data should be ascertained for a particular compound and
application will be apparent to those of skill in the art.
[0278] Similar assays may be utilized to confirm inhibition of
signal transduction cascades initiated by other Fc receptors, such
as Fc.alpha.RI, Fc.gamma.RI and/or Fc.gamma.RIII signaling, with
routine modification. For example, the ability of the compounds to
inhibit Fc.gamma.RI signal transduction may be confirmed in assays
similar to those described above, with the exception that the
Fc.gamma.RI signaling cascade is activated, for example by
incubating the cells with IgG and an IgG-specific allergen or
antibody, instead of IgE and an IgE-specific allergen or antibody.
Suitable cell types, activating agents and agents to quantify to
confirm inhibition of other Fc receptors, such as Fc receptors that
comprise a gamma homodimer, will be apparent to those of skill in
the art.
[0279] One particularly useful class of compounds includes those
2,4-pyrimidinediamine compounds that inhibit the release of
immediate granule-specific mediators and late stage mediators with
approximately equivalent IC.sub.50s. By approximately equivalent is
meant that the IC.sub.50s for each mediator type are within about a
10-fold range of one another. Another particularly useful class of
compounds includes those 2,4-pyrimidinediamine compounds that
inhibit the release of immediate granule-specific mediators, lipid
mediators and cytokine mediators with approximately equivalent
IC.sub.50s. In a specific embodiment, such compounds inhibit the
release of the following mediators with approximately equivalent
IC.sub.50s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6,
IL-13, TNF.alpha. and LTC4. Such compounds are particularly useful
for, among other things, ameliorating or avoiding altogether both
the early and late stage responses associated with atopic or
immediate Type I hypersensitivity reactions.
[0280] Ideally, the ability to inhibit the release of all desired
types of mediators will reside in a single compound. However,
mixtures of compounds can also be identified that achieve the same
result. For example, a first compound which inhibits the release of
granule specific mediators may be used in combination with a second
compound which inhibits the release and/or synthesis of cytokine
mediators.
[0281] In addition to the Fc.epsilon.RI or Fc.gamma.RI
degranulation pathways discussed above, degranulation of mast
and/or basophil cells can be induced by other agents. For example,
ionomycin, a calcium ionophore that bypasses the early
Fc.epsilon.RI or Fc.gamma.RI signal transduction machinery of the
cell, directly induces a calcium flux that triggers degranulation.
Referring again to FIG. 2, activated PLC.gamma. initiates pathways
that lead to, among other things, calcium ion mobilization and
subsequent degranulation. As illustrated, this Ca.sup.2+
mobilization is triggered late in the Fc.epsilon.RI signal
transduction pathway. As mentioned above, and as illustrated in
FIG. 3, ionomycin directly induces Ca.sup.2+ mobilization and a
Ca.sup.2+ flux that leads to degranulation. Other ionophores that
induce degranulation in this manner include A23187. The ability of
granulation-inducing ionophores such as ionomycin to bypass the
early stages of the Fc.epsilon.RI and/or Fc.gamma.RI signaling
cascades may be used as a counter screen to identify active
compounds of the invention that specifically exert their
degranulation-inhibitory activity by blocking or inhibiting the
early Fc.epsilon.RI or Fc.gamma.RI signaling cascades, as discussed
above. Compounds which specifically inhibit such early
Fc.epsilon.RI or Fc.gamma.RI-mediated degranulation inhibit not
only degranulation and subsequent rapid release of histamine,
tryptase and other granule contents, but also inhibit the
pro-inflammatory activation pathways causing the release of
TNF.alpha., IL-4, IL-13 and the lipid mediators such as LTC4. Thus,
compounds which specifically inhibit such early Fc.epsilon.RI
and/or Fc.gamma.RI-mediated degranulation block or inhibit not only
acute atopic or Type I hypersensitivity reactions, but also late
responses involving multiple inflammatory mediators.
[0282] Compounds of the invention that specifically inhibit early
Fc.epsilon.RI and/or Fc.gamma.RI-mediated degranulation are those
compounds that inhibit Fc.epsilon.RI and/or Fc.gamma.RI-mediated
degranulation (for example, have an IC.sub.50 of less than about 20
.mu.M with respect to the release of a granule-specific mediator or
component as measured in an in vitro assay with cells stimulated
with an IgE or IgG binding agent) but that do not appreciably
inhibit ionophore-induced degranulation. In one embodiment,
compounds are considered to not appreciably inhibit
ionophore-induced degranulation if they exhibit an IC.sub.50 of
ionophore-induced degranulation of greater than about 20 .mu.M, as
measured in an in vitro assay. Of course, active compounds that
exhibit even higher IC.sub.50s of ionophore-induced degranulation,
or that do not inhibit ionophore-induced degranulation at all, are
particularly useful. In another embodiment, compounds are
considered to not appreciably inhibit ionophore-induced
degranulation if they exhibit a greater than 10-fold difference in
their IC.sub.50s of Fc.epsilon.RI and/or Fc.gamma.RI-mediated
degranulation and ionophore-induced degranulation, as measured in
an in vitro assay. Assays suitable for determining the IC.sub.50 of
ionophore-induced degranulation include any of the
previously-described degranulation assays, with the modification
that the cells are stimulated or activated with a
degranulation-inducing calcium ionophore such as ionomycin or
A23187 (A.G. Scientific, San Diego, Calif.) instead of anti-IgE
antibodies or an IgE-specific allergen. Specific assays for
assessing the ability of a particular 2,4-pyrimidinediamine
compound of the invention to inhibit ionophore-induced
degranulation are provided in the Examples section.
[0283] As will be recognized by skilled artisans, compounds which
exhibit a high degree of selectivity of Fc.epsilon.RI-mediated
degranulation find particular use, as such compounds selectively
target the Fc.epsilon.RI cascade and do not interfere with other
degranulation mechanisms. Similarly, compounds which exhibit a high
degree of selectivity of Fc.gamma.RI-mediated degranulation find
particular use, as such compounds selectively target the
Fc.gamma.RI cascade and do not interfere with other degranulation
mechanisms. Compounds which exhibit a high degree of selectivity
are generally 10-fold or more selective for Fc.epsilon.RI- or
Fc.gamma.RI-mediated degranulation over ionophore-induced
degranulation, such as ionomycin-induced degranulation.
[0284] Accordingly, the activity of the 2,4-pyrimidinediamine
compounds of the invention may also be confirmed in biochemical or
cellular assays of Syk kinase activity. Referring again to FIG. 2,
in the Fc.epsilon.RI signaling cascade in mast and/or basophil
cells, Syk kinase phosphorylates LAT and PLC-gamma1, which leads
to, among other things, degranulation. Any of these activities may
be used to confirm the activity of the 2,4-pyrimidinediamine
compounds of the invention. In one embodiment, the activity is
confirmed by contacting an isolated Syk kinase, or an active
fragment thereof with a 2,4-pyrimidinediamine compound in the
presence of a Syk kinase substrate (e.g., a synthetic peptide or a
protein that is known to be phosphorylated by Syk in a signaling
cascade) and assessing whether the Syk kinase phosphorylated the
substrate. Alternatively, the assay may be carried out with cells
that express a Syk kinase. The cells may express the Syk kinase
endogenously or they may be engineered to express a recombinant Syk
kinase. The cells may optionally also express the Syk kinase
substrate. Cells suitable for performing such confirmation assays,
as well as methods of engineering suitable cells will be apparent
to those of skill in the art. Specific examples of biochemical and
cellular assays suitable for confirming the activity of the
2,4-pyrimidinediamine compounds are provided in the Examples
section.
[0285] Generally, compounds that are Syk kinase inhibitors will
exhibit an IC.sub.50 with respect to a Syk kinase activity, such as
the ability of Syk kinase to phosphorylate a synthetic or
endogenous substrate, in an in vitro or cellular assay in the range
of about 20 .mu.M or less. Skilled artisans will appreciate that
compounds that exhibit lower IC.sub.50s, such as in the range of 10
.mu.M, 1 .mu.M, 100 nM, 10 nM, 1 nM, or even lower, are
particularly useful.
6.5 Uses and Compositions
[0286] As previously discussed, the active compounds of the
invention inhibit Fc receptor signaling cascades, especially those
Fc receptors including a gamma homodimer, such as the Fc.epsilon.RI
and/or Fc.gamma.RI signaling cascades, that lead to, among other
things, the release and/or synthesis of chemical mediators from
cells, either via degranulation or other processes. As also
discussed, the active compounds are also potent inhibitors of Syk
kinase. As a consequence of these activities, the active compounds
of the invention may be used in a variety of in vitro, in vivo and
ex vivo contexts to regulate or inhibit Syk kinase, signaling
cascades in which Syk kinase plays a role, Fc receptor signaling
cascades, and the biological responses effected by such signaling
cascades. For example, in one embodiment, the compounds may be used
to inhibit Syk kinase, either in vitro or in vivo, in virtually any
cell type expressing Syk kinase. They may also be used to regulate
signal transduction cascades in which Syk kinase plays a role. Such
Syk-dependent signal transduction cascades include, but are not
limited to, the Fc.epsilon.RI, Fc.gamma.RI, Fc.gamma.RIII, BCR and
integrin signal transduction cascades. The compounds may also be
used in vitro or in vivo to regulate, and in particular inhibit,
cellular or biological responses effected by such Syk-dependent
signal transduction cascades. Such cellular or biological responses
include, but are not limited to, respiratory burst, cellular
adhesion, cellular degranulation, cell spreading, cell migration,
cell aggregation, phagcytosis, cytokine synthesis and release, cell
maturation and Ca.sup.2+ flux. Importantly, the compounds may be
used to inhibit Syk kinase in vivo as a therapeutic approach
towards the treatment or prevention of diseases mediated, either
wholly or in part, by a Syk kinase activity. Non-limiting examples
of Syk kinase mediated diseases that may be treated or prevented
with the compounds are those discussed in more detail, below.
[0287] In another embodiment, the active compounds may be used to
regulate or inhibit the Fc receptor signaling cascades and/or
Fc.epsilon.RI- and/or Fc.gamma.RI-mediated degranulation as a
therapeutic approach towards the treatment or prevention of
diseases characterized by, caused by and/or associated with the
release or synthesis of chemical mediators of such Fc receptor
signaling cascades or degranulation. Such treatments may be
administered to animals in veterinary contexts or to humans.
Diseases that are characterized by, caused by or associated with
such mediator release, synthesis or degranulation, and that can
therefore be treated or prevented with the active compounds
include, by way of example and not limitation, atopy or
anaphylactic hypersensitivity or allergic reactions, allergies
(e.g., allergic conjunctivitis, allergic rhinitis, atopic asthma,
atopic dermatitis and food allergies), low grade scarring (e.g., of
scleroderma, increased fibrosis, keloids, post-surgical scars,
pulmonary fibrosis, vascular spasms, migraine, reperfusion injury
and post myocardial infarction), diseases associated with tissue
destruction (e.g., of COPD, cardiobronchitis and post myocardial
infarction), diseases associated with tissue inflammation (e.g.,
irritable bowel syndrome, spastic colon and inflammatory bowel
disease), inflammation and scarring.
[0288] In addition to the myriad diseases discussed above, cellular
and animal empirical data confirm that the 2,4-pyrimidinediamine
compounds described herein are also useful for the treatment or
prevention of autoimmune diseases, as well as the various symptoms
associated with such diseases. The types of autoimmune diseases
that may be treated or prevented with the 2,4-pyrimidinediamine
compounds generally include those disorders involving tissue injury
that occurs as a result of a humoral and/or cell-mediated response
to immunogens or antigens of endogenous and/or exogenous origin.
Such diseases are frequently referred to as diseases involving the
nonanaphylactic (i.e., Type II, Type III and/or Type IV)
hypersensitivity reactions.
[0289] As discussed previously, Type I hypersensitivity reactions
generally result from the release of pharmacologically active
substances, such as histamine, from mast and/or basophil cells
following contact with a specific exogenous antigen. As mentioned
above, such Type I reactions play a role in numerous diseases,
including allergic asthma, allergic rhinitis, etc.
[0290] Type II hypersensitivity reactions (also referred to as
cytotoxic, cytolytic complement-dependent or cell-stimulating
hypersensitivity reactions) result when immunoglobulins react with
antigenic components of cells or tissue, or with an antigen or
hapten that has become intimately coupled to cells or tissue.
Diseases that are commonly associated with Type II hypersensitivity
reactions include, but are not limited, to autoimmune hemolytic
anemia, erythroblastosis fetalis and Goodpasture's disease.
[0291] Type III hypersensitivity reactions, (also referred to as
toxic complex, soluble complex, or immune complex hypersensitivity
reactions) result from the deposition of soluble circulating
antigen-immunoglobulin complexes in vessels or in tissues, with
accompanying acute inflammatory reactions at the site of immune
complex deposition. Non-limiting examples of prototypical Type III
reaction diseases include the Arthus reaction, rheumatoid
arthritis, serum sickness, systemic lupus erythematosis, certain
types of glomerulonephritis, multiple sclerosis and bullous
pemphingoid.
[0292] Type IV hypersensitivity reactions (frequently called
cellular, cell-mediated, delayed, or tuberculin-type
hypersensitivity reactions) are caused by sensitized T-lymphocytes
which result from contact with a specific antigen. Non-limiting
examples of diseases cited as involving Type IV reactions are
contact dermatitis and allograft rejection including, but not
limited to, heart transplant.
[0293] Autoimmune diseases associated with any of the above
nonanaphylactic hypersensitivity reactions may be treated or
prevented with the 2,4-pyrimidinediamine compounds of the
invention. In particular, the methods may be used to treat or
prevent those autoimmune diseases frequently characterized as
single organ or single cell-type autoimmune disorders including,
but not limited to: 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 and membranous
glomerulopathy, as well as those autoimmune diseases frequently
characterized as involving systemic autoimmune disorder, which
include but are not limited to: systemic lupus erythematosis,
rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome,
polymyositis-dermatomyositis, systemic sclerosis, polyarteritis
nodosa, multiple sclerosis and bullous pemphigoid.
[0294] It will be appreciated by skilled artisans that many of the
above-listed autoimmune diseases are associated with severe
symptoms, the amelioration of which provides significant
therapeutic benefit even in instances where the underlying
autoimmune disease may not be ameliorated. Many of these symptoms,
as well as their underlying disease states, result as a consequence
of activating the Fc.gamma.R signaling cascade in monocyte cells.
As the 2,4-pyrimidinediamine compounds described herein are potent
inhibitors of such Fc.gamma.R signaling in monocytes and other
cells, the methods find use in the treatment and/or prevention of
myriad adverse symptoms associated with the above-listed autoimmune
diseases.
[0295] As a specific example, rheumatoid arthritis (RA) typically
results in swelling, pain, loss of motion and tenderness of target
joints throughout the body. RA is characterized by chronically
inflamed synovium that is densely crowded with lymphocytes. The
synovial membrane, which is typically one cell layer thick, becomes
intensely cellular and assumes a form similar to lymphoid tissue,
including dentritic cells, T-, B- and NK cells, macrophages and
clusters of plasma cells. This process, as well as a plethora of
immunopathological mechanisms including the formation of
antigen-immunoglobulin complexes, eventually result in destruction
of the integrity of the joint, resulting in deformity, permanent
loss of function and/or bone erosion at or near the joint. The
methods may be used to treat or ameliorate any one, several or all
of these symptoms of RA. Thus, in the context of RA, the methods
are considered to provide therapeutic benefit (discussed more
generally, infra) when a reduction or amelioration of any of the
symptoms commonly associated with RA is achieved, regardless of
whether the treatment results in a concomitant treatment of the
underlying RA and/or a reduction in the amount of circulating
rheumatoid factor ("RF").
[0296] As another specific example, systemic lupus erythematosis
("SLE") is typically associated with symptoms such as fever, joint
pain (arthralgias), arthritis, and serositis (pleurisy or
pericarditis). In the context of SLE, the methods are considered to
provide therapeutic benefit when a reduction or amelioration of any
of the symptoms commonly associated with SLE are achieved,
regardless of whether the treatment results in a concomitant
treatment of the underlying SLE.
[0297] As another specific example, multiple sclerosis ("MS")
cripples the patient by disturbing visual acuity; stimulating
double vision; disturbing motor functions affecting walking and use
of the hands; producing bowel and bladder incontinence; spasticity;
and sensory deficits (touch, pain and temperature sensitivity). In
the context of MS, the methods are considered to provide
therapeutic benefit when an improvement or a reduction in the
progression of any one or more of the crippling effects commonly
associated with MS is achieved, regardless of whether the treatment
results in a concomitant treatment of the underlying MS.
[0298] When used to treat or prevent such diseases, the active
compounds may be administered singly, as mixtures of one or more
active compounds or in mixture or combination with other agents
useful for treating such diseases and/or the symptoms associated
with such diseases. The active compounds may also be administered
in mixture or in combination with agents useful to treat other
disorders or maladies, such as steroids, membrane stablizers, 5LO
inhibitors, leukotriene synthesis and receptor inhibitors,
inhibitors of IgE isotype switching or IgE synthesis, IgG isotype
switching or IgG synthesis, .beta.-agonists, tryptase inhibitors,
aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4
inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to
name a few. The active compounds may be administered per se in the
form of prodrugs or as pharmaceutical compositions, comprising an
active compound or prodrug.
[0299] Pharmaceutical compositions comprising the active compounds
of the invention (or prodrugs thereof) may be manufactured by means
of conventional mixing, dissolving, granulating, dragee-making
levigating, emulsifying, encapsulating, entrapping or
lyophilization processes. The compositions may be formulated in
conventional manner using one or more physiologically acceptable
carriers, diluents, excipients or auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically.
[0300] The active compound or prodrug may be formulated in the
pharmaceutical compositions per se, or in the form of a hydrate,
solvate, N-oxide or pharmaceutically acceptable salt, as previously
described. Typically, such salts are more soluble in aqueous
solutions than the corresponding free acids and bases, but salts
having lower solubility than the corresponding free acids and bases
may also be formed.
[0301] Pharmaceutical compositions of the invention may take a form
suitable for virtually any mode of administration, including, for
example, topical, ocular, oral, buccal, systemic, nasal, injection,
transdermal, rectal, vaginal, etc., or a form suitable for
administration by inhalation or insufflation.
[0302] For topical administration, the active compound(s) or
prodrug(s) may be formulated as solutions, gels, ointments, creams,
suspensions, etc. as are well-known in the art.
[0303] Systemic formulations include those designed for
administration by injection, e.g., subcutaneous, intravenous,
intramuscular, intrathecal or intraperitoneal injection, as well as
those designed for transdermal, transmucosal oral or pulmonary
administration.
[0304] Useful injectable preparations include sterile suspensions,
solutions or emulsions of the active compound(s) in aqueous or oily
vehicles. The compositions may also contain formulating agents,
such as suspending, stabilizing and/or dispersing agent. The
formulations for injection may be presented in unit dosage form,
e.g., in ampules or in multidose containers, and may contain added
preservatives.
[0305] Alternatively, the injectable formulation may be provided in
powder form for reconstitution with a suitable vehicle, including
but not limited to sterile pyrogen free water, buffer, dextrose
solution, etc., before use. To this end, the active compound(s) may
be dried by any art-known technique, such as lyophilization, and
reconstituted prior to use.
[0306] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are known in the art.
[0307] For oral administration, the pharmaceutical compositions may
take the form of, for example, lozenges, tablets or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g., pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g., lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or
silica); disintegrants (e.g., potato starch or sodium starch
glycolate); or wetting agents (e.g., sodium lauryl sulfate). The
tablets may be coated by methods well known in the art with, for
example, sugars, films or enteric coatings.
[0308] Liquid preparations for oral administration may take the
form of, for example, elixirs, solutions, syrups or suspensions, or
they may be presented as a dry product for constitution with water
or other suitable vehicle before use. Such liquid preparations may
be prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats); emulsifying
agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,
almond oil, oily esters, ethyl alcohol, Cremophore.TM. or
fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations may
also contain buffer salts, preservatives, flavoring, coloring and
sweetening agents as appropriate.
[0309] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound or
prodrug, as is well known.
[0310] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0311] For rectal and vaginal routes of administration, the active
compound(s) may be formulated as solutions (for retention enemas)
suppositories or ointments containing conventional suppository
bases such as cocoa butter or other glycerides.
[0312] For nasal administration or administration by inhalation or
insufflation, the active compound(s) or prodrug(s) can be
conveniently delivered in the form of an aerosol spray from
pressurized packs or a nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other
suitable gas. In the case of a pressurized aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount.
Capsules and cartridges for use in an inhaler or insufflator (for
example capsules and cartridges comprised of gelatin) may be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0313] A specific example of an aqueous suspension formulation
suitable for nasal administration using commercially-available
nasal spray devices includes the following ingredients: active
compound or prodrug (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2
mg/mL); polysorbate 80 (TWEEN.RTM. 80; 0.5-5 mg/ml);
carboxymethylcellulose sodium or microcrystalline cellulose (1-15
mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50 mg/ml). The
pH of the final suspension can be adjusted to range from about pH5
to pH7, with a pH of about pH 5.5 being typical.
[0314] Another specific example of an aqueous suspension suitable
for administration of the compounds via inhalation, and in
particular for such administration of a compound of the invention,
contains 1-20 mg/mL of the compound or prodrug, 0.1-1% (v/v)
Polysorbate 80 (TWEEN.RTM.80), 50 mM citrate and/or 0.9% sodium
chloride.
[0315] For ocular administration, the active compound(s) or
prodrug(s) may be formulated as a solution, emulsion, suspension,
etc. suitable for administration to the eye. A variety of vehicles
suitable for administering compounds to the eye are known in the
art. Specific non-limiting examples are described in U.S. Pat. No.
6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S.
Pat. No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No.
5,698,219; U.S. Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S.
Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat. No.
4,738,851.
[0316] For prolonged delivery, the active compound(s) or prodrug(s)
can be formulated as a depot preparation for administration by
implantation or intramuscular injection. The active ingredient may
be formulated with suitable polymeric or hydrophobic materials
(e.g., as an emulsion in an acceptable oil) or ion exchange resins,
or as sparingly soluble derivatives, e.g., as a sparingly soluble
salt. Alternatively, transdermal delivery systems manufactured as
an adhesive disc or patch which slowly releases the active
compound(s) for percutaneous absorption may be used. To this end,
permeation enhancers may be used to facilitate transdermal
penetration of the active compound(s). Suitable transdermal patches
are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.
No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168;
U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No.
5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S.
Pat. No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No.
4,921,475.
[0317] Alternatively, other pharmaceutical delivery systems may be
employed. Liposomes and emulsions are well-known examples of
delivery vehicles that may be used to deliver active compound(s) or
prodrug(s). Certain organic solvents such as dimethylsulfoxide
(DMSO) may also be employed, although usually at the cost of
greater toxicity.
[0318] The pharmaceutical compositions may, if desired, be
presented in a pack or dispenser device which may contain one or
more unit dosage forms containing the active compound(s). The pack
may, for example, comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device may be accompanied by
instructions for administration.
6.6 Effective Dosages
[0319] The active compound(s) or prodrug(s) of the invention, or
compositions thereof, will generally be used in an amount effective
to achieve the intended result, for example in an amount effective
to treat or prevent the particular disease being treated. The
compound(s) may be administered therapeutically to achieve
therapeutic benefit or prophylactically to achieve prophylactic
benefit. By therapeutic benefit is meant eradication or
amelioration of the underlying disorder being treated and/or
eradication or amelioration of one or more of the symptoms,
associated with the underlying disorder such that the patient
reports an improvement in feeling or condition, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For example, administration of a compound to a patient
suffering from an allergy provides therapeutic benefit not only
when the underlying allergic response is eradicated or ameliorated,
but also when the patient reports a decrease in the severity or
duration of the symptoms associated with the allergy following
exposure to the allergen. As another example, therapeutic benefit
in the context of asthma includes an improvement in respiration
following the onset of an asthmatic attack, or a reduction in the
frequency or severity of asthmatic episodes. Therapeutic benefit
also includes halting or slowing the progression of the disease,
regardless of whether improvement is realized.
[0320] For prophylactic administration, the compound may be
administered to a patient at risk of developing one of the
previously described diseases. For example, if it is unknown
whether a patient is allergic to a particular drug, the compound
may be administered prior to administration of the drug to avoid or
ameliorate an allergic response to the drug. Alternatively,
prophylactic administration may be applied to avoid the onset of
symptoms in a patient diagnosed with the underlying disorder. For
example, a compound may be administered to an allergy sufferer
prior to expected exposure to the allergen. Compounds may also be
administered prophylactically to healthy individuals who are
repeatedly exposed to agents known to one of the above-described
maladies to prevent the onset of the disorder. For example, a
compound may be administered to a healthy individual who is
repeatedly exposed to an allergen known to induce allergies, such
as latex, in an effort to prevent the individual from developing an
allergy. Alternatively, a compound may be administered to a patient
suffering from asthma prior to partaking in activities which
trigger asthma attacks to lessen the severity of, or avoid
altogether, an asthmatic episode.
[0321] The amount of compound administered will depend upon a
variety of factors, including, for example, the particular
indication being treated, the mode of administration, whether the
desired benefit is prophylactic or therapeutic, the severity of the
indication being treated and the age and weight of the patient, the
bioavailability of the particular active compound, etc.
Determination of an effective dosage is well within the
capabilities of those skilled in the art.
[0322] Effective dosages may be estimated initially from in vitro
assays. For example, an initial dosage for use in animals may be
formulated to achieve a circulating blood or serum concentration of
active compound that is at or above an IC.sub.50 of the particular
compound as measured in as in vitro assay, such as the in vitro
CHMC or BMMC and other in vitro assays described in the Examples
section. Calculating dosages to achieve such circulating blood or
serum concentrations taking into account the bioavailability of the
particular compound is well within the capabilities of skilled
artisans. For guidance, the reader is referred to Fingl &
Woodbury, "General Principles," In: Goodman and Gilman's The
Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest
edition, Pagamonon Press, and the references cited therein.
[0323] Initial dosages can also be estimated from in vivo data,
such as animal models. Animal models useful for testing the
efficacy of compounds to treat or prevent the various diseases
described above are well-known in the art. Suitable animal models
of hypersensitivity or allergic reactions are described in Foster,
1995, Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al.,
2001, J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal
models of allergic rhinitis are described in Szelenyi et al., 2000,
Arzneimittelforschung 50(11):1037-42; Kawaguchi et al., 1994, Clin.
Exp. Allergy 24(3):238-244 and Sugimoto et al., 2000,
Immunopharmacology 48(1):1-7. Suitable animal models of allergic
conjunctivitis are described in Carreras et al., 1993, Br. J.
Ophthalmol. 77(8):509-514; Saiga et al., 1992, Ophthalmic Res.
24(1):45-50; and Kunert et al., 2001, Invest. Ophthalmol. Vis. Sci.
42(11):2483-2489. Suitable animal models of systemic mastocytosis
are described in O'Keefe et al., 1987, J. Vet. Intern. Med.
1(2):75-80 and Bean-Knudsen et al., 1989, Vet. Pathol. 26(1):90-92.
Suitable animal models of hyper IgE syndrome are described in
Claman et al., 1990, Clin. Immunol. Immunopathol. 56(1):46-53.
Suitable animal models of B-cell lymphoma are described in Hough et
al., 1998, Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et
al., 1996, J. Immunol. 157(12):5503-5511. Suitable animal models of
atopic disorders such as atopic dermatitis, atopic eczema and
atopic asthma are described in Chan et al., 2001, J. Invest.
Dermatol. 117(4):977-983 and Suto et al., 1999, Int. Arch. Allergy
Immunol. 120(Suppl 1):70-75. Ordinarily skilled artisans can
routinely adapt such information to determine dosages suitable for
human administration. Additional suitable animal models are
described in the Examples section.
[0324] Dosage amounts will typically be in the range of from about
0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may
be higher or lower, depending upon, among other factors, the
activity of the compound, its bioavailability, the mode of
administration and various factors discussed above. Dosage amount
and interval may be adjusted individually to provide plasma levels
of the compound(s) which are sufficient to maintain therapeutic or
prophylactic effect. For example, the compounds may be administered
once per week, several times per week (e.g., every other day), once
per day or multiple times per day, depending upon, among other
things, the mode of administration, the specific indication being
treated and the judgment of the prescribing physician. In cases of
local administration or selective uptake, such as local topical
administration, the effective local concentration of active
compound(s) may not be related to plasma concentration. Skilled
artisans will be able to optimize effective local dosages without
undue experimentation.
[0325] Preferably, the compound(s) will provide therapeutic or
prophylactic benefit without causing substantial toxicity. Toxicity
of the compound(s) may be determined using standard pharmaceutical
procedures. The dose ratio between toxic and therapeutic (or
prophylactic) effect is the therapeutic index. Compounds(s) that
exhibit high therapeutic indices are preferred.
[0326] The invention having been described, the following examples
are offered by way of illustration and not limitation.
7. EXAMPLES
7.1 2,4-Pyrimidinediamine Compounds
[0327] A variety of
N4-substituted-N2-monosubstituted-4-pyrimidinediamines were
prepared based on procedures described herein. Such compounds are
depicted in Table 1.
7.2 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit
Fc.epsilon.RI Receptor-Mediated Degranulation
[0328] The ability of the 2,4-pyrimidinediamine compounds of the
invention to inhibit IgE-induced degranulation was demonstrated in
a variety of cellular assays with cultured human mast cells (CHMC)
and/or mouse bone marrow derived cells (BMMC). Inhibition of
degranulation was measured at both low and high cell density by
quantifying the release of the granule specific factors tryptase,
histamine and hexosaminidase. Inhibition of release and/or
synthesis of lipid mediators was assessed by measuring the release
of leukotriene LTC4 and inhibition of release and/or synthesis of
cytokines was monitored by quantifying TNF-.alpha., IL-6 and IL-13.
Tryptase and hexosaminidase were quantified using fluorogenic
substrates as described in their respective examples. Histamine,
TNF.alpha., IL-6, IL-13 and LTC4 were quantified using the
following commercial ELISA kits: histamine (Immunotech #2015,
Beckman Coulter), TNF.alpha. (Biosource #KHC3011), IL-6 (Biosource
#KMC0061), IL-13 (Biosource #KHC0132) and LTC4 (Cayman Chemical
#520211). The protocols of the various assays are provided
below.
7.2.1 Culturing of Human Mast and Basophil Cells
[0329] Human mast and basophil cells were cultured from
CD34-negative progenitor cells as described below (see also the
methods described in copending U.S. application Ser. No.
10/053,355, filed Nov. 8, 2001, the disclosure of which is
incorporated herein by reference).
7.2.1.1 Preparation of STEMPRO-34 Complete Medium
[0330] To prepare STEMPRO-34 complete medium ("CM"), 250 mL
STEMPRO-34.TM. serum free medium ("SFM"; GibcoBRL, Catalog No.
10640) was added to a filter flask. To this was added 13 mL
STEMPRO-34 Nutrient Supplement ("NS"; GibcoBRL, Catalog No. 10641)
(prepared as described in more detail, below). The NS container was
rinsed with approximately 10 mL SFM and the rinse added to the
filter flask. Following addition of 5 mL L-glutamine (200 mM;
Mediatech, Catalog No. MT 25-005-CI and 5 mL 100.times.
penicillin/streptomycin ("pen-strep"; HyClone, Catalog No.
SV30010), the volume was brought to 500 mL with SFM and the
solution was filtered. The most variable aspect of preparing the CM
is the method by which the NS is thawed and mixed prior to addition
to the SFM. The NS should be thawed in a 37.degree. C. water bath
and swirled, not vortexed or shaken, until it is completely in
solution. While swirling, take note whether there are any lipids
that are not yet in solution. If lipids are present and the NS is
not uniform in appearance, return it to the water bath and repeat
the swirling process until it is uniform in appearance. Sometimes
this component goes into solution immediately, sometimes after a
couple of swirling cycles, and sometimes not at all. If, after a
couple of hours, the NS is still not in solution, discard it and
thaw a fresh unit. NS that appears non-uniform after thaw should
not be used.
7.2.1.2 Expansion of CD34+ Cells
[0331] A starting population of CD34-positive (CD34+) cells of
relatively small number (1-5.times.10.sup.6 cells) was expanded to
a relatively large number of CD34-negative progenitor cells (about
2-4.times.10.sup.9 cells) using the culture media and methods
described below. The CD34+ cells (from a single donor) were
obtained from Allcells (Berkeley, Calif.). Because there is a
degree of variation in the quality and number of CD34+ cells that
Allcells typically provides, the newly delivered cells were
transferred to a 15 mL conical tube and brought up to 10 mL in CM
prior to use.
[0332] On day 0, a cell count was performed on the viable
(phase-bright) cells and the cells were spun at 1200 rpm to pellet.
The cells were resuspended to a density of 275,000 cells/mL with CM
containing 200 ng/mL recombinant human Stem Cell Factor ("SCF";
Peprotech, Catalog No. 300-07) and 20 ng/mL human flt-3 ligand
(Peprotech, Catalog No. 300-19) ("CM/SCF/flt-3 medium"). On about
day 4 or 5, the density of the culture was checked by performing a
cell count and the culture was diluted to a density of 275,000
cells/mL with fresh CM/SCF/flt-3 medium. On about day 7, the
culture was transferred to a sterile tube and a cell count was
performed. The cells were spun at 1200 rpm and resuspended to a
density of 275,000 cells/mL with fresh CM/SCF/flt-3 medium.
[0333] This cycle was repeated, starting from day 0, a total of 3-5
times over the expansion period.
[0334] When the culture is large and being maintained in multiple
flasks and is to be resuspended, the contents of all of the flasks
are combined into a single container prior to performing a cell
count. This ensures that an accurate cell count is achieved and
provides for a degree of uniformity of treatment for the entire
population. Each flask is checked separately for contamination
under the microscope prior to combining to prevent contamination of
the entire population.
[0335] Between days 17-24, the culture can begin to go into decline
(i.e., approximately 5-10% of the total number of cells die) and
fail to expand as rapidly as before. The cells are then monitored
on a daily basis during this time, as complete failure of the
culture can take place in as little as 24 hours. Once the decline
has begun, the cells are counted, spun down at 850 rpm for 15
minutes, and resuspended at a density of 350,000 cells/mL in
CM/SCF/flt-3 medium to induce one or two more divisions out of the
culture. The cells are monitored daily to avoid failure of the
culture.
[0336] When greater than 15% cell death is evident in the
progenitor cell culture and some debris is present in the culture,
the CD34-negative progenitor cells are ready to be
differentiated.
7.2.1.3 Differentiation of CD34-Negative Progenitor Cells into
Mucosal Mast Cells
[0337] A second phase is performed to convert the expanded
CD34-negative progenitor cells into differentiated mucosal mast
cells. These mucosal cultured human mast cells ("CHMC") are derived
from CD34+ cells isolated from umbilical cord blood and treated to
form a proliferated population of CD34-negative progenitor cells,
as described above. To produce the CD43-negative progenitor cells,
the resuspension cycle for the culture was the same as that
described above, except that the culture was seeded at a density of
425,000 cells/mL and 15% additional media was added on about day
four or five without performing a cell count. Also, the cytokine
composition of the medium was modified such that it contained SCF
(200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech,
Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM
acetic acid) ("CM/SCF/IL-6 medium").
[0338] Phases I and II together span approximately 5 weeks. Some
death and debris in the culture is evident during weeks 1-3 and
there is a period during weeks 2-5 during which a small percentage
of the culture is no longer in suspension, but is instead attached
to the surface of the culture vessel.
[0339] As during Phase I, when the culture is to be resuspended on
day seven of each cycle, the contents of all flasks are combined
into a single container prior to performing a cell count to ensure
uniformity of the entire population. Each flask is checked
separately for contamination under the microscope prior to
combining to prevent contamination of the entire population.
[0340] When the flasks are combined, approximately 75% of the
volume is transferred to the communal container, leaving behind
about 10 mL or so in the flask. The flask containing the remaining
volume was rapped sharply and laterally to dislodge the attached
cells. The rapping was repeated at a right angle to the first rap
to completely dislodge the cells.
[0341] The flask was leaned at a 45 degree angle for a couple of
minutes before the remaining volume was transferred to the counting
vessel. The cells were spun at 950 rpm for 15 min prior to seeding
at 35-50 mL per flask (at a density of 425,000 cells/mL).
7.2.1.4 Differentiation of CD34-Negative Progenitor Cells into
Connective Tissue-Type Mast Cells
[0342] A proliferated population of CD34-negative progenitor cells
is prepared as above and treated to form a tryptase/chymase
positive (connective tissue) phenotype. The methods are performed
as described above for mucosal mast cells, but with the
substitution of IL-4 for IL-6 in the culture medium. The cells
obtained are typical of connective tissue mast cells.
7.2.1.5 Differentiation of CD34-Negative Progenitor Cells into
Basophil Cells
[0343] A proliferated population of CD34-negative progenitor cells
is prepared as described in Section 7.2.1.3, above, and used to
form a proliferated population of basophil cells. The CD34-negative
cells are treated as described for mucosal mast cells, but with the
substitution of IL-3 (at 20-50 ng/mL) for IL-6 in the culture
medium.
7.2.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4
Assays
[0344] To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul
of compound dilutions or control samples that have been prepared in
MT [137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl.sub.2, 1.0 mM MgCl.sub.2,
5.6 mM Glucose, 20 mM Hepes (pH 7.4), 0.1% Bovine Serum Albumin,
(Sigma A4503)] containing 2% MeOH and 1% DMSO. Pellet CHMC cells
(980 rpm, 10 mM) and resuspend in pre-warmed MT. Add 65 ul of cells
to each 96-well plate. Depending on the degranulation activity for
each particular CHMC donor, load 1000-1500 cells/well. Mix four
times followed by a 1 hr incubation at 37.degree. C. During the 1
hr incubation, prepare 6.times. anti-IgE solution [rabbit
anti-human IgE (1 mg/ml, Bethyl Laboratories A80-109A) diluted
1:167 in MT buffer]. Stimulate cells by adding 25 ul of 6.times.
anti-IgE solution to the appropriate plates. Add 25 ul MT to
un-stimulated control wells. Mix twice following addition of the
anti-IgE. Incubate at 37.degree. C. for 30 minutes. During the 30
minute incubation, dilute the 20 mM tryptase substrate stock
solution [(Z-Ala-Lys-Arg-AMC.cndot.2TFA; Enzyme Systems Products,
#AMC-246)] 1:2000 in tryptase assay buffer [0.1 M Hepes (pH 7.5),
10% w/v Glycerol, 10 uM Heparin (Sigma H-4898) 0.01% NaN.sub.3].
Spin plates at 1000 rpm for 10 mM to pellet cells. Transfer 25 ul
of supernatant to a 96-well black bottom plate and add 100 ul of
freshly diluted tryptase substrate solution to each well. Incubate
plates at room temperature for 30 min. Read the optical density of
the plates at 355 nm/460 nm on a spectrophotometric plate
reader.
[0345] Leukotriene C4 (LTC4) is also quantified using an ELISA kit
on appropriately diluted supernatant samples (determined
empirically for each donor cell population so that the sample
measurement falls within the standard curve) following the
supplier's instructions.
7.2.3 CHMC High Cell Density IgE Activation: Degranulation
(Tryptase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha,
IL-13) Assays
[0346] Cultured human mast cells (CHMC) are sensitized for 5 days
with IL-4 (20 ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human
IgE (CP 1035K from Cortx Biochem, 100-500 ng/ml depending on
generation) in CM medium. After sensitizing, cells are counted,
pelleted (1000 rpm, 5-10 minutes), and resuspended at
1-2.times.10.sup.6 cells/ml in MT buffer. Add 100 ul of cell
suspension to each well and 100 ul of compound dilutions. The final
vehicle concentration is 0.5% DMSO. Incubate at 37.degree. C. (5%
CO.sub.2) for 1 hour. After 1 hour of compound treatment, stimulate
cells with 6.times. anti-IgE. Mix wells with the cells and allow
plates to incubate at 37.degree. C. (5% CO.sub.2) for one hour.
After 1 hour incubation, pellet cells (10 minutes, 1000 RPM) and
collect 200 ul per well of the supernatant, being careful not to
disturb pellet. Place the supernatant plate on ice. During the
7-hour step (see next) perform tryptase assay on supernatant that
had been diluted 1:500. Resuspend cell pellet in 240 ul of CM media
containing 0.5% DMSO and corresponding concentration of compound.
Incubate CHMC cells for 7 hours at 37.degree. C. (5% CO.sub.2).
After incubation, pellet cells (1000 RPM, 10 minutes) and collect
225 ul per well and place in -80.degree. C. until ready to perform
ELISAS. ELISAS are performed on appropriately diluted samples
(determined empirically for each donor cell population so that the
sample measurement falls within the standard curve) following the
supplier's instructions.
7.2.4 Results
[0347] The results of low density CHMC assays are provided in Table
1. In Table 1, all reported values are IC.sub.50s (in .mu.M). Most
compounds tested had IC.sub.50s of less than 10 .mu.M, with many
exhibiting IC.sub.50s in the sub-micromolar range. In Table 1, all
reported values are IC.sub.50s (in .mu.M). A value of "-" indicates
an IC.sub.50>10 .mu.M, with no measurable activity at a 10 .mu.M
concentration. Most compounds tested had IC.sub.50s of less than 10
.mu.M, with many exhibiting IC.sub.50s in the sub-micromolar range.
A value of "+" indicates an IC.sub.50<10 .mu.M. Of the compounds
tested, BMMC values are comparable to those noted for the CHMC
results.
7.3 The 2,4-Pyrimidinediamine Compounds of the Invention
Selectively Inhibit the Upstream IgE Receptor Cascade
[0348] To confirm that many of the 2,4-pyrimidinediamine compounds
of the invention exert their inhibitory activity by blocking or
inhibiting the early IgE receptor signal transduction cascade,
several of the compounds were tested in cellular assays for
ionomycin-induced degranulation, as described below.
7.3.1 CHMC Low Cell Density Ionomycin Activation: Tryptase
Assay
[0349] Assays for ionomycin-induced mast cell degranulation were
carried out as described for the CHMC Low Density IgE Activation
assays (Section 7.2.2, supra), with the exception that during the 1
hour incubation, 6.times. ionomycin solution [5 mM ionomycin (Sigma
I-0634) in MeOH (stock) diluted 1:416.7 in MT buffer (2 .mu.M
final)] was prepared and cells were stimulated by adding 25 .mu.l
of the 6.times. ionomycin solution to the appropriate plates.
7.3.2 Results
[0350] The results of the ionomycin-induced degranulation assays,
reported as IC.sub.50 values (in .mu.M) are provided in Table 1. Of
the active compounds tested (i.e., those that inhibit IgE-induced
degranulation), the vast majority do not inhibit ionomycin-induced
degranulation, confirming that these active compounds selectively
inhibit the early (or upstream) IgE receptor signal transduction
cascade. In Table 1, all reported values are IC.sub.50s (in .mu.M).
A value of "-" indicates an IC.sub.50>10 .mu.M, with no
measurable activity at a 10 .mu.M concentration. A value of "+"
indicates an IC.sub.50<10 .mu.M.
7.4 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in
Biochemical Assays
[0351] Many of the 2,4-pyrimidinediamine compounds were tested for
the ability to inhibit Syk kinase catalyzed phosphorylation of a
peptide substrate in a biochemical fluorescenced polarization assay
with isolated Syk kinase. In this experiment, Compounds were
diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM
MgCl.sub.2, 2 mM MnCl.sub.2, 1 mM DTT, 0.1 mg/mL acetylated Bovine
Gamma Globulin). Compound in 1% DMSO (0.2% DMSO final) was mixed
with ATP/substrate solution at room temperature. Syk kinase
(Upstate, Lake Placid N.Y.) was added to a final reaction volume of
20 uL, and the reaction was incubated for 30 minutes at room
temperature. Final enzyme reaction conditions were 20 mM HEPES, pH
7.4, 5 mM MgCl.sub.2, 2 mM MnCl.sub.2, 1 mM DTT, 0.1 mg/mL
acetylated Bovine Gamma Globulin, 0.125 ng Syk, 4 uM ATP, 2.5 uM
peptide substrate (biotin-EQEDEPEGDYEEVLE-CONH2, SynPep
Corporation). EDTA (10 mM final)/anti-phosphotyrosine antibody
(1.times. final)/fluorescent phosphopeptide tracer (0.5.times.
final) was added in FP Dilution Buffer to stop the reaction for a
total volume of 40 uL according to manufacturer's instructions
(PanVera Corporation) The plate was incubated for 30 minutes in the
dark at room temperature. Plates were read on a Polarion
fluorescence polarization plate reader (Tecan). Data were converted
to amount of phosphopeptide present using a calibration curve
generated by competition with the phosphopeptide competitor
provided in the Tyrosine Kinase Assay Kit, Green (PanVera
Corporation).
[0352] These data, shown in Table 1, demonstrate that most all of
the compounds tested, inhibit Syk kinase phosphorylation with
IC.sub.50s in the submicromolar range. A vast majority of the
compounds tested inhibit Syk kinase phosphorylation with IC.sub.50s
in the micromolar range. In Table 1, all reported values are
IC.sub.50s (in .mu.M). A value of "-" indicates an IC.sub.50>10
.mu.M, with no measurable activity at a 10 .mu.M concentration. A
value of "+" indicates an IC.sub.50<10 .mu.M.
TABLE-US-00001 LD LD LD Com- Tryptase, Tryptase, Tryptase, pound
CHMC, CHMC, CHMC, fp_syk, Number Compound Name Physical Data IgE, 3
pt IgE, 8 pt Iono, 3 pt 11 pt 200
(S)-5-Fluoro-N2-(indazol-6-yl)-N4-(2-methyl-3-oxo-2H,4H- .sup.1H
NMR (DMSO-d6): d 8.08 (d, 1H), 7.95 (s, 1H), 7.58 (d, 1H), 7.40 (m,
+ benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.25 (m, 3H),
6.94 (m, 1H), 4.80 (m, 1H), 1.40 (s, 3H); LCMS: purity: 96%; MS
(m/e): 406 (MH+). 201
(S)-5-Fluoro-N2-(1-methylindazol-6-yl)-N4-(2-methyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 8.17 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.52 (m, 1H),
7.32 (m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s,
3H), 1.45 (s, 3H); LCMS: purity: 94%; MS (m/e): 420 (MH+). 202
(S)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 8.01 (d, 1H), 7.28 (m, 2H), 7.20 (s, 2H), +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 6.95 (m, 1H),
6.58 (s, 1H), 4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d,
3H); LCMS: purity: 92%; MS (m/e): 393 (MH+). 203
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-N2-
.sup.1H NMR (DMSO-d6): d 8.02 (d, 1H), 6.98 (m, 2H), 6.90 (m, 2H),
+ + (3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 6.80 (m,
1H), 6.03 (s, 1H), 3.72 (s, 2H), 3.60 (s, 6H), 1.05 (s, 6H); LCMS:
purity: 96%; MS (m/e): 425 (MH+). 204
(R)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 8.01 (d, 1H), 7.28 (m, 2H), 7.20 (s, 2H), +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 6.95 (m, 1H),
6.58 (s, 1H), 4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d,
3H); LCMS: purity: 92%; MS (m/e): 393 (MH+). 205
(R)-5-Fluoro-N2-[6-(2-hydroxyethyl)-2,3-dihydropyrrolo[1,2,3-
.sup.1H NMR (MeOD-d4): d 7.75 (d, 1H), 7.38 (m, 1H), 7.02 (m, 3H),
+ d,e]benzoxazin-8-yl]-N4-(2-methyl-3-oxo-2H,4H- 6.78 (m, 2H), 4.54
(m, 1H), 4.4 (m, 2H), 4.14 (m, 2H), 3.62 (m, 2H),
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 3.62 (m, 2H), 2.80 (m,
2H), 1.41 (d, 3H); LCMS: purity: 93%; MS (m/e): 491 (MH+). 206
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- .sup.1H
NMR (MeOD-d4): d 7.62 (d, 1H), 7.04 (s, 1H), 6.98 (m, 2H), +
fluoro-N2-[6-(2-hydroxyethyl)-2,3-dihydropyrrolo[1,2,3- 6.75 (m,
1H), 6.59 (m, 2H), 4.47 (m, 1H), 4.4 (m, 2H), 4.14 (m, 2H),
d,e]benzoxazin-8-yl]-2,4-pyrimidinediamine 3.62 (m, 4H), 2.80 (m,
2H), 1.07 (s, 6H); LCMS: purity: 98%; MS (m/e): 491 (MH+). 207
(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (MeOD-d4): d 7.98 (d, 1H), 7.82 (m, 2H), 7.48 (s, 1H), +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.41 (m, 3H),
7.25 (dd, 1H), 7.15 (m, 3H), 6.94 (d, 1H), 4.62 (q, 1H), Benzene
Sulfonic Acid Salt 3.82 (s, 3H), 1.50 (d, 3H); LCMS: purity: 97%;
MS (m/e): 430 (MH+). 208
(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (MeOD-d4): d 7.98 (d, 1H), 7.48 (s, 1H), 7.25 (dd, 1H), +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.15 (m, 3H),
6.94 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 2.68 (s, 3H), 1.50 (d,
Methanesulfonic Acid Salt 3H); LCMS: purity: 98%; MS (m/e): 430
(MH+). 209
(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (DMSO-d6): d 8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1S)- 7.21
(m, 1H), 7.12 (m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H),
3.40 (q, (+)-Camphorsulfonic Acid Salt 1H), 2.91 (m, 1H), 2.61 (m,
1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31
(m, 2H), 1.03 (s, 210
(R)-5-Fluoro-N2-(1-methylindazol-6-yl)-N4-(2-methyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 8.16 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.52 (m, 1H),
7.32 (m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s,
3H), 1.45 (s, 3H); LCMS: purity: 97%; MS (m/e): 420 (MH+). 211
(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (DMSO-d6): d 8.12 (d, 1H), 7.41 (dd, 1H), 7.22 (m, 3H), + +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 6.97 (m, 1H),
4.61 (q, 1H), 3.78 (s, 3H), 1.40 (d, 3H); LCMS: purity: 97%;
Hydrogen Chloride Salt MS (m/e): 430 (MH+). 212
(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (DMSO-d6): d 8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), + +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1R)-(-)-
7.21 (m, 1H), 7.12 (m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s,
3H), 3.40 (q, Camphorsulfonic Acid Salt 1H), 2.91 (m, 1H), 2.61 (m,
1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31
(m, 2H), 1.03 (s, 213
(R)-N2-(3-Chloro-4-methoxy-6-methylphenyl)-5-fluoro-N4-(2- .sup.1H
NMR (DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), + +
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 7.32 (m, 1H), 7.15
(s, 1H), 6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s,
pyrimidinediamine 3H), 2.17 (s, 3H), 1.38 (d, 3H); LCMS: purity:
97%; MS (m/e): 444 (MH+). 214
(S)-N2-(3-Chloro-4-methoxy-6-methylphenyl)-5-fluoro-N4-(2- .sup.1H
NMR (DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), + + -
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 7.32 (m, 1H), 7.15
(s, 1H), 6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s,
pyrimidinediamine 3H), 2.17 (s, 3H), 1.38 (d, 3H); LCMS: purity:
99%; MS (m/e): 444 (MH+). 215
(S)-(3-Chloro-4,6-dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3- 1H NMR
(DMSO-d6): d 1.38 (d, 3H), 3.82 (s, 3H), 3.90 (s, 3H), + + -
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 4.58 (q, 1H),
6.85 (m, 2H), 7.19 (m, 1H), 7.37 (m, 1H), 7.43 (m, 1H), 7.59 (s,
1H), 8.17 (m, 2H) purity: 99%; MS (m/e): 460 (MH+). 216
N2-(3-Chloro-4-methoxy-6-methylphenyl)-N4-(3,4-dihydro-3,3- 1H NMR
(DMSO-d6): d 1.38 (s, 6H), 2.17 (s, 3H), 3.64 (s, 3H), + + -
dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 3.81 (s, 3H),
6.48 (m, 1H), 6.77 (m, 1H), 6.93 (m, 1H), 6.99 (m, 1H),
pyrimidinediamine 7.41 (s, 1H), 7.82 (d, 1H) purity: 99%; MS (m/e):
444 (MH+). 217
N4-(3,4-Dihydro-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3- .sup.1H
NMR (DMSO-d6): d 8.19 (m, 1H), 8.15 (d, 1H), 7.78 (m, 1H), + + -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.39 (m, 2H), 6.90 (m,
1H), 6.47 (m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LCMS: purity: 97%;
MS (m/e): 405 (MH+). 218
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 1.18 (s, 6H), 3.81 (s, 2H), 6.77 (m, 1H), + + -
fluoro-N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.93 (m,
1H), 6.99 (m, 1H), 7.38 (m, 2H), 7.63 (m, 1H), 7.71 (m, 1H), 8.12
(s, 1H), 8.22 (m, 2H) purity: 99%; MS (m/e): 433 (MH+). 219
5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.50 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), + + -
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.23 (m, 1H), 7.38 (m,
2H), 7.59 (m, 1H), 7.77 (m, 1H), 8.22 (m, 3H) purity: 99%; MS
(m/e): 419 (MH+). 220
5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.50 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), + + -
benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.23 (m, 1H), 7.41 (m,
2H), 7.59 (m, 1H), 7.78 (m, 1H), 8.22 (m, 3H) purity: 97%; MS
(m/e): 419 (MH+). 221
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR
(DMSO-d6): d 1.98 (m, 1H), 3.58 (m, 2H), 6.78 (m, 1H), + + -
6-yl]-N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.18 (m,
1H), 7.38 (m, 3H), 7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H) purity:
99%; MS (m/e): 463 (MH+). 222
N4-(3,4-Dihydro-2H,4H-Benz[1,4]oxazin-6-yl)-5-fluoro-N2-[4- .sup.1H
NMR (DMSO-d6): d 8.29 (m, 1H), 8.17 (d, 1H), 7.76 (m, 1H), + + -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.59 (m, 3H), 6.90 (m,
1H), 6.77 (m, 1H), 6.62 (m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LCMS:
purity: 90%; MS (m/e): 405 (MH+). 223
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 1.18 (s, 6H), 3.80 (s, 2H), 6.71 (m, 2H), + + -
fluoro-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.95 (m,
1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38
(s, 1H) purity: 95%; MS (m/e): 433 (MH+). 224
5-Fluoro-N2-[4-(oxazol-5-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.68 (s, 2H), 6.98 (m, 2H), 7.22 (m, 1H), + + -
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.57 (m,
2H), 7.78 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H) purity: 98%; MS
(m/e): 419 (MH+). 225
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
.sup.1H NMR (DMSO-d6): d 8.28 (s, 1H), 8.22 (d, 1H), 7.62 (m, 2H),
+ + - N2-[4-(oxazol-5-yl-phenyl]-2,4-pyrimidinediamine 7.57 (m,
2H), 7.49 (s, 1H), 7.25 (m, 2H), 6.98 (m, 1H), 4.62 (q, 1H), 1.42
(d, 3H); LCMS: purity: 88%; MS (m/e): 433 (MH+). 226
5-Fluoro-N2-[4-(oxazol-5-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.66 (s, 2H), 6.98 (m, 2H), 7.22 (m, 1H), + + -
benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.57 (m,
2H), 7.76 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H) purity: 92%; MS
(m/e): 419 (MH+). 227
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + - +
6-yl]-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.98 (m,
2H), 7.22 (m, 2H), 7.51 (s, 1H), 7.57 (m, 2H), 7.76 (m, 2H), 8.28
(d, 1H), 8.38 (s, 1H) purity: 95%; MS (m/e): 463 (MH+). 228
N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- .sup.1H
NMR (DMSO-d6): d 8.29 (s, 1H), 8.15 (d, 1H), 7.76 (m, 1H), + + -
N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.57 (m, 3H), 6.88
(m, 1H), 6.77 (m, 1H), 6.62 (m, 1H), 4.10 (m, 2H), 3.20 (m, 2H),
2.80 (s, 3H); LCMS: purity: 94%; MS (m/e): 419 (MH+). 229
N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-7-yl)-5-fluoro- .sup.1H
NMR (DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H), 7.61 (m, 5H), + + -
N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.07 (m, 2H), 6.68
(m, 1H), 4.22 (m, 2H), 3.22 (m, 2H), 2.81 (s, 3H); LCMS: purity:
94%; MS (m/e): 419 (MH+). 230
5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-7-yl)-N2-[4- .sup.1H
NMR (DMSO-d6): d 8.36 (s, 1H), 8.20 (m, 1H), 8.19 (d, 1H), - - -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.77 (m, 2H), 7.54 (m,
2H), 7.37 (s, 1H), 7.25 (m, 1H), 6.97 (m, 1H), 4.58 (s, 2H), 2.97
(s, 3H); LCMS: purity: 98%; MS (m/e): 433 (MH+). 231
5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-N2-[4- .sup.1H
NMR (DMSO-d6): d 8.34 (s, 1H), 8.20 (m, 1H), 8.17 (d, 1H), - - -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.71 (m, 2H), 7.54 (m,
2H), 7.33 (s, 1H), 7.25 (m, 1H), 6.92 (m, 1H), 4.60 (s, 2H), 2.90
(s, 3H); LCMS: purity: 95%; MS (m/e): 433 (MH+). 232
N4-(3,4-Dihydro-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3- .sup.1H
NMR (DMSO-d6): d 8.39 (m, 1H), 8.22 (d, 1H), 7.86 (m, 1H), + + -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.59 (m, 4H), 6.87 (m,
2H), 6.52 (m, 1H), 4.09 (m, 2H), 3.23 (m, 2H); LCMS: purity: 90%;
MS (m/e): 405 (MH+). 233
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- .sup.1H
NMR (DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H), 7.82 (m, 1H), + + -
fluoro-N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.63 (m,
2H), 7.50 (s, 1H), 7.38 (m, 1H), 6.87 (m, 1H), 6.65 (m, 2H), 3.82
(s, 2H), 1.19 (s, 6H); LCMS: purity: 95%; MS (m/e): 433 (MH+). 234
5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.42 (s, 2H), 6.61 (m, 2H), 6.95 (m, 1H), + + -
benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.49 (m,
2H), 7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 90%; MS
(m/e): 419 (MH+). 235
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + -
6-yl]-N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.61 (m,
2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20
(d, 1H), 8.38 (s, 1H) purity: 90%; MS (m/e): 463 (MH+). 236
N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + -
N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.61 (m, 2H), 6.95
(m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H),
8.38 (s, 1H) purity: 95%; MS (m/e): 419 (MH+). 237
N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-7-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 2.82 (s, 3H), 3.58 (m, 2H), + -
N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 4.62 (m, 1H), 6.61
(m, 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H),
8.20 (d, 1H), 8.38 (s, 1H) purity: 95%; MS (m/e): 419 (MH+). 238
N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 1.38 (s, 6H), 3.81 (s, 2H), 6.71 (m, 2H), + + -
fluoro-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.95 (m,
1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38
(s, 1H) purity: 99%; MS (m/e): 433 (MH+). 239
5-Fluoro-N2-[4-(oxazol-2-yl)phenyl]-N4-(3-oxo-2H,4H- .sup.1H NMR
(DMSO-d6): d 8.15 (d 1H), 8.10 (s, 1H), 7.78 (m, 3H), + + -
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.14 (m, 3H), 6.97 (m,
2H), 4.56 (s, 2H); LCMS: purity: 98%; MS (m/e): 419 (MH+). 240
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
.sup.1H NMR (DMSO-d6): d 8.25 (m, 1H), 8.22 (d, 1H), 8.12 (m, 1H),
+ + - N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.77 (m,
2H), 7.34 (s, 1H), 7.23 (m, 2H), 6.98 (m, 2H), 4.63 (q, 1H), 1.42
(d, 3H); LCMS: purity: 95%; MS (m/e): 433 (MH+). 241
5-Fluoro-N2-[4-(oxazol-2-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.45 (s, 2H), 6.71 (m, 2H), 6.95 (m, 1H), - -
benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.69 (m,
2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 95%; MS
(m/e): 419 (MH+). 242
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin-
.sup.1H NMR (DMSO-d6): d 8.25 (d 1H), 8.20 (d, 1H), 8.16 (s, 1H),
7.82 (m, + + -
6-yl]-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 3H), 7.35
(s, 1H), 7.20 (m, 2H), 6.95 (m, 1H), 4.62 (m, 1H), 3.58 (m, 1H),
1.95 (m, 2H); LCMS: purity: 99%; MS (m/e): 463 (MH+). 243
N4-(2,3-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 2.80 (s, 3H), 3.58 (m, 2H), + + -
N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 4.62 (m, 1H), 6.71
(m, 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H),
8.20 (d, 1H), 8.38 (s, 1H) purity: 99%; MS (m/e): 419 (MH+). 244
5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-7-yl)-N2-[4- .sup.1H
NMR (DMSO-d6): d 8.18 (d, 1H), 8.14 (s, 1H), 7.82 (d, 2H), - -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.56 (m, 2H), 7.40 (m,
2H), 7.30 (s, 1H), 6.95 (m, 1H), 4.62 (s, 2H), 2.78 (s, 3H); LCMS:
purity: 99%; MS (m/e): 433 (MH+). 245
5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-N2-[4- .sup.1H
NMR (DMSO-d6): d 8.20 (d, 1H), 8.12 (s, 1H), 7.82 (d, 2H), - -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.55 (m, 2H), 7.40 (m,
2H), 7.33 (s, 1H), 6.88 (m, 1H), 4.59 (s, 2H), 2.77 (s, 3H); LCMS:
purity: 98%; MS (m/e): 433 (MH+). 246
5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4-[3-oxo-2H,4H- 1H NMR
(DMSO-d6): d 4.45 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), + + -
benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.38 (m, 3H), 7.57 (m,
1H), 7.79 (m, 1H), 8.22 (m, 2H) purity: 93%; MS (m/e): 419 (MH+).
247 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H
NMR (DMSO-d6): d 1.38 (d, 3H), 4.58 (q, 1H), 6.78 (m, 1H), + + -
N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.18 (m, 1H), 7.38
(m, 3H), 7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H) purity: 90%; MS
(m/e): 433 (MH+). 248
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + -
7-yl]-N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.88 (m,
2H), 7.22 (m, 3H), 7.57 (m, 2H), 7.79 (m, 2H), 8.22 (m, 2H) purity:
99%; MS (m/e): 463 (MH+). 249
5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR
(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + - -
7-yl]-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.71 (m,
2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20
(d, 1H), 8.38 (s, 1H) purity: 99%; MS (m/e): 463 (MH+). 250
(R)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d d 1.38 (d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), + + +
N2-[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 7.22 (m, 4H), 7.57
(m, 1H), 7.99 (m, 2H), 8.12 (m, 2H) purity: 95%; MS (m/e): 433
(MH+). 251
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d d 1.38 (d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), + + -
N2-[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 7.22 (m, 4H), 7.57
(m, 1H), 7.99 (m, 2H), 8.12 (m, 2H) purity: 99%; MS (m/e): 433
(MH+). 252 (R,S)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 2.18 (s, 6H), 2.25 (m, 2H) 3.75 (t, 2H) +
(tetrahydrofurano[2,3]-2H-benz[1,4]oxazin-6-yl)-2,4- 4.58 (q, 1H),
6.52 (d, 1H), 6.92 (dd, 2H), 7.37 (m, 3H), 8.12 (d, 1H)
pyrimidinediamine purity: 90%; MS (m/e): 406 (MH+). 253
N4-[3,4-Dihydro-2-(2-hydroxyethyl)-2H,4H-benz[1,4]oxazin-6- 1H NMR
(DMSO-d6): d 1.88 (m, 2H), 2.97 (m, 2H), 3.55 (m, 2H), + + -
yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 3.61
(s, 6H), 4.08 (q, 1H), 6.02 (m, 1H), 6.58 (d, 1H), 6.96 (m, 5H),
8.02 (d, 1H) purity: 96%; MS (m/e): 442 (MH+). 254
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR
(DMSO-d6): d 2.62 (d, 3H), 3.32 (s, 2H), 4.37 (s, 2H), + + -
N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- 6.60 (m, 1H), 7.22 (m,
3H), 7.37 (m, 1H), 7.43 (m, 1H), 8.02 (m, 1H), pyrimidinediamine
8.22 (d, 1H) purity: 94%; MS (m/e): 455 (MH+). 255
N4-[2,3-Dihydro-2-(2-hydroxyethyl)-2H,4H-benz[1,4]oxazin-6- 1H NMR
(DMSO-d6): d 1.88 (m, 2H), 2.18 (s, 6H), 2.97 (m, 2H), + + -
yl]-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 3.58 (m,
2H), 4.09 (q, 1H), 6.19 (m, 1H), 6.42 (m, 1H), 6.58 (m, 1H), 6.81
(m, 2H), 7.22 (s, 2H), 8.02 (d, 1H) purity: 97%; MS (m/e): 410
(MH+). 256 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H- 1H
NMR (DMSO-d6): d 3.37 (s, 2H), 3.61 (s, 6H), 6.18 (m, 1H), + + -
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 6.75 (m, 2H), 7.22
(m, 2H), 7.43 (m, 1H), 8.22 (d, 1H) purity: 98%; MS (m/e): 428
(MH+). 257 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H-
1H NMR (DMSO-d6): d 3.47 (s, 2H), 3.88 (s, 3H), 7.08 (m, 1H), + + -
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 7.25 (s, 2H), 7.42
(m, 2H), 7.78 (m, 1H), 8.22 (d, 1H) purity: 99%; MS (m/e): 432
(MH+). 258
N4-(3,4-Dihydro-2H,4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 2.67 (d, 3H), 3.32 (m, 2H), 4.30 (s, 2H), + + -
(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 4.37 (m, 2H), 6.45
(m, 1H), 6.88 (m, 1H), 6.96 (m, 2H), 7.13 (m, 1H),
pyrimidinediamine 7.23 (m, 2H), 8.02 (m, 2H) purity: 92%; MS (m/e):
441 (MH+). 259
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR
(DMSO-d6): d 2.62 (d, 3H), 3.11 (s, 3H), 3.32 (s, 2H), + + -
N4-(4-methyl-3-oxo-2H-benzo[1,4]thiazin-6-yl)-2,4- 4.37 (s, 2H),
6.60 (m, 1H), 7.22 (m, 3H), 7.37 (m, 1H), 7.43 (m, 1H),
pyrimidinediamine 8.02 (m, 1H), 8.22 (d, 1H) purity: 95%; MS (m/e):
469 (MH+). 260
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(4-methyl-3-oxo-2H- 1H NMR
(DMSO-d6): d 3.11 (s, 3H), 3.32 (s, 2H), 3.58 (s, 6H), + + -
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 6.18 (m, 1H), 6.75
(m, 2H), 7.32 (m, 3H), 7.63 (m, 2H), 8.22 (d, 1H) purity: 98%; MS
(m/e): 442 (MH+). 261
N2-(3-Benzothioamide)-5-fluoro-N4-(3-oxo-2H,4H- 1H NMR (DMSO-d6): d
4.58 (s, 2H), 6.98 (m, 1H), 7.19 (m, 2H), + -
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.39 (m, 3H), 7.93 (m,
1H), 8.19 (d, 1H) purity: 90%; MS (m/e): 411 (MH+). 262
N2-(3-Benzothioamide)-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo- 1H NMR
(DMSO-d6): 1.91 (m, 2H), 3.54 (m, 2H), 4.63 (m, 1H), + -
2H,4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 6.98 (m, 1H),
7.19 (m, 2H), 7.39 (m, 3H), 7.93 (m, 1H), 8.19 (d, 1H) purity: 93%;
MS (m/e): 455 (MH+). 263
N2-(3,5-Dimethoxyphenyl)-N4-(dioxide-2-methyl-1,1,3-trioxo- 1H NMR
(DMSO-d6): d 1.42 (d, 3H), 3.63 (s, 6H), 4.69 (q, 1H), + + +
4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 6.14 (s,
1H), 6.92 (m, 2H), 7.72 (s, 2H), 7.92 (m, 2H), 8.27 (d, 1H) purity:
99%; MS (m/e): 474 (MH+). 264
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-1,1,3-trioxo- 1H NMR
(DMSO-d6): d 1.42 (d, 3H), 2.18 (s, 6H), 4.72 (q, 1H), + + +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 6.64 (m, 1H),
7.21 (m, 2H), 7.72 (s, 2H), 7.68 (m, 2H), 8.27 (d, 1H) purity: 99%;
MS (m/e): 442 (MH+). 265
5-Fluoro-N2-(indazol-6-yl)-N4-(2-methyl-1,1,3-trioxo-2H,4H- 1H NMR
(DMSO-d6): d 1.42 (d, 3H), 4.79 (q, 1H), 7.23 (m, 1H), + + +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 7.60 (m, 1H), 7.77
(m, 1H), 7.82 (m, 3H), 8.16 (m, 1H), 8.27 (d, 1H) purity: 94%; MS
(m/e): 454 (MH+). 266
5-Fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6- 1H
NMR (DMSO-d6): d 1.42 (d, 3H), 3.66 (s, 9H), 4.70 (q, 1H), + + +
yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 7.04 (m, 2H),
7.72 (s, 2H), 7.72 (m, 3H), 8.22 (d, 1H) purity: 96%; MS (m/e): 504
(MH+). 267
N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H- LCMS:
ret time 12.32 min purity: 100%; MS (m/e): 488 (MH.sup.+) + +
benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 268
N2-(3,5-Dimethylphenyl)--N4-(2,2-dimethyl-1,1,3-trioxo-4H- LCMS:
ret time 13.35 min purity: 99%; MS (m/e): 456 (MH+) + +
benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 269
N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[thiazin-6-yl)-5-fluoro-
LCMS: ret time 11.28 min purity: 99%; MS (m/e): 518 (MH+) + +
2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 270
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo- LCMS: ret
time 11.69 min purity: 95%; MS (m/e): 442 (MH+) +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 271
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo-2H,4H- LCMS:
ret time 12.12 min purity: 98%; MS (m/e): 410 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 272
5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)- LCMS:
ret time 10.44 min purity: 99%; MS (m/e): 472 (MH+) +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 273
N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS:
ret time 10.49 min purity: 95%; MS (m/e): 468 (MH+) +
fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine 274
N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS:
ret time 8.66 min purity: 96%; MS (m/e): 468 (MH+) +
fluoro-N2-(indazol-5-yl)-2,4-pyrimidinediamine 275
N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS:
ret time 10.16 min purity: 93%; MS (m/e): 515 (MH+) +
fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-
2,4-pyrimidinediamine 276
N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-1,1,3-trioxo- LCMS:
ret time 12.66 min purity: 99%; MS (m/e): 492 (MH+) +
4H-benzo[thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 277
5-Fluoro-N2-(indazol-6-yl)-N4-(2-methyl-3-oxo-2H,4H- LCMS: ret time
9.40 min purity: 95%; MS (m/e): 422 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 278
5-Fluoro-N2-(indazol-5-yl)-N4-(2-methyl-3-oxo-2H,4H- LCMS: ret time
8.23 min purity: 98%; MS (m/e): 422 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 279
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- LCMS:
ret time 9.51 min purity: 96%; MS (m/e): 469 (MH+) +
N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-
pyrimidinediamine 280
N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo- LCMS:
ret time 11.77 min purity: 97%; MS (m/e): 446 (MH+) +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 281
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-oxo-2H,4H- LCMS: ret time 8.18
min purity: 99%; MS (m/e): 384 (MH+) + +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 282
racemic-5-Fluoro-N2-(3-hydroxyphenyl)-N4-(2-methyl-3-oxo- LCMS: ret
time 9.11 min purity: 99%; MS (m/e): 398 (MH+) +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 283
racemic-N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6- LCMS:
ret time 9.89 min purity: 99%; MS (m/e): 444 (MH+) +
yl)-5-fluoro-N2-[3-hydoxyphenyl]-2,4-pyrimidinediamine 284
racemic-5-Fluoro-N2-[3-hydoxyphenyl]-N4-(2-methyl-1,1,3- LCMS: ret
time 9.33 min purity: 97%; MS (m/e): 430 (MH+) +
trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 285
racemic-5-Fluoro-N2-[3-(N- LCMS: ret time 9.44 min purity: 93%; MS
(m/e): 501 (MH+) +
methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-
1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine
286 racemic-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2- LCMS: ret
time 11.68 min purity: 95%; MS (m/e): 478 (MH+) +
methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-
pyrimidinediamine 287
5-Fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(3,4,5- LCMS:
ret time 9.49 min purity: 99%; MS (m/e): 458 (MH+) +
trimethoxyphenyl)-2,4-pyrimidinediamine 288
5-Fluoro-N2-(indazol-5-yl)-N4-(3-oxo-2H,4H-benzo[1,4]thiazin- LCMS:
ret time 7.28 min purity: 98%; MS (m/e): 408 (MH+) +
6-yl)-2,4-pyrimidinediamine 289
N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- LCMS: ret
time 12.45 min purity: 97%; MS (m/e): 460 (MH+) +
benzo[thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 290
N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- LCMS: ret time
12.81 min purity: 99%; MS (m/e): 456 (MH+) +
benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 291
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-N2-(3,5- LCMS:
ret time 13.44 min purity: 99%; MS (m/e): 424 (MH+) +
dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 292
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-
LCMS: ret time 11.86 min purity: 99%; MS (m/e): 486 (MH+) +
(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 293
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:
ret time 10.39 min purity: 99%; MS (m/e): 412 (MH+) +
N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 294
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:
ret time 10.04 min purity: 97%; MS (m/e): 483 (MH+) + +
N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-
pyrimidinediamine 295
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:
ret time 10.54 min purity: 96%; MS (m/e): 436 (MH+) + + +
N2-(indazol-6-yl)-2,4-pyrimidinediamine 296
racemic-5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2- LCMS: ret
time 11.91 min purity: 96%; MS (m/e): 462 (MH+) + +
methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-
pyrimidinediamine 297
N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS:
ret time 12.11 min purity: 96%; MS (m/e): 476 (MH+) + +
fluoro-N2-(3-fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine 298
racemic-5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2- LCMS: ret
time 11.29 min purity: 98%; MS (m/e): 430 (MH+) + +
methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine
299 N4-(2,2-Dimethyl-3-oxo-4H-benzo[thiazin-6-yl)-5-fluoro-N2-(3-
LCMS: ret time 12.14 min purity: 99%; MS (m/e): 444 (MH+) + +
fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine 300
5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(3-oxo-2H,4H- LCMS: ret
time 10.56 min purity: 97%; MS (m/e): 415 (MH+) + +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 301
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(3-oxo-2H,4H- LCMS: ret time
11.76 min purity: 98%; MS (m/e): 396 (MH+) + +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 302
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(1,1,3-trioxo-2H,4H- LCMS: ret
time 10.72 min purity: 96%; MS (m/e): 428 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 303
N2-(3,5-Dimethoxylphenyl)-5-fluoro-N4-(1,1,3-trioxo-2H,4H- LCMS:
ret time 10.06 min purity: 95%; MS (m/e): 460 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 304
N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(1,1,3-trioxo- LCMS: ret
time 10.13 min purity: 97%; MS (m/e): 464 (MH+) +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 305
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- LCMS:
ret time 8.40 min purity: 97%; MS (m/e): 487 (MH+) +
N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-
pyrimidinediamine 306
5-Fluoro-N2-(3,4,5-triimethoxylphenyl)-N4-(1,1,3-trioxo-2H,4H-
LCMS: ret time 9.19 min purity: 95%; MS (m/e): 490 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 307
5-Fluoro-N2-(indazol-6-yl)-N4-(1,1,3-trioxo-2H,4H- LCMS: ret time
8.33 min purity: 91%; MS (m/e): 440 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 308
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(1,1,3-trioxo-2H,4H- LCMS: ret
time 8.07 min purity: 96%; MS (m/e): 416 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 309
5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(1,1,3-trioxo- LCMS: ret
time 9.74 min purity: 95%; MS (m/e): 448 (MH+) +
2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 310
5-Fluoro-N2-(indazol-5-yl)-N4-(1,1,3-trioxo-2H,4H- LCMS: ret time
7.40 min purity: 94%; MS (m/e): 440 (MH+) +
benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 311
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:
ret time 10.15 min purity: 99%; MS (m/e): 450 (MH+) + +
N2-(1-methylindazol-6-yl)-2,4-pyrimidinediamine 312
N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:
ret time 10.54 min purity: 100%; MS (m/e): 436 (MH+)
N2-(indazol-6-yl)-2,4-pyrimidinediamine Trifuoro Acetate Salt 313
N2-Chloro-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-4- LCMS:
ret time 5.58 min purity: 95%; MS (m/e): 311 (MH+) +
pyrimidineamine 314
racemic-N2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-2H,4H- LCMS: ret time
11.18 min purity: 95%; MS (m/e): 325 (MH+) +
benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 315
N2-Chloro-5-fluoro-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin- LCMS:
ret time 10.03 min purity: 95%; MS (m/e): 343 (MH+) -
6-yl)-4-pyrimidineamine 316
N2-Chloro-N4-(2,2,-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)- LCMS:
ret time 12.29 min purity: 95%; MS (m/e): 339 (MH+) +
5-fluoro-4-pyrimidineamine 317
racemic-N2-Chloro-5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H- LCMS:
ret time 10.16 min purity: 96%; MS (m/e): 357 (MH+) -
benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 318
N2-Chloro-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin- LCMS:
ret time 10.50 min purity: 96%; MS (m/e): 371 (MH+) +
6-yl)-5-fluoro-4-pyrimidineamine 319
N4-[benzoxathiazin-3(4H)-one-6-yl]2-chloro-5-fluoro-4- LCMS: ret
time 6.40 min purity: 99%: MS (m/e): 296 (MH+) + pyrimidineamine
320 N2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro- LCMS:
ret time 12.20 min purity 99% MS (m/e): 309 (MH.sup.+) +
pyrimidineamine 324 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3- 1H NMR
(DMSO-d6): d 9.57 (bs, 1H), 9.21 (bs, 1H), 8.16 (d, J = 3.6 Hz, +
trifluoromethoxyphenyl)-2,4-pyrimidinediamine 1H), 8.01 (d, J = 8.1
Hz, 1H), 7.75 (s, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.4
Hz, 1H), 6.91 (d, J = 2.1 Hz, 2H), 6.09-6.06 (m, 1H), 3.65 (s, 6H);
19F NMR (282 MHz, DMSO-d6): -57.17, -163.27; LCMS: purity: 99%; MS
(m/e): 425 (MH+) 325 N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(3-
.sup.1H NMR (DMSO-d6): d 9.54 (bs, 1H), 9.12 (bs, 1H), 8.15 (dd, J
= 1.8 + trifluoromethoxyphenyl)-2,4-pyrimidinediamine and 3.6 Hz,
1H), 7.96 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.41 (t, J = 8.1 Hz,
1H), 7.01 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 2.18 (s, 6H); 19F NMR
(282 MHz, DMSO-d6): -57.01, -163.96; LCMS: pu 326
5-Fluoro-N2-(indol-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4- .sup.1H
NMR (DMSO-d6): d 10.83 (bs, 1H), 9.49 (s, 1H), 9.11 (s, 1H), + +
pyrimidinediamine 8.13 (dd, J = 1.2 and 3.3 Hz, 1H), 8.05 (d, J =
8.1 Hz, 1H), 7.80 (d, J = 13.2 Hz, 2H), 7.40-7.32 (m, 2H),
7.21-7.16 (m, 2H), 6.99-6.95 (m, 1H), 6.34-6.28 (m, 1H); 19F NMR
(282 MHz, DMSO-d6): - 327
5-Fluoro-N4-[1-(N-methylamino)carbonylindol-6-yl]-N2-[3-(N- .sup.1H
NMR (DMSO-d6): d 10.87 (bs, 1H), 9.61 (s, 1H), 9.46-9.43 (m, 1H), +
methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.08 (d, J = 3.6 Hz,
1H), 8.04-7.98 (m, 1H), 7.40-7.25 (m, 4H), pyrimidinediamine 7.02
(dd, J = 1.8 and 8.4 Hz, 1H), 6.95-6.90 (m, 1H), 6.77-6.70 (m, 2H),
6.38-6.35 (m, 1H), 4.39 (s, 2H), 2.62 (d, J = 4.8 Hz 328
N2-(3,5-Dimethoxyphenyl)-N4-(3,5-dimethylphenyl)-5-fluoro- .sup.1H
NMR (DMSO-d6): d 9.15 (bs, 1H), 9.11 (s, 1H), 8.07 (d, J = 3.9 Hz,
+ 2,4-pyrimidinediamine 1H), 7.37 (s, 2H), 6.89 (d, J = 1.81 Hz,
2H), 6.68 (s, 1H), 6.05 (t, J = 2.1 Hz, 1H), 3.61 (s, 6H), 2.23 (s,
6H); 19F NMR (282 MHz, DMSO-d6): -163.60; LCMS: purity: 99%; MS
(m/e): 369 (MH 329
N4-(3,5-Dimethylphenyl)-5-fluoro-N2-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.45 (s, 1H), 9.22 (s, 1H), 8.12 (d, J = 3.9 Hz, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.68-7.64 (m,
1H), 7.58-7.54 (m, 1H), 7.33 (s, 2H), 6.71 (s, 2H), 3.69 (s, 3H),
2.23 (s, 6H); LCMS: purity: 99%; MS (m/e): 407 (MH+). 330
N4-(3,5-Dimethylphenyl)-5-fluoro-N4-(3-methyl-5- .sup.1H NMR
(DMSO-d6): d 10.11 (bs, 1H), 9.94 (bs, 1H), 8.25 (d, J = 4.8 Hz, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.67 (s, 2H),
7.24 (s, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 2.25 (s, 3H), 2.21 (s,
6H); 19F NMR (282 MHz, DMSO-d6): -61.76, -161.10; LCMS: purity:
99%; MS (m/e): 390 (M+). 331
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.86 (bs, 1H), 9.42 (bs, 1H), 8.20 (d, J = 4.2 Hz, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.80-7.76 (m,
1H), 7.56-7.51 (m, 1H), 7.18 (s, 2H), 6.94 (s, 1H), 6.59 (s, 1H),
3.74 (s, 3H), 2.15 (s, 6H); LCMS: purity: 97%; MS (m/e): 407 (MH+).
332 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.59 (bs, 1H), 9.24 (bs, 1H), 8.18 (d, J = 3.3 Hz, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.84-7.68 (m,
1H), 7.61-7.57 (m, 1H), 6.89 (d, J = 2.4 Hz, 3H), 6.06 (t, J = 2.4
Hz, 1H), 3.77 (s, 3H), 3.61 (s, 6H); 19F NMR (282 MHz, DMSO-d6):
-61.85, -163.20; LCMS: purity: 97%; 333
N2,N4-Bis(3-methoxy-5-trifluoromethylphenyl)-5-fluoro-2,4- .sup.1H
NMR (DMSO-d6): d 9.80 (bs, 1H), 9.72 (s, 1H), 8.25 (d, J = 3.3 Hz,
+ pyrimidinediamine 1H), 7.77-7.72 (m, 1H), 7.60-7.52 (m, 3H), 6.92
(s, 1H), 6.75 (s, 1H), 3.77 (s, 3H), 3.71 (s, 3H); 19F NMR (282
MHz, DMSO-d6): -61.90, -161.82; LCMS: purity: 97%; MS (m/e): 477
(MH+). 334 5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-(3-
.sup.1H NMR (DMSO-d6): d 9.83 (bs, 1H), 9.72 (bs, 1H), 8.25 (d, J =
3.6 Hz, + methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine
1H), 7.81-7.68 (m, 3H), 7.57-7.52 (m, 1H), 7.06 (s, 1H), 6.96-6.91
(m, 1H), 3.75 (s, 3H), 2.26 (s, 3H); 19F NMR (282 MHz, DMSO-d6):
-61.82, -162.02; LCMS: purity: 91%; MS (m/e): 461 (M 335
5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-(3,4,5- .sup.1H
NMR (DMSO-d6): d 9.67 (bs, 1H), 9.24 (bs, 1H), 8.17 (d, J = 3.6 Hz,
+ trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.84-7.78 (m, 1H),
7.59 (s, 1H), 6.95-6.87 (m, 3H), 3.74 (s, 3H), 3.59 (s, 6H); 19F
NMR (282 MHz, DMSO-d6): -61.86, -163.40; LCMS: purity: 96%; MS
(m/e): 469 (MH+). 336
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3- .sup.1H NMR
(DMSO-d6): d 9.56 (s, 1H), 9.09 (s, 1H), 8.61 (s, 1H), 8.14 (d, +
methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine J = 3.6 Hz,
1H), 7.82-7.77 (m, 1H), 7.57-7.53 (m, 1H), 7.52-7.48 (m, 1H),
7.27-7.23 (m, 1H), 6.89 (bs, 1H), 3.76 (s, 3H), 2.10 (s, 3H); 19F
NMR (282 MHz, DMSO-d6): -61.80, -164.13; LCM 337
N2-(3,5-Dichlorophenyl)-5-fluoro-N4-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.74 (s, 1H), 9.70 (s, 1H), 8.25 (d, J = 3.6 Hz, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.77-7.71 (m,
3H), 7.55-7.50 (m, 1H), 7.03-7.01 (m, 1H), 6.95-6.93 (m, 1H), 3.79
(s, 3H); 19F NMR (282 MHz, DMSO-d6): -61.78, -161.76; LCMS: purity:
96%; MS (m/e): 448 (MH+). 338
N2-[3,5-Bis(hydroxymethylene)phenyl]-5-fluoro-N4-(3- .sup.1H NMR
(DMSO-d6): d 10.11 (bs, 1H), 9.82 (bs, 1H), 8.26 (d, J = 4.2 Hz, +
+ methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 1H),
7.83-7.79 (m, 1H), 7.57-7.51 (m, 1H), 7.34 (bs, 2H), 6.99-6.94 (m,
2H), 4.38 (s, 4H), 3.74 (s, 3H); LCMS: purity: 92%; MS (m/e): 439
(MH+). 339
N2-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-(3-methoxy-5- .sup.1H
NMR (DMSO-d6): d 9.98 (bs, 1H), 9.66 (bs, 1H), 8.24 (d, J = 4.2 Hz,
- trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.76-7.71 (m,
1H), 7.56-7.52 (m, 1H), 7.37 (s, 2H), 6.98-6.95 (m, 1H), 3.75 (s,
3H), 2.20 (s, 6H); LCMS: purity: 98%; MS (m/e): 442 (MH+). 340
N2,N4-Bis(3,5-dimethoxyphenyl)-5-fluoro-2,4- 1H NMR (DMSO-d6): d
9.27 (s, 1H), 9.18 (s, 1H), 8.10 (d, 1H, J = 3.9 Hz), + +
pyrimidinediamine 6.99 (d, 2H, J = 2.1 Hz), 6.92 (d, 2H, J = 2.4
Hz), 6.21 (t, 1H, J = 2.1 Hz), 6.05 (t, 1H, J = 2.4 Hz), 3.68 (s,
6H), 3.62 (s, 6H); LCMS: purity: 100%; MS (m/e): 401 (MH+) 341
N2,N4-Bis(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine
.sup.1H NMR (DMSO-d6): d 9.11 (s, 1H), 8.98 (s, 1H), 8.05 (d, 1H, J
= 3.9 Hz), + 7.33 (bs, 2H), 7.24 (bd, 2H), 6.69 (bs, 1H), 6.51 (bs,
1H), 2.25 (bs, 6H), 2.14 (s, 6H); LCMS: purity: 100%; MS (m/e): 336
(M+). 342 N2-[3,5-Bis(hydroxymethylene)phenyl]-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 9.10 (s, 1H), 9.09 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz),
+ ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.44 (s, 2H),
7.28 (d, 1H, J = 3.0 Hz), 7.24 (d, 1H, J = 2.7 Hz), 6.86 (s, 1H),
6.79 (d, 1H, J = 8.7 Hz), 5.05 (t, 2H, J = 6 Hz), 4.39 (d, 4H, J =
5.4 Hz), 4.22 (bs, 4H); LCMS: purity: 97 343
N2-[3,5-Bis(hydroxymethylene)phenyl]-N4-(3,5- 1H NMR (DMSO-d6): d
9.19 (s, 1H), 9.15 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz), + +
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.46 (s, 2H), 7.01
(d, 2H, J = 2.1 Hz), 6.86 (s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 5.03
(t, 2H, J = 5.4 Hz), 4.38 (d, 4H, J = 5.4 Hz), 3.68 (s, 6H); LCMS:
purity: 86%; MS (m/e): 401 (MH+ 344
N2-[3,5-Bis(hydoxymethylene)phenyl]-N4-(2,2-dimethyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 10.55 (s, 1H), 9.27 (bd, 1H), 8.97 (s, 1H), + +
4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.04 (d,
1H, 3.6 Hz), 7.44 (d, 2H, J = 1.2 Hz), 7.39 (dd, 1H, J = 2.4 and
8.4 Hz), 7.24 (d, 1H, J = 2.4 Hz), 6.88 (d, 1H, J = 8.7 Hz), 6.85
(bs, 1H), 6.38 (s, 2H), 5.08 (t, 1H, J = 5.6 Hz), 4.93 (t 345
N2-[3,5-Bis(hydroxymethylene)phenyl]-N4-(3-chloro-4- .sup.1H NMR
(DMSO-d6): d 9.26 (s, 1H), 9.15 (s, 1H), 8.07 (bd, 1H, J = 3.9 Hz),
+ methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.79 (dd, 1H, J =
2.7 and 9 Hz), 7.74 (d, 1H, J = 2.7 Hz), 7.43 (s, 2H), 7.11 (d, 1H,
J = 9 Hz), 6.86 (s, 1H), 5.06 (t, 2H, J = 5.4 Hz), 4.38 (d, 4H, J =
5.4 Hz), 3.84 (s, 3H); LCMS: puri 346
N2-[3,5-Bis(hydroxymethylene)phenyl]-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 9.50 (bs, 1H), 9.28 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz),
+ dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 8.05 (d, 1H, J =
2.7 Hz), 7.93 (dd, 1H, J = 2.7 and 9.0 Hz), 7.52 (d, 1H, J = 8.7
Hz), 7.44 (s, 2H), 6.87 (s, 1H), 5.09 (t, 2H, J = 5.7 Hz), 4.41 (d,
4H), J = 5.4 Hz); LCMS: purity: 97%; 347
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(N- .sup.1H
NMR (DMSO-d6): d 11.02 (s, 1H), 10.49 (s, 1H), 9.69 (d, 1H, J = 4.8
Hz), + methylaminocarbony)lindol-6-yl)-5-fluoro-2,4- 9.53 (s, 1H),
8.12 (d, 1H, J = 3.6 Hz), 7.52 (d, 1H, J = 8.4 Hz),
pyrimidinediamine 7.38 (t, 1H, J = 2.7 Hz), 7.11 (s, 1H), 6.81 (d,
1H, J = 2.4 Hz), 6.72 (dd, 1H, J = 1.8 and 8.4 Hz), 6.59 (dd, 1H, J
= 2 348 N2-(1-Aminocarbonylindol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H-
1H NMR (DMSO-d6): d 11.01 (s, 1H), 10.44 (s, 1H), 9.50 (s, 1H), -
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.16 (d, 1H, J
= 3.6 Hz), 8.07 (d, 1H, J = 5.4 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.38
(t, 1H, J = 2.7 Hz), 6.73 (dd, 1H, J = 1.5 and 8.4 Hz), 6.54 (m,
2H), 5.69 (d, 1H, J = 8.7 Hz), 2.93 (s, 2H), 1.29 (s, 6H); LCMS:
purity: 95%; MS (m/e): 462 (MH+) 349
N2-(4-Chloro-3,5-dimethylphenyl)-N4-(3,5-dimethoxyphenyl)- .sup.1H
NMR (DMSO-d6): d 9.26 (bs, 1H), 9.20 (s, 1H), 8.10 (d, 1H, J = 3.9
Hz), + 5-fluoro-2,4-pyrimidinediamine 7.48 (s, 2H), 6.94 (d, 2H, J
= 2.4 Hz), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.20 (s, 6H);
LCMS: purity: 92%; MS (m/e): 403 (MH+). 350
N4-(3,5-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- .sup.1H
NMR (DMSO-d6): d 9.20 (s, 1H), 9.05 (s, 1H), 8.08 (d, 1H, J = 3.6
Hz), + + - + 2,4-pyrimidinediamine 7.27 (s, 2H), 6.97 (d, 2H, J =
2.1 Hz), 6.51 (s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 3.67 (s, 6H), 2.15
(s, 6H); LCMS: purity: 96%; MS (m/e): 369 (MH+). 351
N4-(3,5-Dimethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5- .sup.1H
NMR (DMSO-d6): d 9.16 (s, 1H), 9.96 (s, 1H), 8.05 (d, 1H, J = 3.3
Hz), + fluoro-2,4-pyrimidinediamine 7.22 (d, 1H, J = 2.7 Hz), 7.06
(dd, 1H, J = 2.4 and 8.7 Hz), 6.99 (d, 2H, J = 2.1 Hz), 6.65 (d,
1H, J = 8.7 Hz), 6.20 (t, 1H, J = 2.1 Hz), 4.17 (s, 4H), 3.69 (s,
6H); LCMS: purity: 91%; M 352
N2-(3,5-Dichlorophenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro- .sup.1H
NMR (DMSO-d6): d 9.82 (bs, 1H), 9.58 (bs, 1H), 8.21 (d, 1H, J = 3.6
Hz), + 2,4-pyrimidinediamine 7.75 (bs, 2H), 7.04 (t, 1H, J = 1.8
Hz), 6.89 (d, 2H, J = 1.8 Hz), 6.27 (t, 1H, J = 2.1 Hz), 3.67 (s,
6H); LCMS: purity: 95%; MS (m/e): 410 (MH+). 353
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-(3-methyl-5- .sup.1H NMR
(DMSO-d6): d 9.47 (s, 1H), 9.31 (s, 1H), 8.15 (d, 1H, J = 3.6 Hz),
+ trifluoromethylphenyl)-2,4-pyrimidinediamine 7.86 (s, 1H), 7.79
(s, 1H), 6.98 (m, 3H), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.27
(s, 3H); LCMS: putity: 96%; MS (m/e): 423 (MH+). 354
N2-(3,5-Dichlorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5- .sup.1H NMR
(DMSO-d6): d 9.56 (s, 1H), 9.28 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz),
+ fluoro-2,4-pyrimidinediamine 7.76 (d, 2H, J = 1.8 Hz), 7.18 (d,
1H, J = 2.4 Hz), 7.13 (dd, 1H, J = 3.6 and 9 Hz), 6.98 (t, 1H, J =
1.8 Hz), 6.82 (d, 1H, J = 8.7 Hz), 4.21 (bs, 4H); LCMS: purity:
81%; MS (m/e): 407 (M 355
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.53 (s, 1H), 9.33 (d, 1H, J = 1.5 Hz), 8.16 (d, +
trifluoromethylphenyl)-2,4-pyrimidinediamine 1H, J = 3.6 Hz), 7.65
(d, 1H, J = 2.1 Hz), 6.98 (d, 2H, J = 2.1 Hz), 6.72 (bs, 1H), 6.22
(t, 1H, J = 2.4 Hz), 3.72 (s, 3H), 3.69 (s, 6H); LCMS: purity: 96%;
MS (m/e): 439 (MH+). 356
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.47 (s, 1H), 9.23 (s, 1H), 8.09 (d, 1H, J = 3.9 Hz),
+ trifluoromethylphenyl)-2,4-pyrimidinediamine 7.67 (s, 1H), 7.59
(s, 1H), 7.27 (d, 1H, J = 2.7 Hz), 7.18 (dd, 1H, J = 2.4 and 8.4
Hz), 6.78 (d, 1H, J = 8.7 Hz), 6.78 (s, 1H), 4.21, bs, 4H), 3.72
(s, 3H); LCMS: purity: 90%; MS (m/e) 357
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[3,4- .sup.1H NMR (DMSO-d6): d
9.64 (s, 1H), 9.29 (s, 1H), 8.15 (m, 2H), + +
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 7.62 (dd,
1H, J = 2.4 and 9 Hz), 7.39 (d, 1H, J = 8.7 Hz), 6.90 (d, 2H, J =
2.4 Hz), 6.09 (t, 1H, J = 1.8 Hz), 3.66 (s, 6H); LCMS: purity: 97%;
MS (m/e): 471 (MH+) 358
N2-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-[3,4- .sup.1H NMR
(DMSO-d6): d 9.90 (bs, 1H), 9.56 (bs, 1H), 8.21 (bd, 1H, J = 3.6
Hz), - (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.06
(bs, 1H), 7.57 (dd, 1H, J = 2.4 and 9.0 Hz), 7.43 (d, 1H, J = 9.3
Hz), 7.39 (s, 2H), 7.06 (bs, 1H), .25 (s, 6H); LCMS: purity: 97%;
MS (m/e): 473 (MH+).
359 N2-[3,5-Bis(hydroxymethylene)phenyl]-5-fluoro-N4-[3,4- .sup.1H
NMR (DMSO-d6): d 9.60 (s, 1H), 9.32 (s, 1H), 8.16 (d, 2H, J = 3.6
Hz), + (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 7.70
(dd, 1H, J = 2.7 and 9 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J = 9.0 Hz),
6.88 (bs, 1H), 5.11 (t, 2H, J = 5.4 Hz), 4.42 (d, 4H, J = 5.4 Hz);
LCMS: purity: 98%; MS (m/e): 471 (MH+). 360
N2-(3,5-Dichlorophenyl)-5-fluoro-N4-[3,4- .sup.1H NMR (DMSO-d6): d
9.76 (s, 1H), 9.72 (s, 1H), 8.25 (d, 1H, J = 3.6 Hz), -
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.00 (d,
1H, J = 2.4 Hz), 7.74 (d, 2H, J = 1.8 Hz), 7.58 (dd, 1H, J = 2.4
and 9.0 Hz), 7.44 (d, 1H, J = 9.0 Hz), 7.04 (t, 1H, J = 1.8 Hz);
LCMS: purity: 98%; MS (m/e): 480 (MH+). 361
5-Fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-[3,4- .sup.1H
NMR (DMSO-d6): d 9.72 (s, 1H), 9.64 (s, 1H), 8.23 (d, 1H, J = 3.6
Hz), + (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.07
(d, 1H, J = 2.4 Hz), 7.67 (bs, 1H), 7.60 (dd, 1H, J = 2.4 and 9.3
Hz), 7.54 (bs, 1H), 7.39 (d, 1H, J = 9 Hz), 6.75 (bs, 1H), 3.75 (s,
3H); LCMS: purity: 97%: MS (m/e): 509 (MH+) 362
N2-(3,5-Dimethyphenyl)-5-fluoro-N4-[3,4- .sup.1H NMR (DMSO-d6): d
9.60 (s, 1H), 9.19 (s, 1H), 8.15 (d, 1H, J = 3.6 Hz), + -
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.12 (d,
1H, J = 2.4 Hz), 7.60 (dd, 2.4 and 8.7 Hz), 7.40 (d, 1H, J = 9 Hz),
7.22 (s, 2H), 6.56 (s, 1H), 2.18 (s, 6H); LCMS: purity: 100%; MS
(m/e): 439 (MH+). 363
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3,4- .sup.1H NMR
(DMSO-d6): d 9.53 (s, 1H), 9.27 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz),
+ (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 7.93 (d,
1H, J = 2.4 Hz), 7.37 (dd, 1H, J = 2.4 and 9.3 Hz), 7.26 (d, 1H, J
= 9 Hz), 7.11 (dd, 1H, J = 2.4 and 8.7 Hz), 6.80 (d, 1H, J = 8.4
Hz), 4.22 (s, 4H); LCMS: purity: 96%; MS (m/e) 364
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3,4- .sup.1H NMR (DMSO-d6): d
9.59 (s, 1H), 9.37 (d, 1H, J = 0.9 Hz), 8.14 (d, +
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 1H, J = 2.4
Hz), 7.38 (dd, 1H, J = 2.7 and 9.3 Hz), 7.27 (d, 1H, J = 9.0 Hz),
6.91 (d, 2H, J = 2.4 Hz), 6.26 (t, 1H, J = 2.4 Hz), 3.69 (s, 6H);
LCMS: purity: 96%; MS (m/e): 471 (MH+). 365
5-Fluoro-N2-[2-(N-methylamino)carbonylindol-7-yl]-N4-[3,4- .sup.1H
NMR (DMSO-d6): d 11.59 (s, 1H), 9.66 (s, 1H), 9.34 (s, 1H), +
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.46 (d,
1H, J = 4.8 Hz), 8.20 (d, 1H, J = 3.6 Hz), 8.10 (d, 1H, J = 2.4
Hz), 7.91 (d, 1H, J = 7.2 Hz), 7.60 (dd, 1H, J = 2.7 and 9 Hz),
7.39 (d, 1H, J = 9.0 Hz), 7.24 (d, 1H, J = 7.5 Hz), 7.06 (d, 1 366
5-Fluoro-N2-(3-methyl-5-trifluoromethyl)-N4-[3,4- .sup.1H NMR
(DMSO-d6): d 9.70 (s, 1H), 9.60 (s, 1H), 8.22 (d, 1H, J = 2.4 Hz),
+ (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.07 (d,
1H, J = 2.4 Hz), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (dd, 1H, J = 2.1
and 9 Hz), 7.41 (d, 1H, J = 9 Hz), 7.04 (s, 1H), 2.31 (s, 3H);
LCMS: purity: 100%; MS (m/e): 493 (MH+). 367
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3,4- .sup.1H NMR
(DMSO-d6): d 9.48 (s, 1H), 9.12 (s, 1H), 8.11 (d, 2H, J = 3.6 Hz),
+ + (tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 7.59
(dd, 1H, J = 2.4 and 9 Hz), 7.39 (d, 1H, J = 9.3 Hz), 7.22 (d, 1H,
J = 2.4 Hz), 6.99 (dd, 1H, J = 2.4 and 8.7 Hz), 6.70 (d, 1H, J = 9
Hz); LCMS: purity: 96%; MS (m/e): 469 (MH+). 368
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[2-(N- .sup.1H NMR (DMSO-d6):
d 11.70 (s, 1H), 9.31 (s, 1H), 9.28 (s, 1H), + +
methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.43 (d, 1H,
J = 4.8 Hz), 8.14 (d, 1H, J = 4.8 Hz), 8.04 (dd, 1H, J = 0.9 and
8.4 Hz), 7.19 (d, 1H, J = 7.5 Hz), 7.03 (d, 1H, J = 2H, J = 2.4
Hz), 6.89 (t, 1H, J = 8.4 Hz), 6.24 (t, 1H, J = 2.4 Hz), 369
N2-(3-Chloro-5-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.57 (s, 1H), 9.35 (s, 1H), 9.27 (s, 1H), +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.10 (d, 1H, J
= 3.6 Hz), 7.47 (m, 1H), 7.25 (dd, 1H, J = 2.7 and 8.7 Hz), 7.16
(d, 2H, J = 2.1 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 1.8
Hz), 3.66 (s, 3H), 1.40 (s, 6H); LCMS: purity: 10 370
N2-(3-Chloro-5-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)- .sup.1H
NMR (DMSO-d6): d 9.31 (s, 1H), 9.21 (s, 1H), 8.08 (d, 1H, J = 3.9
Hz), + 5-fluoro-2,4-pyrimidinediamine 7.48 (t, 1H, J = 1.8 Hz),
7.20 (m, 3H), 6.80 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 2.4 Hz),
4.21 (s, 4H), 3.67 (s, 3H); LCMS: purity: 95%; MS (m/e): 403 (MH+).
371 5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2-[2-(N- .sup.1H NMR
(DMSO-d6): d 11.27 (s, 1H), 9.25 (s, 2H), 8.43 (d, 1H, J = 4.5 Hz),
+ methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.09 (d,
1H, J = 3.9 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 2.1
Hz), 7.6 (m, 2H), 7.04 (d, 1H, J = 1.8 Hz), 6.92 (t, 1H, J = 7.8
Hz), 6.84 (d, 1H, J = 8.1 Hz), 6.01 (s, 2H), 2.81 372
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3,4- .sup.1H NMR (DMSO-d6): d
9.20 (s, 1H), 9.10 (s, 1H), 8.05 (d, 1H, J = 3.6 Hz), +
methylenedioxyphenyl)-2,4-pyrimidinediamine 7.44 (d, 1H, J = 2.1
Hz), 7.16 (dd, 1H, J = 2.1 and 8.4 Hz), 6.93 (d, 2H, J = 2.4 Hz),
6.84 (d, 1H, J = 8.4 Hz), 6.04 (t, 1H, J = 2.1 Hz), 5.99 (s, 2H),
3.64 (s, 6H); LCMS: purity: 89%; M 373
5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2-(3-methoxy-5- .sup.1H NMR
(DMSO-d6): d 9.49 (s, 1H), 9.30 (s, 1H), 8.10 (d, 1H, J = 3.6 Hz),
+ trifluoromethylphenyl)-2,4-pyrimidinediamine 9.67 (bs, 1H), 7.58
(bs, 1H), 7.40 (d, 1H, J = 1.8 Hz), 7.11 (dd, 1H, J = 1.8 and 8.4
Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.70 (bs, 1H), 6.99 (s, 2H), 3.73
(s, 3H); LCMS: purity: 97%; MS (m/ 374
5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2-(3-methyl-5- .sup.1H NMR
(DMSO-d6): d 9.46 (s, 1H), 9.29 (s, 1H), 8.10 (d, 1H, J = 3.6 Hz),
- trifluoromethylphenyl)-2,4-pyrimidinediamine 7.78 (bs, 1H), 7.39
(d, 1H, J = 2.1 Hz), 7.10 (1H, J = 2.4 and 8.4 Hz), 6.99 (bs, 1H),
6.85 (d, 1H, J = 8.4 Hz), 5.99 (s, 2H), 2.28 (s, 3H); LCMS: purity:
99%; MS (m/e): 407 (MH+). 375
N2-(3,5-Dichlorophenyl)-5-fluoro-N4-(3,4- .sup.1H NMR (DMSO-d6): d
9.59 (s, 1H), 9.36 (s, 1H), 8.12 (d, 1H, J = 3.9 Hz), +
methylenedioxyphenyl)-2,4-pyrimidinediamine 7.74 (d, 2H, J = 2.1
Hz), 7.30 (d, 1H, J = 2.1 Hz), 7.06 (dd, 1H, J = 2.4 and 8.4 Hz),
6.97 (t, 1H, 2.1 Hz), 6.88 (d, 1H, J = 8.4 Hz); 6.00 (s, 2H); LCMS:
purity: 94%; MS (m/e): 393 (M+ 376
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(3,4- .sup.1H NMR (DMSO-d6): d
9.18 (bs, 1H), 9.03 (s, 1H), 8.04 (d, 1H, J = 3.9 Hz), +
methylenedioxyphenyl)-2,4-pyrimidinediamine 7.43 (d, 1H, J = 2.1
Hz), 7.24 (s, 2H), 7.11 (dd, 1H, J = 2.1 and 8.4 Hz), 6.85 (d, 1H,
J = 8.4 Hz), 6.50 (bs, 1H), 5.98 (s, 2H), 2.16 (s, 6H); LCMS:
purity: 87%; MS (m/e): 353 (MH+). 377
N2-(4-Chloro-2,5-dimethoxyphenyl)-N4-(3-chloro-4- LCMS: purity:
100%; MS (m/e): 439 (M+). +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 378
N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.63 (s, 1H), 10.05 (s, 1H), 9.62 (s, 1H), +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- 8.15 (d,
1H, J = 4.8 Hz), 7.66 (bs, 1H), 7.44 (dd, 2H, J = 1.8 and 8.7 Hz),
Toluene Sulfonic Acid Salt 7.35 (bd, 1H, J = 9 Hz), 7.20 (dd, 1H, J
= 2.1 and 8.7 Hz), 7.10 (bd, 2H, J = 7.5 Hz), 7.02 (d, 1H, J = 9
Hz), 6.89 (d, 1 379 N2-(4-Chloro-2,5-dimethoxyphenyl)-N4-(3,4-
.sup.1H NMR (DMSO-d6): d 9.24 (s, 1H), 8.05 (d, 1H, J = 3.9 Hz),
7.87 (s, + ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H),
7.70 (s, 1H), 7.17 (d, 1H, J = 2.4 Hz), 7.06 (m, 2H), 6.74 (d, 1H,
J = 8.7 Hz), 4.21 (s, 4H), 3.79 (s, 3H), 3.54 (s, 3H); LCMS:
purity: 100%; MS (m/e): 433 (MH+). 380
N2-(4-Chloro-2,5-dimethoxyphenyl)-N4-(3,5- LCMS: purity: 100%; MS
(m/e): 435 (MH+). + dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine
381 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-(2- .sup.1H NMR (DMSO-d6):
d 9.36 (s, 1H), 8.25 (d, 1H, J = 1.8 Hz), 8.11 (d, + +
methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine 1H, J = 3.9
Hz), 7.57 (m, 3H), 6.99 (m, 2H), 6.26 (t, 1H, J = 2.1 Hz), 3.88 (s,
3H), 3.69 (s, 6H); LCMS: purity: 92%; MS (m/e): 439 (MH+). 382
N2-(2-Carboxybenzofuran-5-yl)-N4-(3,5-dimethoxyphenyl)-5- LCMS:
purity: 91%; MS (m/e): 425 (MH+). - - fluoro-2,4-pyrimidinediamine
383 N2-(2-Carboxyindol-7-yl)-N4-(3,5-dimethoxyphenyl)-5-fluoro- 1H
NMR (DMSO-d6): d 11.85 (s, 1H), 9.31 (s, 1H), 9.26 (s, 1H), +
2,4-pyrimidinediamine 8.16 (d, 1H, J = 3.6 Hz), 8.12 (d, 1H, J =
8.1 Hz), 7.22 (d, 1H, J = 8.1 Hz), 7.02 (d, 2H, J = 2.1 Hz), 6.91
(t, 1H, J = 7.8 Hz), 6.25 (s, 1H)3.70 (bs, 6H); LCMS: purity: 80%;
MS: 424 (MH+) 384
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethyl-N-
.sup.1H NMR (DMSO-d6): d 11.52 (s, 1H), 9.30 (bs, 1H), 9.27 (s,
1H), + + + methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine
8.14 (d, 1H, J = 3.6 Hz), 8.04 (m, 1H), 7.22 (d, 1H, J = 8.4 Hz),
7.03 (m, 2H), 6.90 9m, 2H), 6.23 9bs, 1H), 3.68 (s, 6H), 3.64 (bs,
4H), 3.20 (s, 3H); LCMS: purity: 94%; MS (m/e): 481 (MH+). 385
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3-(N- 1H NMR
(CDCl3): d 7.50 (bs, 1H), 7.30 (m, 2H), 6.91 (bd, 1H, J = 7.2 Hz),
+ + - methylamino)carbonylmethyleneoxyphenyl]-2,4- 6.73 (m, 5H),
4.49 (s, 2H), 4.31 (s, 4H), 3.60 (s, 3H), 2.92 (d, 3H,
pyrimidinediamine J = 4.5 Hz); :CMS: purity: 97%, MS (m/e): 440
(MH+) 386 N4-(3,4-Ethylenedioxyphenyl)-N2-(3,5-dimethoxyphenyl)-5-
1H NMR (CDCl3): d 7.94 (d, 1H, J = 5.1 Hz), 7.50 (bd, 1H), 6.90 (d,
+ + - fluoro-N4-methyl-2,4-pyrimidinediamine 1H, J = 9 Hz), 6.83
(s, 1H), 6.73 (m, 3H), 6.62 (d. 1H, 2.4 Hz), 4.31 (m, 4H), 3.80 (s,
3H), 3.79 (s, 3H), 3.60 (s, 3H); LCMS: purity: 90%, MS: 413 (MH+).
387 N2-(3,5-Dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5- 1H NMR
(CDCl3): d 7.50 (bd, 1H), 7.40 (s, 1H), 7.27 (m, 1H), + -
fluoro-N4-methyl-2,4-pyrimidinediamine 6.90 (bdd, 1H), 6.81 (m,
1H), 6.77 (d, 2H, J = 2.4 Hz), 6.70 (dd, 1H, J = 2.7 and 8.7 Hz),
4.30 (s, 4H), 3.50 (s, 3H), 2.32 (s, 6H); LCMS: purity: 94%, MS
(m/e): 381 (MH+). 388
N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- 1H NMR
(DMSO-d6): d 10.60 (s, 1H), 9.21 (s, 1H), 7.94 (d, 1H, J = 6.0 Hz),
- - benz[1,4]oxazin-6-yl)-5-fluoro-N4-methyl-2,4- 7.01 (d, 2H, J =
1.2 Hz), 6.88 (m, 2H), 6.75 (d, 1H, J = 2.4 Hz), pyrimidinediamine
6.05 (t, 1H, J = 2.4 Hz), 3.60 (s, 6H), 3.41 (s, 3H), 1.34 (s, 6H);
LCMS: purity: 92%, MS (m/e): 454 (MH+). 389
N4-(3,5-Dimethoxyphenyl)-N2-[2-(N-1,1-dimethyl-2- .sup.1H NMR
(DMSO-d6): d 11.63 (s, 1H), 9.25 (d, 1H, J = 7.8 Hz), 8.14 (d, + -
hydroxyethylamino)carbonylindol-7-yl]-5-fluoro-2,4- 1H, J = 3.6
Hz), 8.02 (d, 1H, J = 8.1 Hz), 7.53 (s, 1H), 7.19 (d, 1H, J = 7.5
Hz), pyrimidinediamine 7.14 (s, 1H), 7.04 (s, 2H), 6.89 (t, 1H, J =
7.5 Hz), 6.23 (s, 1H), 4.94 (t, 1H, J = 6.3 Hz), 3.69 (s, 6H), 390
2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-methyl-4- .sup.1H
NMR (CDCl3): d 7.85 (d, 1H, J = 4.8 Hz), 6.86 (d, 1H, J = 8.4 Hz),
- - - pyrimidineamine 6.73 (d, 1H, J = 2.7 Hz), 6.60 (dd, 1H, J =
2.7 and 8.1 Hz); LCMS: purity: 100%, MS (m/e): 296 (M+). 391
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-methyl-N4-(3-oxo-2,2,4- 1H NMR
(CDCl3): d 7.95 (d, 1H, J = 6.4 Hz), 7.67 (bs, 1H), 7.21 (s, + +
trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H), 6.96 (s,
1H), 6.87 (dd, 1H, J = 2.4 and 8.7 Hz), 6.78 (d, 1H, J = 2.4 Hz),
6.72 (s, 1H), 3.55 (s, 3H), 3.32 (s, 3H), 2.30 (s, 6H), 1.53 (s,
6H); LCMS: purity: 92%, MS (m/e): 436 (MH+). 392
N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-methyl-N4-(3-oxo- 1H NMR
(CD3OD): d 7.77 (d, 1H, J = 2.4 Hz), 7.75 (bd, 1H), 7.34 (dd, + +
2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J =
2.7 and 9.3 Hz), 7.05 (d, 1H, J = 1.8 Hz), 6.95 (m, 3H), 4.62 (s,
3H), 3.83 (s, 3H), 3.51 (s, 3H), 1.48 (s, 6H); LCMS: purity: 94%,
MS (m/e): 472 (M+). 393
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N4-(3-oxo- 1H NMR
(CD3OD): d 7.78 (d, 1H, J = 8.4 Hz), 7.07 (bs, 1H), 6.96 (bs, + +
2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H),
6.87 (d, 2H, J = 2.4 Hz), 6.10 (t, 1H, J = 2.4 Hz), 3.70 (s, 6H),
3.54 (s, 3H), 3.32 (s, 3H), 1.48 (s, 6H); LCMS: purity: 97%, MS
(m/e): 468 (MH+). 394
N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H- LCMS:
purity: 93%, MS (m/e): 351 (MH+). + +
benz[1,4]oxazin-6-yl)-5-fluoro-N4-methyl-2,4- pyrimidinediamine 395
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2- 1H NMR (DMSO-d6): d
7.95 (s, 1H), 7.76 (bd, 1H), 7.54 (s, 1H), + + +
methoxycarbonyl-benzofuran-5-yl)-N4-methyl-2,4- 7.49 (bd, 2H), 6.87
(d, 1H, J = 8.4 Hz), 6.79 (dd, 1H, J = 2.4 and 6.6 Hz),
pyrimidinediamine 6.74 (bd, 1H); LCMS: purity: 94%, MS (m/e): 452
(MH+). 396 N2-(3,5-Dimethylphenyl)-N4-(3-oxo-2,2,4- LCMS: purity:
90%; MS (m/e): 422 (MH+). + + +
trimethylbenz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 397
N2-(3,5-Dimethoxyphenyl)-N4-(3-oxo-2,2,4- LCMS: purity: 94%; MS
(m/e): 454 (MH+). + + +
trimethylbenz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 398
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(N- LCMS: purity:
94%, MS (m/e): 442 (MH+). + -
methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 399
N4-(3,5-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- LCMS:
purity: 92%, MS (m/e): 382 (MH+). + + - +
N4-methyl-2,4-pyrimidinediamine 400
N2,N4-Bis(3,5-dimethoxyphenyl)-5-fluoro-N4-methyl-2,4- 1H NMR
(DMSO-d6): d 9.23 (s, 1H), 7.97 (d, 1H, J = 5.1 Hz), 7.01 (d, + -
pyrimidinediamine 2H, J = 1.8 Hz), 6.45 (d, 2H, J = 1.2 Hz), 6.34
(bt, 1H), 6.05 (bt, 1H), 3.72 (s, 6H), 3.68 (6H), 3.45 (s, 3H);
LCMS: purity: 95%, MS (m/e): 415 (MH+). 401
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl- 1H NMR
(DMSO): d 9.70 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J = 3.8 Hz), + +
benzofuran-5-yl)-N4-methyl-2,4-pyrimidinediamine 7.69 (s, 1H), 7.62
(m, 2H), 6.51 (d, 2H, J = 1.5 Hz), 6.44 (bt, 1H); 3.88 (s, 3H),
3.72 (s, 6H), 3.46 (s, 3H); LCMS: MS (m/e): 453 (MH+), purity: 95%.
402 N4-[3-Chloro-4-(methoxycarbonyl-1,1- LCMS: purity: 81%; MS
(m/e): 459 (MH+) +
dimethylmethyleneoxy)phenyl]-N2-(3,5-dimethylphenyl)-5-
fluoro-2,4-pyrimidinediamine 403
N2-(3,5-Dimethylphenyl)-N4-[4-(methoxycarbonyl-1,1- LCMS: purity:
80%;
MS (m/e): 425 (MH+). +
dimethylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 404
N2-(3-Chloro-4-methoxyphenyl)-N4-(3,5-dimethoxyphenyl)-5- 1H NMR
(DMSO-d6): d 10.00 (s, 1H), 8.08 (d, 1H, J = 6.00 Hz), - -
fluoro-N4-methyl-2,4-pyrimidinediamine 7.89 (d, 1H, J = 5.1 Hz),
7.47 (dd, 1H, J = 2.7 and 9.3 Hz), 7.08 (d, 1H, J = 9.0 Hz), 6.53
(d, 2H, J = 1.8 Hz), 6.46 (t, 1H, J = 2.1 Hz); LCMS: purity: 92%,
419 (MH+). 405
N2-(4-Chloro-3-methoxyphenyl)-N4-(3,5-dimethoxyphenyl)-5- 1H NMR
(DMSO-d6): d 9.30 (s, 1H), 9.03 (s, 1H), 8.07 (d, 1H, J = 4.2 Hz),
+ - fluoro-N4-methyl-2,4-pyrimidinediamine 7.48 (d, 1H, J = 2.1
Hz), 7.37 (dd, 1H, J = 2.4 and 8.4 Hz), 7.24 (s, 2H); LCMS: purity:
91%, MS (m/e): 419 (M+). 406
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[2-(N- 1H NMR
(DMSO-d6): d 11.71 (s, 1H), 9.39 (s, 1H), 8.44 (bd, 1H, J = 4.8
Hz), + - methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.02
(m, 2H), 7.20 (d, 1H, J = 7.5 Hz), 7.04 (d, 1H, J = 2.1 Hz), 6.93
(t, 1H, J = 7.8 Hz), 6.47 (d, 2H, J = 2.1 Hz), 6.41 (t, 1H, J = 2.1
Hz), 3.72 (s, 6H), 3.46 (s, 3H), 2.81 (d, 3H, 407
2-Chloro-N4-[3-chloro-4-(ethoxycarbonyl-1,1- 1H NMR (DMSO-d6): d
8.07 (d, 1H, J = 2.7 Hz), 7.69 (m, 1H), 7.45 (m, +
dimethylmethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine 1H), 6.95
(d, 1H, J = 9 Hz), 6.92 (bs, 1H), 4.28 (q, 2H, J = 6.9 Hz), 1.62
(s, 6H), 1.31 (t, 3H, J = 7.2 Hz); LCMS: purity: 85%; MS (m/e): 388
(M+). 408 N4-[3-Chloro-4-(ethoxycarbonyl-1,1- 1H NMR (CD3OD): d
7.91 (d, 1H, J = 3.6 Hz), 7.74 (d, 1H, J = 2.7 Hz), +
dimethylmethyleneoxy)phenyl]-N2-(3,5-dimethoxyphenyl)-5- 7.66 (dd,
1H, J = 2.7 and 8.7 Hz), 6.91 (d, 1H, J = 9 Hz), 6.78 9d, 2H,
fluoro-2,4-pyrimidinediamine J = 2.1 Hz), 6.12 (t, 1H, J = 2.1 Hz),
4.26 (q, 2H, J = 6.9 Hz), 3.71 (s, 6H), 1.59 (s, 6H), 1.29 (t, 3H,
J = 7.2 Hz); LC 409 N4-[3-Chloro-4-(hydroxycarbonyl-1,1- 1H NMR
(DMSO-d6): d 13.15 (bs, 1H), 9.38 (s, 1H), 9.18 (s, 1H), + + -
dimethylmethyleneoxy)phenyl]-N2-(3,5-dimethoxyphenyl)-5- 8.10 (d,
1H, J = 3.9 Hz), 7.93 (s, 1H), 7.84 (dd, 1H, J = 2.7 and 9.3 Hz),
fluoro-2,4-pyrimidinediamine 7.77 (d, 1H, J = 2.7 Hz), 6.91 (m,
3H), 6.07 (t, 1H, J = 2.1 Hz), 3.65 (s, 6H), 1.52 (s, 6H); LCMS:
purity: 90%; MS (m 410 N4-[3-Chloro-4-(ethoxycarbonyl-1,1- 1H NMR
(DMSO-d6): d 9.36 (s, 1H), 9.17 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz),
+ + + dimethylmethyleneoxy)phenyl]-N2-(3-chloro-4- 7.78 (d, 1H, J =
2.7 Hz), 7.75 (d, 1H, J = 2.1 Hz), 7.70 (dd, 1H, J = 3.0
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 9.3 Hz), 7.44
(dd, 1H, J = 2.7 and 9.0 Hz), 6.99 (d, 1H, J = 9.0 Hz), 6.88 (d,
1H, J = 9.0 Hz), 4.20 (q, 2H, 411
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3- LCMS:
purity: 91%, MS (m/e): 420 (MH+). + + -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 412
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR
(DMSO-d6): d 9.61 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), + +
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 9.97 (d, 1H, J = 6.0
Hz), 7.70 (bd, 1H, J = 4.8 Hz), 7.52 (bd, 1H, J = 7.8 Hz), 7.38 (d,
1H, J = 8.1 Hz), 7.33 (s, 1H), 6.79 (m, 3H), 4.24 (s, 4H), 3.44 (s,
3H); LCMS: purity: 92%, MS (m/e): 420 ( 413
N4-(3,4-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- 1H NMR
(DMSO-d6): d 9.15 (s, 1H), 8.97 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz),
+ + - 2,4-pyrimidinediamine 7.24 (m, 4H), 6.88 (d, 1H, J = J = 8.4
Hz), 6.48 (d, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 2.12 (s, 6H); LCMS:
purity: 97%, MS (m/e): 369 (MH+). 414
N2-(3,5-Dimethoxyphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro- 1H NMR
(DMSO-d6): d 9.17 (s, 1H), 9.05 (s, 1H), 8.03 (d, 1H, J = 3.9 Hz),
+ + - 2,4-pyrimidinediamine 7.32 (dd, 2.4 and 8.7 Hz), 7.24 (d, 1H,
J = 2.4 Hz), 6.92 (d, 2H, J = 2.4 Hz), 6.85 (d, 1H, 8.4 Hz), 6.03
(t, 1H, J = 2.1 Hz), 3.73 (s, 3H), 3.66 (s, 3H), 3.60 (s, 6H);
LCMS: purity: 96 415
N4-(3,4-Dimethoxyphenyl)-N2-[2-(ethoxycarbonyl)indol-7-yl]-5- 1H
NMR (DMSO-d6): d 11.89 (s, 1H), 9.25 (s, 1H), 9.21 (s, 1H), + + -
fluoro-2,4-pyrimidinediamine 8.10 (d, 1H, J = 3.9 Hz), 8.87 (s,
1H), 8.73 (m, 3H), 7.11 (d, 1H, J = 2.1 Hz), 6.88 (m, 2H), 4.32 (q,
2H, J = 3.9 Hz), 3.76 (s, 3H), 3.66 (s, 3H), 1.34 (q, t, 3H, J =
3.9 Hz); LCMS: purity: 93%, 416
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR
(DMSO-d6): d 9.59 (s, 1H), 8.05 (s, 1H), 7.96 (d, 1H), J = 5.7 Hz),
+ - (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.80 (bs, 4H), 7.27
(s, 1H), 6.85 (m, 2H), 6.78 (dd, 1H), 4.52 (s, 4H), 3.41 (s, 3H),
3.31 (s, 3H); LCMS: purity: 91%, MS (m/e): 420 (MH+). 417
2-Chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-N4-methyl-4- 1H NMR
(DMSO-d6): d 8.09 (d, 1H, J = 5.4 Hz), 7.02 (d, 1H, J = 2.4 Hz), -
- - - pyrimidineamine 6.93 (d, 1H, J = 8.4 Hz), 6.84 (dd, 1H, J =
2.1 and 8.4 Hz), 3.75 (s, 3H), 3.71 (s, 3H); LCMS: purity: 87%, MS
(m/e): 298 (M+). 418
2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4- LCMS: purity:
99%, MS (m/e): 354 (M+). - -
(methoxycarbonylmethyl)-4-pyrimidineamine 419
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(oxazol-5-yl)phenyl]- 1 H
NMR (DMSO-d6): d 9.29 (s, 1H), 9.21 (s, 1H), 8.33 (s, 1H), + + -
2,4-pyrimidinediamine 8.07 (d, 1H, J = 3.0 Hz), 8.04 (s, 1H), 7.61
(bd, 1H), 7.39 (s, 1H), 7.29 (bdd, 1H, J = 2.7 and 8.4 Hz), 7.25
(m, 3H), 6.76 (d, 1H, J = 8.7 Hz), 3.70 (s, 3H), 3.64 (s, 3H);
LCMS: purity: 98%, MS 420
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indol-6-yl)-N4- 1H NMR
(DMSO-d6): d 10.77 (s, 1H), 9.05 (s, 1H), 7.94 (d, 1H, J = 5.7 Hz),
+ - (methoxycarbonylmethyl)-2,4-pyrimidinediamine 7.70 (s, 1H),
7.32 (d, 1H, J = 2.8 Hz), 7.19 (d, 1H, J = 1.5 Hz), 7.17 (t, 1H, J
= 3 Hz), 6.82 (m, 3H), 6.28 (d, 1H, J = 2.1 Hz), 4.60 (s, 2H), 4.24
(s, 4H), 3.33 (s, 3H); LCMS: purity: 99 421
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[2-(N- 1H NMR (DMSO-d6): d
11.66 (s, 1H), 9.27 (s, 1H), 9.22 (s, 1H), + -
methylaminocarbonyl)indol-7-yl]-2,4-pyrimidinediamine 8.41 (bd, 1H,
J = 4.8 Hz), 8.09 (d, 1H, J = 3.3 Hz), 7.99 (d, 1H, J = 7.8 Hz),
7.33 (dd, 1H, J = 2.4 and 8.4 Hz), 7.28 (d, 1H, J = 2.7 Hz), 7.18
(d, 1H, J = 7.5 Hz), 7.03 (d, 1H, J = 2.1 Hz), 6.89 (m 422
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[4-(oxazol-5-yl)phenyl]- 1H
NMR (DMSO-d6): d 9.36 (s, 1H), 9.24 (s, 1H), 8.33 (s, 1H), + + -
2,4-pyrimidinediamine 8.07 (d, 1H, J = 3.9 Hz), 7.75 (d, 2H, J =
6.0 Hz), 7.50 (d, 2H, J = 8.7 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.47
(s, 1H), 7.26 (m, 2H), 6.92 (d, 1H, J = 9.6 Hz), 3.76 (s, 3H), 3.69
(s, 3H); LCMS: purity 423
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(oxazol-2-yl)phenyl]- 1H
NMR (DMSO-d6): d 9.36 (s, 1H), 9.22 (s, 1H), 8.29 (s, 1H), 8.12 (s,
+ + - + 2,4-pyrimidinediamine 1H), 8.08 (d, 1H, J = 3 Hz), 7.81
(dd, 1H, J = 1.8 and 7.1 Hz), 7.49 (d, 1H, J = 6.9 Hz), 7.31 (m,
4H), 6.79 (d, 1H, J = 8.7 Hz), 3.71 (s, 3H), 3.67 (s, 3H); LCMS:
purity: 98%, MS (m/e): 40 424
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[4-(oxazol-2-yl)phenyl]- 1H
NMR (DMSO-d6): d 9.50 (s, 1H), 9.28 (s, 1H), 8.09 (s and d, 2H, + -
2,4-pyrimidinediamine J = 4.5 Hz), 7.76 (m, 4H), 7.28 (m, 3H), 6.93
(d, 1H, J = 8.4 Hz), 3.76 (s, 3H), 3.70 (s, 3H); LCMS: purity: 89%,
MS (m/e): 408 (M+). 425
N2-(3-Chloro-4-methoxyphenyl)-N4-(3,4-dimethoxyphenyl)-5- 1H NMR
(DMSO-d6): d 9.17 (s, 1H), 9.08 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz),
+ + - fluoro-2,4-pyrimidinediamine 7.84 (s, 1H, J = 2.7 Hz), 7.41
(dd, 1H, J = 3.0 and 9.3 Hz), 7.27 (dd, 1H, J = 2.4 and 8.7 Hz),
7.21 (d, 1H, J = 2.4 Hz), 6.97 9d, 1H, J = 8.7 Hz), 6.88 (d, 1H, J
= 8.7 Hz), 3.77 (s, 3H), 426
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(3,4- 1H NMR (DMSO-d6): d 9.13
(s, 1H), 8.99 (s, 1H), 8.02 (d, 1H, J = 4.2 Hz), + + -
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.22 (m, 4H),
7.03 (m, 1H), 6.77 (d, 1H, J = 8.7 Hz), 6.50 (bd, 1H, J = 7.2 Hz),
4.21 (bs, 4H), 3.02 (bm, 2H), 2.95 (bm, 2H), 2.02 (s, 3H); LCMS:
purity: 97%, MS (m/e): 465 (MH+). 427
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(3,4- 1H NMR (DMSO-d6): d 9.07
(s, 1H), 8.92 (s, 1H), 7.98 (d, 1H, J = 3.9 Hz), + + -
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.48 (d, J =
8.7 Hz), 7.33 (d, 1H, J = 2.4 Hz), 7.18 (dd, 1H, J = 2.1 and 8.7
Hz), 6.83 (d, 1H, J = 9.3 Hz), 6.73 (d, 1H, J = 1H, J = 8.7 Hz),
4.23 (bs, 4H), 3.56 (bs, 4H), 3.03 (t, 2H, J = 5 428
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(3,5-dimethoxyphenyl)- 1H NMR
(DMSO-d6): d 9.23 (s, 1H), 9.07 (s, 1H), 8.09 (d, 1H, J = 3 Hz), +
- 5-fluoro-2,4-pyrimidinediamine 7.26 (s, 1H), 7.15 (d, 1H, J =
Hz), 7.07 (t, 1H, J = 8.4 Hz), 6.97 (d, 2H, J = 2.4 Hz), 6.50 (bd,
1H, J = 7.5 Hz), 6.18 (d, 1H, J = 2.1 Hz), 5.74 (s, 1H), 3.49 (m,
4H), 3.32 (s, 6H), 2.96 ( 429
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(3,4-dimethoxyphenyl)- 1H NMR
(DMSO-d6): d 9.17 (bs, 1H), 8.99 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz),
+ - 5-fluoro-2,4-pyrimidinediamine 7.27 (m, 2H), 7.01 (bd, 1H, J =
8.4 Hz), 7.00 (t, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.48
(bd, 1H, J = 9.9 Hz), 6.13 (bs, 1H), 3.72 (s, 3H), 3.62 (s, 3H),
3.46 (m, 4H), 2.96 (m, 430
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(3,4-dimethoxyphenyl)- 1H NMR
(DMSO-d6): d 9.11 (s, 1H), 8.88 (s, 1H), 7.98 (d, 1H, J = 3.9 Hz),
+ - 5-fluoro-2,4-pyrimidinediamine 7.46 (d, 2H, J = 9.3 Hz), 7.27
(m, 2H), 6.87 (d, 1H, J = 8.4 Hz), 6.80 (d, 2H, J = 9 Hz), 3.74 (s,
3H), 3.65 (s, 3H), 3.56 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.03
(s, 3H); LCMS: purit 431
N2-[3-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-(3,4- 1H NMR
(DMSO-d6): d 9.62 (s, 1H), 9.19 (s, 1H), 8.14 (m, 1H), + + -
(tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine 7.62 (dd,
1H, J = 2.7 and 9.6 Hz), 7.39 (d, 1H, J = 9 Hz), 7.23 (d, 1H, J = 8
Hz), 7.16 (s, 1H), 7.07 (t, 1H, J = 2.6 Hz), 6.55 (d, 1H, J = 2.6
Hz), 6.12 (s, 1H), 3.54 (bs, 4H), 2.02 (s, 3H); LCMS: 432
N2-[4-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-(3,4- 1H NMR
(DMSO-d6): d 9.57 (s, 1H), 9.11 (s, 1H), 8.15 (bd, 1H), + -
(tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine 8.10 (d, 1H,
J = 3.3 Hz), 7.57 (bdd, 1H, J = 9.6 Hz), 7.45 (d, 2H, J = 8.7 Hz),
7.37 (d, 1H, J = 9 Hz), 6.87 (d, 2H, J = 9.3 Hz), 6.69 (d, 1H, J =
8.7 Hz), 6.47 (d, 1H, J = 8.7 Hz), 3.52 (m, 4H), 2.99 433
N4-(3,4-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- 1H NMR
(DMSO-d6): d 9.05 (s, 1H), 7.89 (d, 1H, J = 6.0 Hz), 7.31 (s, + -
N4-methyl-2,4-pyrimidinediamine 2H), 6.93 (d, 1H, J = 2.7 Hz), 6.90
(s, 1H), 6.81 (dd, 1H, J = 2.4 and 8.1 Hz), 6.50 (s, 1H), 3.75 (s,
3H), 3.71 (s, 1H), 3.42 (s, 3H), 2.18 (s, 6H); LCMS: purity: 95%,
MS (m/e): 383 (MH+). 434
N2-(3,5-Dimethoxyphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro- LCMS:
purity: 96%, MS (m/e): 415 (MH+). + -
N4-methyl-2,4-pyrimidinediamine 435
N4-(3,4-Dimethoxyphenyl)-N2-[2-(ethoxycarbonyl)indol-7-yl]-5- 1H
NMR (DMSO-d6): d 11.94 (s, 1H), 9.32 (s, 1H), 8.15 (d, 1H, J= J =
7.5 Hz), + - fluoro-N4-methyl-2,4-pyrimidinediamine 7.97 (d, 1H, J
= 6.0 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.12 (d, 1H, J = 2.1 Hz), 6.96
(m, 3H), 6.82 (m, 1H), 4.33 (q, 2H, J = 4.2 Hz), 3.76 (s, 3H), 3.72
(s, 3H), 3.46 (s, 3H), 1.35 (t, 436
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(indol-6-yl)-N4-methyl- 1H NMR
(DMSO-d6): d 10.85 (s, 1H), 9.07 (s, 1H), 8.03 (s, 1H), + -
2,4-pyrimidinediamine 7.87 (d, 1H, J = 8.4 Hz), 7.34 (d, 1H, J =
8.7 Hz), 7.16 (m, 2H), 6.93 (m, 2H), 6.90 (s, 1H), 6.80 (m, 1H),
6.28 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H); LCMS:
purity: 94%, MS (m/e): 3 437
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(3,5-dimethoxyphenyl)- LCMS:
purity: 80%, MS (m/e): 467 (MH+). + -
5-fluoro-2,4-pyrimidinediamine 438
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(oxazol- 1 H NMR
(DMSO-d6): d 9.42 (s, 1H), 8.40 (s, 1H), 8.28 (bs, 1H), + + -
5-yl)phenyl]-2,4-pyrimidinediamine 7.93 (d, 1H, J = 8.7 Hz), 7.58
(bd, 1H, J = 6.8 Hz), 7.55 (s, 1H), 7.27 (m, 2H), 6.96 (d, 1H, J =
2.4 Hz), 6.92 (m, 1H), 6.81 (dd, 1H, J = 2.1 and 8.4 Hz), 3.75 (s,
3H), 3.75 2 (s, 3H), 3.47 (s, 439
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(oxazol- 1H NMR
(DMSO-d6): d 9.50 (s, 1H), 8.62 (d, 1H, J = 3.6 Hz), 8.17 (s, + + -
- 2-yl)phenyl]-2,4-pyrimidinediamine 1H), 7.94 (d, 1H, J = 6.0 Hz),
7.70 (dd, 1H, J = 2.4 Hz), 7.33 (m, 2H), 6.97 (d, 1H, J = 2.4 Hz),
6.92 (d, 1H, J = 8.4 Hz), 6.82 (dd, 1H, J = 2.4 and 8.7 Hz), 3.76
(s, 3H), 3.73 (s, 3H), 3.48 440
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[4-(oxazol- 1H NMR
(DMSO-d6): d 9.59 (s, 1H), 8.10 (s, 1H), 7.98 (m, 2H), + -
2-yl)phenyl]-2,4-pyrimidinediamine 7.62 (dd, 1H, J = 2.1 and 6.6
Hz), 7.27 (s, 1H), 6.96 (m, 2H), 6.92 (s, 1H), 6.81 (dd, 2.4 and
8.4 Hz), 6.61 (dd, 1H, J = 2.1 and 6.6 Hz), 5.67 (bs, 1H), 3.77 (s,
3H), 3.72 (s, 3H), 3.45 (s, 3H). 441
N2-(3,5-Dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5- LCMS:
purity: 91%, MS 9m/e): 439 (MH+). + -
fluoro-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine 442
N2-(3,5-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5- 1H NMR
(DMSO-d6): d 9.14 (s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 6.84 (m, + -
fluoro-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine 5H), 6.07
(m, 1H), 4.62 (s, 2H), 4.24 (s, 3H), 3.68 (bs, 4H), 3.34 (s, 6H);
LCMS: purity: 94%, MS: 471 (MH+). 443
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.40
(s, 1H), 8.40 (s, 1H), 8.00 (d, 1H, J= J = 4.2 Hz), + -
(methoxycarbonylmethyl)-N2-[3-(oxazol-5-yl)phenyl]-2,4- 7.93 (bs,
1H), 7.60 (m, 1H), 7.57 (s, 1H), 7.27 (m, 2H), pyrimidinediamine
6.83 (m, 3H), 4.63 (s, 2H), 4.23 (s, 4H), 3.51 (s, 3H); LCMS:
purity: 95%, MS (m/e): 478 (MH+). 444
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.49
(s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), + -
(methoxycarbonylmethyl)-N2-[3-(oxazol-2-yl)phenyl]-2,4- 8.00 (d,
1H, J = 5.7 Hz), 7.76 (bd, 1H, J = 9.6 Hz), 7.51 (bd, 1H, J = 8.1
Hz), pyrimidinediamine 7.34 (m, 2H), 6.86 (m, 1H), 6.83 (m, 1H),
4.64 (s, 2H), 4.24 (s, 4H), 3.54 (s, 3H); LCMS: purity: 91%, MS
(m/e): 478 445 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 9.61 (s, 1H), 8.10 (s, 1H), 8.05 (d, 1H, J = 8.1 Hz),
+ - (methoxycarbonylmethyl)-N2-[4-(oxazol-2-yl)phenyl]-2,4- 7.77
(dd, 2H, J = 8.4 Hz), 7.70 (dd, 2H, J = 8.4 Hz), 7.29 (s, 1H),
pyrimidinediamine 6.85 (m, 3H), 4.64 (s, 2H), 4.25 (s, 4H), 3.63
(s, 3H); LCMS: purity: 92%, MS (m/e): 478 (MH+). 446
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.24
(s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 7.94 (m, + -
(methoxycarbonylmethyl)-N2-[3-(N- 1H), 7.22 (m, 2H), 7.08 (t, 1H, J
= 7.8 Hz), 6.83 (m, 3H), 6.49 (m, 1H),
methylamino)carbonylmethyleneoxyphenyl]-2,4- 4.62 (s, 2H), 4.39 (s,
2H), 4.24 (s, 4H), 3.60 (s, 3H), 2.66 (d, 3H, J = 5.1 Hz);
pyrimidinediamine LCMS: purity: 97%, MS (498 (MH+). 447
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(N- 1H NMR
(DMSO-d6): d 9.24 (s, 1H), 7.94 (bs, 1H), 7.90 (d, 1H, J = 5.7 Hz),
+ - methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.46 (t, 1H, J =
2.1 Hz), 7.27 (bd, 1H, J = 9 Hz), 7.10 (t, 1H, J = 5.1 Hz),
pyrimidinediamine 6.93 (m, 1H), 6.79 (dd, 1H, J = 2.7 and 8.7 Hz),
6.45 (dd, 1H, J = 1.8 and 8.1 Hz), 6.12 (m, 1H), 4.38 (s, 2 448
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.37 (s, 1H), 9.18 (s, 1H), 8.21 (d, 1H, J = 4.5 Hz),
+ + - ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.05 (d,
1H, J = 3.6 Hz), 7.72 (m, 2H), 7.22 (m, 2H), 7.20 (m, 3H), 6.80
(bdd, 1H, J = 2.1 and 9 Hz), 4.11 (bs, 4H), 2.71 (d, 3H, J = 4.5
Hz); LCMS: purity: 95%; MS (m/e): 430 (MH+). 449
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 8.20 (d, 1H), 8.05 (d, 1H, J = 3.9 Hz), 7.75 (d, + -
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H, J = 2.7 Hz),
7.66 (dd, 1H, J = 3.0 and 8.7 Hz), 7.32 (dd, 1H, J = 2.4 and 9.0
Hz), 7.23 (s, 1H), 7.18 (m, 1H), 6.88 (d, 1H, J = 8.7 Hz), 4.00 (s,
4H), 3.76 (s, 3H), 3.71 (s, 3H), 2.69 (d, 450
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(3,5- 1H NMR
(DMSO-d6): d 8.15 (d, 1H, J = 4.2 Hz), 7.82 (dd, 1H, J = 2.7 + -
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 9.0 Hz), 7.61
(d, 1H, J = 2.7 Hz), 7.25 (d, 1H, J = 9.0 Hz), 6.96 (t, 2H, J = 2.4
Hz), 6.26 (t, 1H, J = 2.1 Hz), 3.71 (s, 6H), 2.71 (d, 3H, 3.3 Hz);
LCMS: purity: 87%, MS (m/e): 432 (M+). 451
N4-(3-Chloro-4-methoxyphenyl)-N2-[4-chloro-3-(N- 1H NMR (DMSO-d6):
d 8.16 (d, 1H, J = 3.9 Hz), 7.70 (d, 1H, J = 2.7 Hz), + +
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 7.64 (m,
2H), 7.30 (d, 1H, J = 9.3 Hz), 7.10 (d, 1H, J = 9 Hz), 3.87 (s,
3H), 2.69 (s, 3H); LCMS: purity: 91%, MS (m/e): 536 (M+). 452
N4-[3-Chloro-4-(ethoxycarbonyl-1,1- 1H NMR (DMSO-d6): d 9.65 (bs,
2H), 8.26 (d, 1H, J = 4.8 Hz), 8.17 (s, + +
dimethylmethyleneoxy)phenyl]-N2-[4-chloro-3-(N- 1H), 7.80-7.58 (m,
4H), 7.27 (d, 1H, J = 8.7 Hz), 6.89 (d, 1H, J = 9 Hz),
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 4.20 (q,
2H, J = 6.9 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.54 (s, 6H), 1.21 (t,
3H, J = 7.2 Hz); LCMS: purity: 91%, MS (m/ 453
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.69 (s, 1H), 8.28 (d, 1H, J = 4.5 Hz), 7.98 (d, + -
ethylenedioxyphenyl)-5-fluoro-N4-methyl-4-pyrimidinediamine 1H, J =
6.0 Hz), 7.83 (d, 1H, J = 2.4 Hz), 7.66 (dd, 1H, J = 2.7 and 8.7
Hz), 7.29 (d, 1H, J = 9 Hz), 6.84 (m, 2H), 6.76 (dd, 1H, 2.7 and
8.7 Hz), 4.24 (s, 4H), 3.38 (s, 1H), 2.72 (d, 3H, J= 454
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.50 (s, 1H), 8.26 (d, 1H, J = 4.5 Hz), 7.93 (d, + -
dimethoxyphenyl)-5-fluoro-N4-methyl-4-pyrimidinediamine 1H, 6.0
Hz), 7.87 (d, 1H, J = 2.7 Hz), 7.68 (dd, 1H, J = 2.4 and 5.7 Hz),
7.26 (d, 1H, J = 8.7 Hz), 6.93 (m, 2H), 6.80 (dd, 1H, J = 2.4 and
8.4 Hz), 3.76 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 455
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(2,2- 1H NMR
(DMSO-d6): d 10.71 (s, 1H), 9.87 (s, 1H), 8.26 (d, 1H, J = 4.2 Hz),
+ + - dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.16
(d, 1H, J = 4.2 Hz), 7.63 (m, 2H), 7.25 (m, 2H), 7.17 (d, 1H,
pyrimidinediamine J = 2.1 Hz), 6.90 (d, 1H, J = 8.7 Hz), 2.71 (d,
3H, J = 4.5 Hz), 1.40 (s, 6H); LCMS: purity: 97%, MS (m/e): 471
(M+). 456 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(2,2- 1H
NMR (DMSO-d6): d 10.74 (s, 1H), 10.34 (s, 1H), 10.09 (s, 1H), + + +
dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.24 (d, 1H,
J = 4.8 Hz), 8.15 (d, 1H, J = 4.5 Hz), 7.83 (d, 1H, J = 1.5 Hz),
pyrimidinediamine 7.44 (dd, 1H, J = 1.8 and 8.4 Hz), 7.23 (m, 2H),
6.93 (d, 1H, J = 8.4 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.40 (s, 6H);
LCM 457 N2-(2,6-Dimethoxypyrid-3-yl)-N4-(3,5-dimethoxyphenyl)-5- 1H
NMR (DMSO-d6): d 8.02 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 6.4
Hz), + + + fluoro-N4-methyl-2,4-pyrimidinediamine 7.76 (s, 1H),
6.41 (m, 3H), 6.32 (d, 1H, J= J = 8.4 Hz), 3.89 (s, 3H), 3.82 (s,
3H), 3.71 (s, 3H), 3.34 (s, 3H); LCMS: purity: 95%, MS (m/e): 416
(MH+). 458
N2-(2,6-Dimethoxypyrid-3-yl)-N4-(3,4-ethylenedioxyphenyl)-5- 1H NMR
(DMSO-d6); d 8.02 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 6.6 Hz), -
- fluoro-N4-methyl-2,4-pyrimidinediamine 7.68 (s, 1H), 6.79 (m,
2H), 6.72 (dd, 1H, J = 2.1 and 8.1 Hz), 6.30 (d, 1H, J = 8.1 Hz),
4.23 (s, 4H), 3.89 (s, 3H), 3.81 (s, 3H), 3.28 (s, 3H); LCMS:
purity: 97%, MS (m/e): 414 (MH+). 459
N4-(3,5-Dimethoxyphenyl)-N2-(2,6-dimethoxypyrid-3-yl)-5- 1 H NMR
(DMSO-d6): d 9.12 (s, 1H), 7.97 (d, 1H, J = 5.1 Hz), 7.89 (s, + -
fluoro-2,4-pyrimidinediamine 1H), 7.82 (d, 1H, J = 7.8 Hz), 6.95
(s, 1H), 6.28 (d, 1H, J = 7.8 Hz), 6.15 (s, 1H), 3.84 (s, 3H), 3.83
(s, 3H), 23.64 (s, 6H); LCMS: purity: 85%, MS (m/e): 402 (MH+). 460
N2-(2,6-Dimethoxypyrid-3-yl)-N4-(3,4-ethylenedioxyphenyl)-5- LCMS:
purity: 93%, MS (m/e): 400 (MH+). + - fluoro-2,4-pyrimidinediamine
461 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-methyl-N4-methyl- 1H
NMR (DMSO-d6): d 7.72 (d, 1H, J = 5.1 Hz), 6.79 (d, 1H, J = 9.0
Hz), - - 2,4-pyrimidinediamine 6.73 (bs, 1H), 6.66 (bd, 1H), 2.74
(d, 3H, J = 4.5 Hz); LCMS: purity: 93%, MS (m/e): 291 (MH+). 462
N2-Dimethyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 7.78 (d, 1H, J = 6.0 Hz), 6.80 (d, 1H, J = 8.4 Hz), -
- methyl-2,4-pyrimidinediamine 6.75 (d, 1H, J = 2.7 Hz), 6.66 (dd,
1H, J = 1.8 and 8.4 Hz), 4.22 (s, 4H), 3.31 (s, 3H), 3.30 (s, 3H);
LCMS: purity: 95%; MS (m/e): 305 (MH+). 463
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.45 (s, 1H), 9.24 (s, 1H), 8.11 (m, 2H), + + -
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.89 (d, 1H, J
= 2.1 Hz), 7.54 (dd, 2.1 and 8.7 Hz), 7.20 (m, 3H), 6.82 (d, 1H, J
= 8.4 Hz), 4.22 (bs, 4H), 2.71 (d, 3H, J = 4.5 Hz); LCMS: purity:
99%, MS (m/e): 430 (MH+). 464
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 10.34 (s, 1H), 10.10 (s, 1H), 8.25 (d, 1H, J = 4.5
Hz), + - dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.18 (d,
1H, J = 4.8 Hz), 7.81 (s, 1H), 7.41 (d, 1H, J = 8.1 Hz), 7.27 (d,
1H, J = 8.4 Hz), 7.18 (m, 2H), 6.95 (d, 1H, J = 8.7 Hz), 3.75 (s,
3H), 3.68 (s, 3H), 2.71 (d, 3H); LCMS: puri 465
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(3,5- LCMS:
purity: 100%, MS (m/e): 432 (MH+). + -
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 466
N4-(3-Chloro-4-methoxyphenyl)-N2-[3-chloro-4-(N- LCMS: purity:
100%, MS (m/e): 436 (MH+). + + -
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 467
N4-[3-Chloro-4-(ethoxycarbonyl-1,1- LCMS: purity: 95%, MS (m/e):
536 (MH+). + + + dimethylmethyleneoxy)phenyl]-N2-[3-chloro-4-(N-
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 468
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N4- LCMS:
purity: 100%, MS (m/e): 388 (MH+). + + -
(3-hydroxyphenyl)-2,4-pyrimidinediamine 469
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)- 1H NMR
(DMSO-d6): d 7.70 (d, 1H, J = 5.7 Hz), 6.79 (d, 1H, J = 8.7 Hz), -
- N4-methyl-2,4-pyrimidinediamine 6.74 (d, 1H, J = 2.4 Hz), 6.66
(dd, 1H, J = 2.4 and 8.4 Hz), 6.50 (t, 1H, J = 5.1 Hz), 4.61 (t,
1H, J = 5.4 Hz), 4.22 (s, 4H), 3.47 (q, 2H, J = 6.3 Hz), 3.29 (t,
2H, J = 5.4 Hz), 3.25 (s, 3H) 470
2-Chloro-N4-[3-chloro-4-(ethoxycarbonyl-1,1- 1H NMR (CDCl3): d 7.87
(d, 1H, J = 7.8 Hz), 7.25 (m, 1H), 6.95 (m, - +
dimethylmethyleneoxy)phenyl]-5-fluoro-N4-methyl-4- 2H), 4.25 (q,
2H, J = 4.8 Hz), 3.46 (s, 3H), 1.65 (s, 6H), 1.29 (t, 3H, J = 4.8
Hz); pyrimidineamine LCMS: purity: 95%, MS (m/e): 404 (MH+; Cl37).
471 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-isopropyl-N4- 1H NMR
(DMSO-d6): d 7.70 (d, 1H, J = 5.7 Hz), 6.77 (d, 1H, J = 8.7 Hz), -
- methyl-2,4-pyrimidinediamine 6.37 (d, 1H, J = 2.4 Hz), 6.68 (dd,
1H, J = 2.4 and 8.7 Hz), 6.44 (d, 1H, J = 8.1 Hz), 4.22 (s, 4H),
3.90 (sept, 1H, J = 7.5 Hz), 3.27 (s, 3H), 1.12 (d, 6H, J = 6.6
Hz); LCMS: purity: 93%, MS 472
N2-(2,6-Dimethoxypyrid-3-yl)-5-fluoro-N4-(3-hydroxyphenyl)- 1H NMR
(DMSO-d6): d 10.39 (s, 1H), 9.52 (s, 1H), 8.20 (d, 1H, J = 5.7 Hz),
+ - 2,4-pyrimidinediamine 7.77 (m, 1H), 7.08 (m, 1H), 6.59 (m, 1H),
6.45 (d, 1H, J = 8.4 Hz), 6.37 (d, 1H, J = 8.1 Hz), 3.88 (s, 3H),
3.86 (s, 3H); LCMS: purity: 89%, MS (m/e): 358 (MH+). 473
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.71 (s, 1H), 8.16 (d, 1H, J = 4.5 Hz), 8.00 (d, + -
ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H, J = 5.7 Hz), 7.95
(d, 1H, J = 1.8 Hz) 7.53 (dd, 1H, J = 2.1 and 8.4 Hz),
pyrimidinediamine 7.29 (d, 1H, J = 8.4 Hz), 6.85 (m, 2H), 6.77 (dd,
1H, J = 2.1 and 8.4 Hz), 4.24 (s, 4H), 3.40 (s, 3H), 2.71 (d, 3H,
474 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.86 (bs, 1H), 8.18 (d, 1H, J = 4.5 Hz), + -
dimethoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine 8.03 (dd,
1H, J = 1.2 and 6.3 Hz), 7.94 (d, 1H, J = 1.8 Hz), 7.52 (dd, 1H, J
= 2.1 and 8.4 Hz), 7.30 (d, 1H, J = 8.4 Hz), 6.99 (d, 1H, J = 2.4
Hz), 6.93 (d, 1H, J = 8.4 Hz), 6.86 (dd, 1H, J = 2.4 and 8. 475
N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 10.11 (s, 1H), 9.83 (s, 1H), 8.30 (d, 1H, J = 4.5 Hz),
+ + - dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.24 (d, 1H,
J = 4.5 Hz), 8.00 (dd, 1H, J = 2.7 and 8.7 Hz), 7.63 (d, 1H, J =
2.4 Hz), 7.36 (d, 1H, J = 8.7 Hz), 6.78 (d, 2H, J = 2.1 Hz), 6.20
(t, 1H, J = 2.1 Hz), 3.67 (s, 6H), 2.73 (d, 476
N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 9.91 (s, 1H), 9.52 (s, 1H), 8.29 (d, 1H, J = 4.8 Hz),
+ + - dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 8.19 (d, 1H, J
= 4.2 Hz), 8.00 (bdd, 1H, J = 8.7 Hz), 7.62 (d, 1H, J = 2.1 Hz),
7.38 (d, 1H, J = 9.0 Hz), 7.17 (s, 2H), 6.63 (s, 1H), 2.72 (d, 3H,
J = 4.8 Hz), 2.19 (s, 6H); LCMS: purity: 477
N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 9.55 (s, 1H), 9.32 (s, 1H), 8.31 (bd, 1H), + + -
[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.15 (bs, 1H),
7.99 (m, 2H), 7.79 (m, 1H), 7.39 (d, 1H, J = 9 Hz), 7.29 (m,
pyrimidinediamine 2H), 7.14 (m, 1H), 6.49 (bd, 1H, J = 7.8 Hz),
4.36 (s, 2H), 2.72 (s, 3H), 2.64 (s, 3H); LCMS: purity: 99%, MS
(m/e): 4 478
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-[4-chloro- 1H NMR
(DMSO-d6): d 9.69 (s, 1H), 8.34 (d, 1H, J = 4.5 Hz), 8.22 (d, + -
3-(N-methylamino)carbonylphenyl]-5-fluoro-2,4- 1H, J = 3.6 Hz),
8.17 (d, 1H, J = 4.5 Hz), 7.95 (dd, 1H, J = 2.7 and 8.7 Hz),
pyrimidinediamine 7.81 (d, 1H, J = 2.1 Hz), 7.71 (d, 1H, J = 2.7
Hz), 7.56 (dd, 1H, J = 2.1 and 8.4 Hz), 7.43 (d, 1H, J = 9.0 Hz),
7.3 479 N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2-(indol-6-
1H NMR (DMSO-d6): d 11.98 (s, 1H), 10.28 (s, 1H), 10.05 (s, 1H), +
- yl)-2,4-pyrimidinediamine 8.35 (d, 1H, J = 4.2 Hz), 8.21 (d, 1H,
J = 4.8 Hz), 7.86 (bd, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 2.7 Hz),
7.54 (s, 1H), 7.47 (d, 1H, J = 8.4 Hz), 7.35 (d, 1H, J = 8.7 Hz),
7.30 (m, 1H), 7.05 (dd, 1 480
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2-methoxy-N4-methyl- LCMS:
purity: 97%, MS (m/e): 292 (M+). - - 4-pyrimidineamine 481
N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 9.85 (bs, 1H), 9.50 (bs, 1H), 8.22 (m, 2H), + + -
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.89 (m, 2H), 7.33
(d, 1H, J = 9.0 Hz), 6.85 (d, 2H, J = 1.5 Hz), 6.13 (d, 1H, J = 1.8
Hz), 3.66 (s, 1H), 2.74 (d, 3H, J = 4.5 Hz); LCMS: purity: 98%, MS
(m/e): 432 (M+). 482
N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 10.01 (s, 1H), 9.65 (s, 1H), 8.24 (d, 1H, J = 4.5 Hz),
+ + - dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.85 (bs, 1H),
7.35 (d, 1H, J = 8.7 Hz), 7.16 (s, 2H), 6.94 (s, 2H), 6.65 (s, 1H),
2.74 (d, 3H, J = 4.8 Hz), 2.29 (s, 3H), 2.20 (s, 3H); LCMS: purity:
98%, MS (m/e): 400 (M+). 483
N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 9.82 (bs, 1H), 9.56 (bs, 1H), 8.22 (m, 2H), +
[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.98 (bd, 1H),
7.91 (d, 1H, J = 1.5 Hz), 7.82 (bd, 1H, J = 8.7 Hz),
pyrimidinediamine 7.37 (d, 1H, J = 8.7 Hz), 7.22 (m, 3H), 6.56 (m,
1H), 4.38 (s, 2H), 2.74 (d, 3H, J = 4.5 Hz), 2.64 (d, 3H, J = 4.8
Hz); LCMS: pu 484
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-[3-chloro- 1H NMR
(DMSO-d6): d 9.69 (s, 1H), 9.60 (s, 1H), 8.25 (m, 3H), -
4-(N-methylamino)carbonylphenyl]-5-fluoro-2,4- 7.85 (m, 3H), 7.36
(m, 3H), 2.75 (d, 3H, J 4.8 Hz), 2.70 (d, 3H, J = 4.5 Hz);
pyrimidinediamine LCMS: purity: 86%, MS (m/e): 463 (M+). 485
N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.99 (s, 1H), 10.10 (s, 1H), 9.80 (bs, 1H), + +
(indol-6-yl)-2,4-pyrimidinediamine 8.25 (d, 1H, J = 4.5 Hz), 8.20
(d, 1H, J = 4.2 Hz), 7.93 (d, 1H, J = 1.8 Hz), 7.83 (bd, 1H, J =
9.6 Hz), 7.58 (s, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.12 (bd, 1H, J
= 8.1 Hz), 6.38 (s, 1H); LCMS: p 486
N4-(2-Aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine 1H NMR
(CD3OD): d 8.16 (d, 1H, J = 3.6 Hz), 7.46 (m, 2H), 6.32 (dd, - -
1H, J = 3.9 and 5.1 Hz); LCMS: purity: 92%, MS (m/e): 240 (M+). 487
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H NMR
(CD3OD): d 7.43 (d, 1H, J = 7.2 Hz), 6.83 (d, 1H, J = 8.4 Hz), - -
pyrimidinediamine 6.78 (d, 1H, J = 2.4 Hz), 6.72 (dd, 1H, J = 2.7
and 8.4
Hz), 4.25 (s, 4H), 3.40 (s, 3H); LCMS: purity: 100%, MS (m/e): 278
(MH+). 488 2-Chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-N4-methyl-4-
1H NMR (CD3OD): d 7.93 (d, 1H, J = 5.4 Hz), 6.46 (s, 3H,), 4.62 (s,
+ - pyrimidineamine 6H), 3.77 (s, 3H); LCMS: purity: 100%, MS
(m/e): 298 (MH+). 489
N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4-(2-hydroxyethyl)- 1H
NMR (CD3OD): d 7.73 (m, 2H), 7.34 (dd, 1H, J = 1.2 and 8.1 Hz), - -
2,4-pyrimidinediamine 7.17 (s, 1H), 7.04 (t, 2H, J = 7.8 Hz), 4.38
(q, 2H, J = 6.9 Hz), 3.69 (t, 2H, J = 5.1 Hz), 3.58 (t, 2H, J = 6.6
Hz), 1.42 (t, 3H, J = 7.2 Hz); LCMS: purity: 98%, MS (m/e): 360
(MH+). 490
2-Chloro-N4-(2,6-dimethoxypyrid-5-yl)-5-fluoro-N4-methyl-4- 1H NMR
(CD3OD): d 7.89 (d, 1H, J = 5.7 Hz), 7.57 (d, 1H, J = 8.1 Hz), - -
pyrimidineamine 6.37 (d, 1H, J = 8.7 Hz), 3.94 (s, 3H), 3.91 (s,
3H), 3.37 (s, 3H); LCMS: purity: 97%, MS (m/e): 299 (MH+). 491
2-Chloro-N4-(3,5-dichloro-4-methoxyphenyl-5-fluoro-N4- 1H NMR
(CD3OD): d 8.02 (d, 1H, J = 5.4 Hz), 7.43 (s, 2H), 3.91 (s, - -
methyl-4-pyrimidineamine 3H), 3.47 (s, 3H); LCMS: purity: 89%, MS
(m/e): 366 (MH+). 492
N2-(Bis-2-hydroxyethyl)-N4-(3,4-ethylenedioxyphenyl)-5- 1H NMR
(DMSO-d6): d 7.76 (d, 1H, J = 4.7 Hz), 6.79 (d, 1H, J = 6.3 Hz), -
- fluoro-N4-methyl-2,4-pyrimidinediamine 6.75 (d, 1H, J = 2.4 Hz),
6.67 (dd, 1H, J = 2.7 and 9.3 Hz), 4.71 (bs, 2H), 4.22 (bs, 4H),
3.57 (bs, 4H), 3.31 (bs, 4H), 3.28 (s, 3H); LCMS: purity: 97%, MS
(m/e): 416 (MH+). 493
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(N- 1H NMR (DMSO-d6): d
9.58 (s, 1H), 9.29 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz), + + -
methylamino)sulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine 7.47
(m, 2H), 7.42 (bdd, 1H), 7.27 (d, 1H, J = 2.1 Hz), 7.13 (dd, 1H, J
= 2.1 and 8.4 Hz), 6.79 (d, 1H, J = 8.7 Hz), 6.73 (m, 1H), 4.22 (s,
4H), 3.68 (s, 3H), 2.34 (d, 3H, J = 4.8 Hz); L 494
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-methoxyphenyl-4- 1H NMR
(DMSO-d6): d 9.57 (s, 1H), 9.33 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz),
+ + - (N-methylamino)sulfonyl]-2,4-pyrimidinediamine 7.51 (d, 1H, J
= 1.8 Hz), 7.45 (d, 1H, J = 8.4 Hz), 7.34 (dd, 1H, J = 1.8 and 8.7
Hz), 7.24 (m, 2H), 6.90 (d, 1H, J = 9.0 Hz), 6.72 (d, 1H, J = 4.8
Hz), 3.75 (s, 3H), 3.67 (s, 3H), 3.63 ( 495
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-methoxyphenyl-4- 1H NMR
(DMSO-d6): d 9.64 (s, 1H), 9.37 (s, 1H), 8.16 (bd, 1H), + -
(methylamino)sulfonyl]-2,4-pyrimidinediamine 7.51 (m, 3H), 6.97
(bs, 2H), 6.71 (bd, 1H), 6.24 (bs, 1H), 3.69 (s, 6H), 3.31 (s, 3H),
2.34 (d, 3H, J = 4.8 Hz); LCMS: purity: 94%, MS (m/e): 464 (M+).
496 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H
NMR (DMSO-d6): d 10.62 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), + + +
[3-methoxyphenyl-4-(methylamino)sulfonyl]-2,4- 8.12 (d, 1H, J = 3.9
Hz), 7.46 (s, 1H), 7.44 (s, 1H), 7.26 (dd, 1H, J = 2.4 and
pyrimidinediamine 8.7 Hz), 7.14 (d, 1H, J = 2.4 Hz), 6.90 (d, 1H, J
= 8.4 Hz), 6.70 (d, 1H, J = 5.4 Hz), 3.69 (s, 3H), 2.32 (d, 3H, J =
497 N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3- 1H NMR
(DMSO-d6): d 9.88 (s, 1H), 9.72 (s, 1H), 8.26 (m, 2H), + + -
methoxyphenyl-4-(methylamino)sulfonyl]-2,4- 8.18 (d, 1H, J = 4.5
Hz), 7.65 (d, 1H, J = 8.7 Hz), 7.51 (d, 1H, J = 8.7 Hz),
pyrimidinediamine 7.44 (m, 2H), 6.74 (d, 1H, J = 8.4 Hz), 3.72 (s,
3H), 2.34 (d, 3H, J = 5.1 Hz); LCMS: purity: 97%, MS (m/e): 506
(M+). 498 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[4-(3-
1H NMR (DMSO-d6): d 9.78 (s, 1H), 9.72 (s, 1H), 8.25 (m, 1H), + + -
methoxyphenyl-N-methylamino)sulfonyl]-2,4- 8.15 (d, 1H, J = 3.6
Hz), 7.84 (dd, 1H, J = 2.4 and 9.0 Hz), 7.52 (m, 2H),
pyrimidinediamine 7.43 (m, 2H), 6.74 (m, 1H), 3.74 (s, 3H), 2.33
(d, 3H, J = 2.1 Hz); LCMS: purity: 83%, MS (m/e): 522 (M+). 499
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-methoxyphenyl-4-(N- 1H NMR
(DMSO-d6): d 9.57 (s, 1H), 9.38 (s, 1H), 9.31 (s, 1H), + + -
methylamino)sulfonyl]-2,4-pyrimidinediamine 8.13 (d, 1H, J = 3.9
Hz), 7.51 (m, 1H), 7.47 (m, 2H), 7.21 (d, 1H, J = 1.5 Hz), 7.08 (m,
2H), 6.70 (d, 1H, J = 5.4 Hz), 6.51 (bdd, 1H, J = 8.1 Hz), 3.31 (s,
3H), 2.30 (d, 3H, J = 2.4 Hz); LCMS: puri 500
N4-(2,6-Dimethoxypyrid-3-yl)-N2,N4-dimethyl-5-fluoro-2,4- 1H NMR
(DMSO-d6): d 7.66 (d, 1H, J = 5.4 Hz), 7.59 (d, 1H, J = 7.5 Hz), -
- pyrimidinediamine 6.54 (bd, 1H), 6.35 (d, 1H, J = 8.4 Hz), 3.85
(s, 3H), 3.83 (s, 3H), 2.71 (d, 3H, J = 3.9 Hz); LCMS: purity: 92%,
MS (m/e): 294 (M+). 501
N4-(3,5-Dichloro-4-methoxyphenyl)-N2,N4-dimethyl-5-fluoro- 1H NMR
(DMSO-d6): d 7.86 (d, 1H, J = 5.4 Hz), 7.42 (s, 2H), 3.80 (s, - -
2,4-pyrimidinediamine 3H), 3.38 (s, 3H), 2.73 (d, 3H, J = 4.8 Hz);
LCMS: purity: 98%, MS (m/e): 331 (M+). 502
2-Chloro-5-fluoro-N4-[4-(N-methylamino)sulfonyl-3- 1H NMR
(DMSO-d6): d 10.28 (s, 1H), 8.42 (d, 1H, J = 3.0 Hz), 7.71 (d, - -
methoxyphenyl]-2,4-pyrimidineamine 1H, J = 1.8 Hz), 7.67 (d, 1H, J
= 8.4 Hz), 7.46 (dd, 1H, J = 1.5 and 8.4 Hz), 6.95 (d, 1H, J = 5.4
Hz), 3.87 (s, 3H), 2.38 (2.38 (d, 3H, J = 4.8 Hz); LCMS: purity:
80%, MS (m/e): 349 (M + 2). 503
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[2-(2- 1H NMR (DMSO-d6): d
9.34 (s, 1H), 9.14 (s, 1H), 8.57 (d, 1H, J = 2.7 Hz), + + -
hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine 8.08 (d, 1H, J
= 3.0 Hz), 7.98 (dd, 1H, J = 2.7 and 8.7 Hz), 6.91 (d, 2H, J = 1.8
Hz), 6.77 (d, 1H, J = 8.7 Hz), 6.03 (t, 1H, J = 3.6 Hz), 4.23 (t,
2H, J = 4.5 Hz), 3.69 (m, 2H), 3.65 (s, 504
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[2-(2- 1H NMR (DMSO-d6): d 9.30
(s, 1H), 9.06 (s, 1H), 8.54 (d, 1H, J = 2.4 Hz), + + -
hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine 8.06 (d, 1H, J
= 3.6 Hz), 7.94 (dd, 1H, J = 2.7 and 9.0 Hz), 7.20 (d, 2H, J = 0.9
Hz), 6.79 (d, 1H, J = 9.0 Hz), 6.50 (s, 1H), 4.8 (t, 1H, J = 5.7
Hz), 4.23 (t, 2H, J = 5.7 Hz), 3.70 (q, 2 505
N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-[2-(2- 1H NMR (DMSO-d6):
d 9.35 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), + + -
hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine 8.07 (d, 1H, J
= 3.6 Hz), 7.98 (dd, 1H, J = 2.7 and 9.0 Hz), 7.81 (s, 1H), 7.40
(bd, 1H, J = 8.7 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.80 (d, 1H, J =
8.7 Hz), 4.83 (t, 1H, J = 5.7 Hz), 4.24 (t, 1H, J = 4.8 506
N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H
NMR (DMSO-d6): d 7.70 (d, 1H, J = 4.4 Hz), 7.68 (m, 2H), 7.66 (dd,
- - pyrimidinediamine 1H, J = 1.2 and 7.8 Hz), 5.85 (m, 1H), 5.10
(dd, 1H, J = 1.5 and 16.8 Hz), 5.00 (dd, 1H, J = 1.8 and 12.0 Hz),
4.22 (s, 4H), 3.83 (t, 2H, J = 4.5 Hz), 3.28 (s, 3H); LCMS: purity:
100%, MS (m 507 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[4-(N- LCMS:
purity: 80%, MS (m/e): 464 (MH+). + + -
methylamino)sulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine 508
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3-methylpyrid-6-yl)- 1H NMR
(DMSO-d6): d 9.50 (s, 1H), 9.22 (s, 1H), 8.16 (s, 1H), + + -
2,4-pyrimidinediamine 8.13 (dd, 1H, J = 0.9 and 6.6 Hz), 8.06 (d,
1H, J = 8.7 Hz), 7.55 (bdd, 1H, J = 5.7 Hz), 6.94 (d, 2H, J = 1.2
Hz), 6.07 (t, 1H, J = 1.2 Hz), 3.68 (s, 3H), 3.66 (s, 3H), 2.49 (s,
6H); LCMS: purity: 9 509
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(3-methylpyrid-6-yl)-2,4- 1H
NMR (DMSO-d6): d 9.46 (s, 1H), 9.14 (s, 1H), 3.17 (bs, 1H), + + -
pyrimidinediamine 8.13 (d, 1H, J = 3.3 Hz), 8.04 (d, 1H, J = 8.4
Hz), 7.55 (dd, 1H, J = 2.1 and 8.4 Hz), 7.24 (s, 2H), 6.24 (s, 1H),
3.33 (s, 3H), 3.32 (s, 3H), 2.18 (s, 3H);; LCMS: purity: 93%, MS
(m/e): 324 (MH+ 510
N4-(5-Chloropyrid-2-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro- LCMS:
purity: 93%, MS (m/e): 376 (MH+). + + - 2,4-pyrimidinediamine 511
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(oxazol-2-yl)phenyl]-2,4- 1H
NMR (DMSO-d6): d 9.39 (s, 1H), 9.30 (s, 1H), 9.22 (s, 1H), +
pyrimidinediamine 8.29 (bs, 1H), 8.14 (s, 1H), 8.11 (d, 1H, J = 3.9
Hz), 7.90 (dd, 1H, J = 1.2 and 9.0 Hz), 7.50 (dd, 1H, J = 1.5 and
6.3 Hz), 7.33 (m, 3H), 7.09 (t, 1H, J = 2.1 Hz), 7.01 (t, 1H, J =
8.1 Hz), 6.45 9d 512
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,2,4-oxadiazol- 1H
NMR (DMSO-d6): d 9.54 (s, 1H), 9.26 (s, 1H), 8.18 (s, 1H), + -
3-yl)phenyl]-2,4-pyrimidinediamine 8.10 (d, 1H, J = 2.4 Hz), 7.83
(bd, 1H, J = 8.1 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13
(bd, 1H, J = 8.7 Hz), 6.82 (d, 1H, j = 9.0 Hz), 4.22 (s, 4H); LCMS:
purity: 91%, MS (m/e): 406 (M+). 513
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(1,2,4-oxadiazol-3- 1H NMR
(DMSO-d6): d 9.53 (s, 1H), 9.29 (s, 1H), 8.21 (s, 1H), + -
yl)phenyl]-2,4-pyrimidinediamine 8.10 (d, 1H, J = 3.9 Hz), 7.79
(dd, 1H, J = 1.2 and 8.4 Hz), 7.33 (m, 3H), 7.16 (s, 1H), 6.94 (d,
1H, J = 8.7 Hz), 3.75 (s, 3H), 3.70 (s, 3H); LCMS: purity: 95%, MS
(m/e): 407 (MH-). 514
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 1.6 (s, 1H), 9.49 (s, 1H), 9.40 (, s, 1H), + -
[3-(1,2,4-oxadiazol-3-yl)phenyl]-2,4-pyrimidinediamine 8.15 (d, 1H,
J = 8.1 Hz), 8.11 (d, 1H, J = 3.9 Hz), 7.85 (bd, 1H, J = 8.4 Hz),
7.29 (m, 3H), 7.13 (d, 1H, J = 2.4 Hz), 6.91 (dd, 1H, J = 3.0 and
8.4 Hz), 5.73 (d, 1H, J = 3.6 Hz), 1.40 (s, 3H); LCMS 515
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[5-methoxycarbonyl-3- 1H NMR
(DMSO-d6): d 9.61 (s, 1H), 9.27 (s, 1H), 8.62 (s, 1H), 8.38 (s, + -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.17 (d, 1H, J =
0.9 Hz), 8.12 (d, 1H, J = 3.6 Hz), 8.04 (d, 1H, J = 1.5 Hz), 7.35
(m, 2H), 7.27 (m, 1H), 6.76 (d, 1H, J = 7.8 Hz), 3.82 (s, 3H), 3.70
(s, 3H), 3.65 (s, 3H); LCMS: pur 516
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[5- 1H NMR (DMSO-d6): d
9.64 (s, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 8.37 (s, - -
methoxycarbonyl-3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H),
8.19 (s, 1H), 8.12 (d, 1H, J = 3.3 Hz), 8.05 (s, 1H), 7.38 (m, 2H),
7.22 (dd, 1H, J = 2.7 and 8.7 Hz), 6.70 (d, 1H, J = 8.7 Hz), 5.74
(s, 1H), 4.15 (s, 4H), 3.85 (s, 3H); LCMS: purit 517
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.51 (s, 1H), 9.54 (s, 1H), 9.40 (s, 1H), - -
[5-methoxycarbonyl-3-(oxazol-2-yl)phenyl]-2,4- 8.63 (s, 1H), 8.39
(s, 1H), 8.18 (s, 1H), 8.14 (d, 1H, J = 3.9 Hz), 8.04 (s, 1H),
pyrimidinediamine 7.44 (dd, 1H, J = 2.1 and 8.7 Hz), 7.37 (s, 1H),
6.77 (d, 1H, J = 8.4 Hz), 3.84 (s, 3H), 1.38 (s, 6H); LCMS: puri
518 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[5-methoxycarbonyl-3- 1H NMR
(DMSO-d6): d 9.64 (s, 1H), 9.25 (s, 1H), 8.62 (s, 1H), 8.43 (s, + -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.19 (s, 1H), 8.15
(d, 1H, J = 3.9 Hz), 8.05 (s, 1H), 7.38 (s, 2H), 7.36 (s, 2H), 7.13
(s, 1H), 6.98 (t, 1H, J = 8.7 Hz), 6.42 (dd, 1H, J = 2.4 and 6.6
Hz), 3.83 (s, 3H); LCMS: purit 519
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(oxazol-2-yl)-5- 1H NMR
(DMSO-d6): d 9.75 (s, 1H), 9.23 (s, 1H), 8.59 (s, 1H), 8.22 (t, + -
trifluoromethylphenyl]-2,4-pyrimidinediamine 2H, J = 0.9 Hz), 8.14
(d, 1H, J = 3.9 Hz), 7.69 (s, 1H), 7.40 (s, 1H), 7.31 (d, 1H, J =
2.4 Hz), 7.19 (dd, 1H, J = 2.7 and 9.0 Hz), 6.72 (d, 1H, J = 8.4
Hz), 4.17 (s, 4H); LCMS: purity: 92% 520
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(oxazol-2-yl)-5- 1H NMR
(DMSO-d6): d 9.73 (s, 1H), 9.31 (s, 1H), 8.57 (s, 1H), 8.24 (s, + -
trifluoromethylphenyl]-2,4-pyrimidinediamine 1H), 8.20 (bs, 1H),
8.14 (d, 1H, J = 4.2 Hz), 7.68 (s, 1H), 7.40 (s, 1H), 7.33 (bdd,
1H, J = 9.0 Hz), 7.23 (bs, 1H), 6.82 (d, 1H, J = 7.5 Hz), 3.71 (s,
3H), 3.68 (s, 3H); LCMS: purity: 97 521
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.54 (s, 1H), 9.70 (s, 1H), 9.42 (s, 1H), + -
[3-(oxazol-2-yl)-5-trifluoromethylphenyl]-2,4-pyrimidinediamine
8.54 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.16 (d, 1H, J = 2.7 Hz),
7.67 (s, 1H), 7.40 (d, 1H), 7.33 (bdd, 1H, J = 8.4 Hz), 7.17 (d,
1H, J = 2.4 Hz), 6.81 (d, 1H, J = 8.4 Hz), 1.39 (s, 6H); LCMS: 522
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1,2,4-oxadiazol-3- 1H NMR
(DMSO-d6): d 9.55 (s, 1H), 9.36 (s, 1H), 9.30 (s, 1H), +
yl)phenyl]-2,4-pyrimidinediamine 8.13 (m, 2H), 7.88 (bd, 1H, J =
7.8 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13 (t, 1H, J =
7.8 Hz), 7.02 (s, 1H), 6.50 (bdd, 1H, J = 5.7 Hz); LCMS: purity:
95%; MS (m/e): 364 (M+). 523
2-Chloro-5-fluoro-N4-methyl-N4-(3,4,5-trimethoxyphenyl)-4- 1H NMR
(DMSO-d6): d 8.11 (d, 1H, J = 5.4 Hz), 6.79 (s, 2H), 3.74 (s, -
pyrimidineamine 3H), 3.72 (s, 3H), 3.65 (s, 3H), 3.38 (s, 3H);
LCMS: purity: 94%, MS (m/e): 329 (MH+). 524
5-Fluoro-N4-(5-methylisoxazol-3-yl)-N2-[3-(oxazol-2- 1H NMR
(DMSO-d6): d 10.45 (s, 1H), 9.59 (s, 1H), 8.33 (s, 1H), +
yl)phenyl]-2,4-pyrimidinediamine 8.21 (d, 1H, J = 2.7 Hz), 8.18 (s,
1H), 7.83 (bd, 1H, J = 7.2 Hz), 7.55 (bd, 1H, J = 8.1 Hz), 7.40 (t,
1H, J = 8.1 Hz), 7.35 (s, 1H, J = 6.92 (s, 1H), 2.29 9s, 3H); LCMS:
purity: 100%, MS (m/e): 35 525
5-Fluoro-N4-(5-methyl-3-phenylisoxazol-4-yl)-N2-[3-(oxazol-2- 1H
NMR (DMSO-d6): d 9.33 (s, 1H), 9.06 (s, 1H), 8.23 (s, 1H), +
yl)phenyl]-2,4-pyrimidinediamine 8.14 (bs, 1H), 8.09 (d, 1H, J =
3.6 Hz), 7.66 (m, 3H), 7.43 (m, 4H), 7.32 (s, 1H), 7.24 (t, 1H, J =
7.2 Hz), 2.36 (s, 3H); LCMS: purity: 85%, MS (m/e): 429 (MH+). 526
5-Fluoro-N4-(1-methyl-3-phenylpyrazol-5-yl)-N2-[3-(oxazol-2- 1H NMR
(DMSO-d6): d 9.48 (m, 2H), 8.19 (m, 2H), 8.11 (m, 2H), +
yl)phenyl]-2,4-pyrimidinediamine 7.77 (m, 2H), 7.35 (m, 6H), 6.73
(s, 1H), 3.32 (s, 3H); LCMS: purity: 83%, MS (m/e): 428 (MH+). 527
N2,N4-Bis[3-methoxycarbonyl-5-(oxazol-2-yl)phenyl]-5-fluoro- 1H NMR
(DMSO-d6): d 9.89 (s, 1H), 9.83 (s, 1H), 8.58 (s, 1H), 8.49 (s, +
2,4-pyrimidinediamine 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.27 (d, 1H,
J = 3.6 Hz), 8.08 (m, 3H), 7.30 (s, 1H), 7.27 (s, 3H), 3.71 (s,
3H), 3.68 (s, 3H); LCMS: purity: 86%, MS (M/e): 531 (MH+). 528
N2,N4-Bis(3,5-dimethylisoxazol-4-yl)-5-fluoro-2,4- 1H NMR
(DMSO-d6): d 8.76 (s, 1H), 8.13 (s, 1H), 7.83 (d, 1H, J = 3.9 Hz),
-
pyrimidinediamine 2.19 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.85
(s, 3H); LCMS: purity: 91%, MS (m/e): 319 (MH+). 529
N2,N4-Bis[3-(oxazol-2-yl)-5-trifluoromethylphenyl]-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 9.99 (s, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.54 (s,
+ pyrimidinediamine 1H), 8.31 (d, 1H, J = 2.7 Hz), 8.11 (d, 1H, J =
5.1 Hz), 8.05 (s, 1H), 7.79 (s, 1H), 7.61 (s, 1H), 7.31 (s, 1H),
7.27 (s, 1H); LCMS: purity: 92%, MS (m/e): 551 (MH+). 530
N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.43 (s, 1H), 9.23 (s, 1H), 8.25 (s, 1H), + + +
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.08 (d, 1H, J =
3.6 Hz), 7.93 (bd, 1H, J = 8.7 Hz), 7.49 9bd, 1H, J = 7.5 Hz), 7.35
(m, 2H), 7.25 (d, 1H, J = 2.4 Hz), 6.75 (d, 1H, J = 8.7 Hz), 3.70
(s, 3H), 3.66 (s, 3H), 1.37 (s, 9H). 531
N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.45 (s, 1H), 9.19 (s, 1H), 8.25 (t, 1H, J = 1.8 Hz),
+ ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.07 (d, 1H,
J = 3.3 Hz), 7.87 (bd, 1H, J = 2.4 Hz), 7.51 (bd, 1H, J = 7.8 Hz),
7.40 (m, 2H), 7.16 (dd, 1H, J = 2.4 and 8.7 Hz), 6.70 (d, 1H, J = 9
Hz), 4.15 (m, 4H), 1.37 (s, 9H); LCMS: 532
N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N4-(3- 1H
NMR (DMSO-d6): d 9.45 (s, 1H), 9.28 (s, 1H), 9.23 (s, 1H), 8.24 (s,
+ hydroxyphenyl)-2,4-pyrimidinediamine 1H), 8.11 (d, 1H, J = 3.9
Hz), 8.00 (bd, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.39 (t,
1H, J = 8.4 Hz), 7.30 (bd, 1H, J = 8.4 Hz), 7.12 (t, 1H, J = 2.1
Hz), 6.99 (t, 1H, J = 8.4 Hz), 6. 533
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-2-hydrazine- 1H NMR
(DMSO-d6): d 7.61 (d, 1H, J = 5.4 Hz), 6.86 (m, 1H), 6.69 (m, -
4-pyrimidineamine 2H), 4.29 (s, 4H), 3.51 (s, 3H); LCMS: purity:
90%, MS (m/e): 292 (MH+). 534
N4-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-N2-[3-(oxazol-2- 1H NMR
(DMSO-d6): d 9.35 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 8.14 (s, +
yl)phenyl]-2,4-pyrimidinediamine 1H), 8.10 (d, 1H, J = 3.6 Hz),
7.71 (bd, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 6.6 Hz), 7.32 (d, 1H, J
= 0.9 Hz), 7.29 (t, 1H, J = 8.1 Hz), 2.87 (s, 3H), 2.10 (s, 3H);
LCMS: purity: 96%, MS (m/ 535
N4-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-N2-[5- LCMS: purity: 85%,
MS (m/e): 425 (MH+). +
methoxycarbonyl-3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 536
N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo- 1H NMR
(DMSO-d6): d 11.16 (s, 1H), 10.00 (s, 1H), 9.52 (s, 1H), -
4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- 8.16
(d, 1H, J = 4.2 Hz), 7.46 (m, 2H), 7.35 (d, 1H, J = 8.1 Hz), 7.13
(s, 2H), Toluene Sulfonic Acid Salt 7.08 (d, 1H, J = 2.4 Hz), 3.60
(s, 3H), 2.28 (s, 3H), 2.14 (s, 6H), 1.43 (s, 6H); LCMS: purity:
99%, MS (m/e): 439 537
N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo- 1H NMR
(DMSO-d6): d 11.19 (s, 1H), 10.52 (s, 1H), 9.65 (s, 1H), -
4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.19 (d,
1H, J = 4.5 Hz), 7.56 (m, 2H), 7.44 (d, 1H, J = 8.4 Hz), 7.35 (d,
1H, Benzenesulfonic Acid Salt J = 8.4 Hz), 7.30 (m, 3H), 7.10 (s,
2H), 3.60 (s, 3H), 2.14 (s, 6H), 1.43 (s, 6H); LCMS: purity: 93%,
MS (m/e): 439 538
N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo- 1H NMR
(DMSO-d6): d 11.80 (s, 1H), 10.16 (s, 1H), 9.73 (s, 1H), -
4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.21 (d,
1H, J = 4.2 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.36 (d, 1H, J = 8.4
Hz), Methanesulfonic Acid Salt 7.12 (s, 2H), 3.60 (s, 3H), 2.32 (s,
3H), 2.13 (s, 6H), 1.43 (s, 6H); LCMS: purity: 97%, MS (m/e): 439
(MH+, for par 539
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.67 (s, 1H), 10.60 (s, 1H), 10.05 (s, 1H), +
(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.20
(d, 1H, J = 4.8 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J = 9 Hz), 7.45
(bd, p-Toluenesulfonic Acid Salt 2H, J = 7.8 Hz), 7.23 (d, 1H, J =
8.7 Hz), 7.15 (s, 1H), 7.09 (d, 1H, J = 7.8 Hz), 6.85 (d, 1H, J =
8.7 Hz), 2.28 (s, 3H), 540
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.66 (s, 1H), 10.20 (s, 1H), 9.90 (s, 1H), +
(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.17
(d, 1H, J = 4.5 Hz), 7.88 (s, 1H), 7.57 (m, 3H), 7.48 (d, 1H, J =
8.4 Hz), Benzenesulfonic Acid Salt 7.29 (m, 4H), 7.15 (s, 1H), 6.85
(d, 1H), J = 8.4 Hz); LCMS: purity: 95%, MS (m/e): MH+, for parent
ion). 541
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.67 (s, 1H), 10.45 (s, 1H), 10.19 (s, 1H), +
(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.23
(d, 1H, J = 5.1 Hz), 7.80 (s, 1H), 7.62 (d, 1H, J = 8.7 Hz), 7.45
(d, Methanesulfonic Acid Salt 1H, J = 8.4 Hz), 7.11 9s, 1H), 6.85
(d, 1H, J = 8.4 Hz), 2.38 (s, 3H), 1.37 (s, 6H); LCMS: purity: 99%,
MS (m/e): 488 (M 542
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.64 (s, 1H), 9.90 (s, 1H), 9.80 (s, 1H), +
(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.15
(d, 1H, J = 4.8 Hz), 7.96 (s, 1H), 7.59 (d, 1H, J = 8.7 Hz), 7.50
(dd, 1H, Hydrogen Chloride Salt J = 1.5 and 9.3 Hz), 7.25 (m, 2H),
6.87 (d, 1H, J = 8.4 Hz); LCMS: purity: 99%, MS (m/e): 488 (MH+,
for parent ion). 543
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
purity: 98%; MS (m/e): 470 (MH+); + + +
(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 544
N4-(2-Amino-3-methoxy-pyrid-6-yl)-N2-(3,5-dimethoxyphenyl)- LCMS:
purity: 92%; MS (m/e): 387 (MH+) + 5-fluoro-2,4-pyrimidinediamine
545 N4-(2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2-(3,4,5- LCMS:
purity: 94%; MS (m/e): 417 (MH+) +
trimethoxyphenyl)-2,4-pyrimidinediamine 546
N4-(2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2-(2- LCMS: purity: 82%;
MS (m/e): 425 (MH+) +
methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine 547
N4-(2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2[3-(N- LCMS: purity:
89%; MS (m/e): 414 (MH+) +
methylaminocarbonylmethyleneoxy)phenyl]-2,4- pyrimidinediamine 548
N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(3,5-dichloro-4- LCMS: purity:
92%; MS (m/e): 465 (MH+) + +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 549
N4-(4-Acetyl-2,2-dimethyl-3-oxo-pyrid[1,4]oxazin-6-yl)-5- LCMS:
purity: 97%; MS (m/e): 513 (M+)
fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 550
N4-Acetyl-N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5- LCMS:
purity: 96%; MS (m/e): 513 (M+)
fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 551
N2-Acetyl-N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5- LCMS:
purity: 95%; 514 (MH+)
fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 552
2,N4-Bis[3-methyl-4-(4-methylpiperazinyl)phenyl)-5-fluoro-2,4-
LCMS: purity: 99%; MS(m/e): 506 (MH+) pyrimidinediamine 553
N4-(3,5-Dimethylphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-
.sup.1H NMR (DMSO-d6): d 9.14 (bs, 1H), 9.04 (s, 1H), 8.06 (d, J =
3.9 Hz, + 2,4-pyrimidinediamine 1H), 7.40-7.36 (m, 2H), 6.95 (s,
2H), 6.67 (s, 1H), 3.58-3.56 (m, 9H), 2.19 (s, 6H); LCMS: purity:
96%; MS (m/e): 399 (MH+). 554
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3,5- .sup.1H
NMR (DMSO-d6): d 9.21 (bs, 1H), 9.04 (bs, 1H), 8.63 (bs, 1H), +
dimethylphenyl)-2,4-pyrimidinediamine 8.05 (d, J = 3.6 Hz, 1H),
7.53-7.49 (m, 1H), 7.34-7.30 (m, 2H), 7.24-7.20 (m, 1H), 6.69 (bs,
1H), 2.22 (s, 6H), 2.09 (s, 3H); LCMS: purity: 93%; MS (m/e): 373
(MH+). 555 N2-[3,5-Bis(hydroxymethylene)phenyl]-N4-(3,5- .sup.1H
NMR (DMSO-d6): d 9.11 (s, 2H), 8.06 (d, J = 3.9 Hz, 1H), 7.45 (s, +
dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 2H), 7.38 (s, 2H),
6.85 (s, 1H), 6.68 (s, 1H), 4.38-4.34 (m, 4H), 2.22 (s, 6H); LCMS:
purity: 99%; MS (m/e): 369 (MH+). 556
N2-(3,5-Dichlorophenyl)-N4-(3,5-dimethylphenyl)-5-fluoro-2,4-
.sup.1H NMR (DMSO-d6): d 9.76 (bs, 1H), 9.51 (bs, 1H), 8.18 (d, J =
3.9 Hz, + + pyrimidinediamine 1H), 7.73-7.69 (m, 2H), 7.29-7.25 (m,
2H), 7.04 (t, J = 1.8 Hz, 1H), 6.75 (s, 1H), 2.25 (s, 6H); LCMS:
purity: 92%; MS (m/e): 378 (MH+). 557
N4-(3,5-Dimethylphenyl)-5-fluoro-N2-[2-(N- .sup.1H NMR (DMSO-d6): d
11.66 (s, 1H), 9.37 (s, 1H), 9.28 (s, 1H), -
methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.48-8.40 (m,
1H), 8.13 (d, J = 3.6 Hz, 1H), 7.98-7.88 (m, 1H), 7.33 (s, 2H),
7.22 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.90 (t, J =
8.1 Hz. 1H), 6.71 (s, 1H), 2.80 (d, J = 3.0 Hz, 3H), 2 558
5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[2-(N- .sup.1H
NMR (DMSO-d6): d 11.57 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), +
methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.39-8.35 (m,
1H), 8.15 (d, J = 3.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.73-7.69
(m, 1H), 7.57-7.52 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 9.98 (d, J =
1.8 Hz, 1H), 6.87-6.80 (m, 2H), 3.70 (s, 3H), 2. 559
N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(3,5-dimethylphenyl)-5-
.sup.1H NMR (DMSO-d6): d 9.49 (s, 1H), 9.21 (s, 1H), 9.19 (s, 1H),
8.08 (d, + + fluoro-2,4-pyrimidinediamine J = 3.3 Hz, 1H), 7.66 (d,
J = 1.5 Hz, 2H), 7.29 (s, 2H), 6.70 (s, 1H), 2.24 (s, 6H); LCMS:
purity: 95%; MS (m/e): 394 (MH+). 560
N2-(4-Chloro-3,5-dimethylphenyl)-N4-(3,5-dimethylphenyl)-5- .sup.1H
NMR (DMSO-d6): d 9.17 (s, 1H), 9.13 (s, 1H), 8.07 (d, J = 3.9 Hz, -
fluoro-2,4-pyrimidinediamine 1H), 7.45 (s, 2H), 7.30 (s, 2H), 6.72
(s, 1H), 2.22 (s, 6H), 2.18 (s, 6H); LCMS: purity: 93%; MS (m/e):
372 (MH+). 561
N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2-(3,4,5- .sup.1H
NMR (DMSO-d6): d 9.53 (s, 1H), 9.13 (s, 1H), 8.17-8.12 (m, 1H), +
trimethoxyphenyl)-2,4-pyrimidinediamine 8.11 (d, J = 3.9 Hz, 1H),
7.42 (dd, J = 2.4 and 9.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.00
(s, 2H), 3.64 (s, 6H); 19F NMR (282 MHz, DMSO- d6): -49.77,
-164.19; LCMS: purity: 93%; MS (m/e): 4 562
N4-[3,4-(Difluoromethylenedioxy)phenyl]-N2-(3,5- .sup.1H NMR
(DMSO-d6): d 9.54 (s, 1H), 9.22 (s, 1H), 8.12 (d, J = 3.6 Hz, + +
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 8.11-8.08 (m,
1H), 7.42 (dd, J = 2.1 and 9.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H),
6.90 (d, J = 2.1 Hz, 2H), 6.07 (t, J = 2.4 Hz, 1H), 3.65 (s, 6H);
19F NMR (282 MHz, DMSO-d6): -49.69, -16 563
N4-[3,4-(Difluoromethylenedioxy)phenyl]-N2-(3,5- .sup.1H NMR
(DMSO-d6): d 9.51 (s, 1H), 9.13 (s, 1H), 8.11 (d, J = 3.6 Hz, + +
dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 8.09-8.06 (m,
1H), 7.39 (dd, J = 2.1 and 8.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H),
7.22 (s, 2H), 6.53 (s, 1H), 2.16 (s, 6H); 19F NMR (282 MHz,
DMSO-d6): -49.67, -164.51; LCMS: purity: 98 564
N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-[3,4- .sup.1H NMR (DMSO-d6): d
9.59 (s, 1H), 9.45 (bs, 1H), 9.31 (s, 1H), +
(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 8.08 (d, J = 3.6 Hz,
1H), 7.85-7.79 (m, 1H), 7.55 (s, 1H), 7.29 (s, 1H); 19F
pyrimidinediamine NMR (282 MHz, DMSO-d6): -49.50, -163.68; LCMS:
purity: 96%; MS (m/e): 446 (MH+). 565
N2-(3,5-Dichlorophenyl)-N4-[3,4- .sup.1H NMR (DMSO-d6): d 9.62-9.68
(m, 2H), 8.19 (d, J = 3.6 Hz, 1H), +
(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 7.92-7.88 (m, 1H),
7.71 (s, 1H), 7.70 (s, 1H), 7.38-7.33 (m, 2H), pyrimidinediamine
7.00 (t, J = 1.8 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): -49.51,
-162.64; LCMS: purity: 99%; MS (m/e): 430 (MH+). 566
N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3,4- .sup.1H NMR (DMSO-d6): d
9.84 (s, 1H), 9.51 (s, 1H), 8.18 (s, J = 2.7 Hz, -
(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 1H), 7.99 (bs, 1H),
7.41-7.35 (m, 4H), 2.22 (s, 6H); LCMS: purity: 94%;
pyrimidinediamine MS (m/e): 424 (MH+). 567
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-[3,4- .sup.1H NMR
(DMSO-d6): d 9.57 (s, 1H), 9.14 (s, 1H), 8.58 (bs, 1H), +
(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 8.05 (d, J = 3.9 Hz,
1H), 7.90 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 1.8
pyrimidinediamine and 8.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H),
7.14-7.09 (m, 1H), 2.06 (s, 3H); 19F NMR (282 MHz, DMSO-d6):
-49.60, 568 N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2-(3-
.sup.1H NMR (DMSO-d6): d 9.60 (s, 1H), 9.56 (s, 1H), 8.17 (d, J =
3.3 Hz, - methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine
1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.41-7.31 (m, 2H),
6.72 (s, 1H), 3.74 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -49.75,
-61.96, -162.93; LCMS: purity: 93%; MS (m/e): 459 (MH+). 569
N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2-(3- .sup.1H NMR
(DMSO-d6): d 9.66 (s, 1H), 9.59 (s, 1H), 8.19 (d, J = 3.6 Hz, +
methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 1H),
8.04-7.97 (m, 1H), 7.84 (bs, 1H), 7.68 (bs, 1H), 7.36 (bs, 2H),
7.03 (s, 1H), 2.29 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -49.63,
-61.86, -163.10; LCMS: purity: 98%; MS (m/e): 443 (MH 570
N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2-[2-(N- .sup.1H
NMR (DMSO-d6): d 11.56 (s, 1H), 9.63 (s, 1H), 9.34 (s, 1H), +
methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.44-8.38 (m,
1H), 8.12 (d, J = 3.6 Hz, 1H), 7.97 (bs, 1H), 7.84-7.78 (m, 1H),
7.38-7.32 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.1 Hz,
1H), 7.00 (s, 1H), 6.87 (t, J = 7.8 Hz, 1H), 2.74 ( 571
N4-(3-Chloro-4-methoxyphenyl)-N2-[3,5-dimethyl-4-(N- .sup.1H NMR
(DMSO-d6): d 9.28 (s, 1H), 9.03 (s, 1H), 8.15-8.07 (m, 1H), + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 8.05 (d, J =
3.3 Hz, 1H), 7.76-7.72 (m, 2H), 7.68-7.60 (m, 1H), 7.23 (s,
pyrimidinediamine 2H), 7.09 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 3.83
(s, 3H), 2.69 (d, J = 4.2 Hz, 3H), 2.11 (s, 6H); LCMS: purity: 99%;
572 N2-[3,5-dimethyl-4-(N- .sup.1H NMR (DMSO-d6): d 9.08 (s, 1H),
8.95 (s, 1H), 8.14-8.06 (m, 1H), + +
methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4- 8.00 (d, J = 3.6
Hz, 1H), 7.23-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.78 (d,
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine J = 8.7 Hz,
1H), 4.21 (s, 4H), 4.11 (s, 2H), 2.69 (d, J = 4.5 Hz, 3H), 2.13 (s,
6H); LCMS: purity: 99%; MS (m/e): 454 573
N4-(3,5-Dimethoxyphenyl)-N2-[3,5-dimethyl-4-(N- .sup.1H NMR
(DMSO-d6): d 9.20 (s, 1H), 9.01 (s, 1H), 8.14-8.05 (m, 2H), + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 7.29 (s, 2H),
7.00-6.96 (m, 2H), 6.24-6.19 (m, 1H), 4.11 (s, 2H),
pyrimidinediamine 3.67 (s, 6H), 2.70 (d, J = 4.8 Hz, 3H), 2.12 (s,
6H);
LCMS: purity: 99%; MS (m/e): 456 (MH+). 574 N2-[3,5-dimethyl-4-(N-
.sup.1H NMR (DMSO-d6): d 10.59 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H),
+ + methylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl-
8.11-8.06 (m, 1H), 8.04 (d, J = 3.9 Hz, 1H), 7.34-7.23 (m, 3H),
7.21-7.18 (m,
3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 1H),
6.87 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H),
2.11 (s, 6H), 1.40 (s, 6H); LCMS: purity: 95%; 575
N2-[3,5-dimethyl-4-(N- .sup.1H NMR (DMSO-d6): d 9.15 (s, 1H), 8.96
(s, 1H), 8.12-8.05 (m, 1H), + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3,4- 8.01 (d,
J = 3.9 Hz, 1H), 7.44-7.40 (m, 1H), 7.25 (s, 2H), 7.15-7.07 (m,
methylenedioxyphenyl)-2,4-pyrimidinediamine 1H), 6.84 (d, J = 8.1
Hz, 1H), 5.98 (s, 2H), 4.11 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.13
(s, 6H); LCMS: purity: 99%; 576
2-Chloro-5-fluoro-N4-(2-isopropoxypyrid-5-yl)-N4-methyl-4- 1H NMR
(DMSO-d6): d 8.17 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 5.4 Hz, - -
pyrimidineamine 1H), 7.74 (dd, J = 2.7 and 8.7 Hz, 1H), 6.77 (dd, J
= 0.6 and 8.7 Hz, 1H), 5.21 (quintet, J = 6.3 Hz, 1H), 3.38 (s,
3H), 1.29 (d, J = 6.3 Hz, 6H); LCMS: purity: 95%; MS (m/e): 298
(MH+). 577
N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5- 1H NMR
(DMSO-d6): d 7.95 (d, J = 5.7 Hz, 1H), 7.46 (d, J = 2.7 Hz, + -
fluoro-N4-methyl-2,4-pyrimidinediamine 1H), 7.28 (dd, J = 2.4 and
9.0 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.97 (s, 1H),
6.09-6.06 (m, 1H), 3.86 (s, 3H), 3.69 (s, 6H), 3.44 (s, 3H); LCMS:
purity: 96%; MS (m/e): 419 (MH+ 578
N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(3-chloro-4- 1H NMR
(DMSO-d6): d 9.41 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.69 (d, + -
methoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine J = 2.7 Hz,
1H), 7.47 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.28 (dd,
J = 2.7 and 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H),
3.68 (s, 3H), 3.42 (s, 3H), 2.19 (s, 3H); LCMS: 579
N4-(3-Chloro-4-methoxyphenyl)-N2-[3,5-dimethyl-4-(N- 1H NMR
(DMSO-d6): d 9.24 (s, 1H), 8.16-8.04 (m, 1H), 7.96 (d, J = 6.0 Hz,
+ - methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 1H), 7.47
(d, J = 2.4 Hz, 1H), 7.31-7.24 (m, 3H), 7.15 (d, J = 8.7 Hz,
methyl-2,4-pyrimidinediamine 1H), 4.12 (s, 2H), 3.87 (s, 3H), 3.42
(s, 3H), 2.69 (d, J = 4.8 Hz, 3H), 2.15 (s, 6H); LCMS: purity: 92%;
MS (m/e 580 N4-(3-Chloro-4-methoxyphenyl)-N2-[3-(N- 1H NMR
(DMSO-d6): d 9.63 (bs, 1H), 8.02 (d, J = 6.3 Hz, 1H), + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 8.00-7.97 (m,
1H), 7.50 (d, J = 2.7 Hz, 1H), 7.36-7.34 (m, 1H), 7.33-7.20 (m,
methyl-2,4-pyrimidinediamine 3H), 7.16 (d, J = 9.0 Hz, 2H),
6.57-6.52 (m, 1H), 4.41 (s, 2H), 3.87 (s, 3H), 3.44 (s, 3H), 2.64
(d, J = 4.8 Hz, 3H); L 581
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-isopropoxypyrid-5- 1H NMR
(DMSO-d6): d 9.47 (bs, 1H), 8.14 (d, J = 2.7 Hz, 1H), 7.99 (d, + -
yl)-N4-methyl-2,4-pyrimidinediamine J = 6.0 Hz, 1H), 7.71 (dd, J =
3.0 and 8.7 Hz, 1H), 6.96-6.93 (m, 2H), 6.77 (dd, J = 0.6 and 8.7
Hz, 1H), 6.12 (t, J = 2.1 Hz, 1H), 5.21 (quintet, J = 6.3 Hz, 1H),
3.70 (s, 6H), 3.45 (s, 3H) 582
5-Fluoro-N4-(2-isopropoxypyrid-5-yl)-N4-methyl-N2-[3-(N- 1H NMR
(DMSO-d6): d 9.53 (s, 1H), 8.14 (d, J = 3.0 Hz, 1H), + -
methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.02-7.93 (m, 2H),
7.70 (dd, J = 2.7 and 8.7 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H),
pyrimidinediamine 7.26-7.20 (m, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.78
(d, J = 8.7 Hz, 1H), 6.56-6.50 (m, 1H), 5.22 (quintet, J = 6.0 Hz,
1H) 583
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-isopropoxypyrid-5-yl)- 1H
NMR (DMSO-d6): d 9.42 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.01 (d, +
- N4-methyl-2,4-pyrimidinediamine J = 6.6 Hz, 1H), 3.45 (s, 3H),
2.19 (s, 6H), 1.29 (d, J = 6.3 Hz, 6H), 7.70 (dd, J = 2.7 and 8.7
Hz, 1H), 7.24 (s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.22
(quintet, J = 6.3 Hz, 1H); 584
N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dimethylphenyl)-5- 1H NMR
(DMSO-d6): d 9.09 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.45 (d, + -
fluoro-N4-methyl-2,4-pyrimidinediamine J = 2.1 Hz, 1H), 7.31-7.23
(m, 3H), 7.13 (d, J = 9.0 Hz, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.42
(s, 3H), 2.18 (s, 6H); LCMS: purity: 88%; MS (m/e): 387 (MH+). 585
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2- 1H NMR (DMSO-d6): d
9.45 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.05 (d, - -
methoxycarbonylbenzofuran-5-yl)-N4-methyl-2,4- J = 6.0 Hz, 1H),
7.68 (dd, J = 2.1 and 9.0 Hz, 1H), 7.65 (d, J = 0.9 Hz,
pyrimidinediamine 1H), 7.63-7.57 (m, 1H), 7.54 (d, J = 2.7 Hz, 1H),
7.35 (dd, J = 2.7 and 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 3.95
(s, 586 5-Fluoro-N4-(2-isopropoxypyrid-5-yl)-N2-(2- 1H NMR
(DMSO-d6): d; 9.39 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.09 (d, + +
methoxycarbonylbenzofuran-5-yl)-N4-methyl-2,4- J = 1.8 Hz, 1H),
7.98 (d, J = 6.3 Hz, 1H), 7.70 (dd, J = 3.0 and 8.7 Hz,
pyrimidinediamine 1H), 7.64-7.57 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H),
6.79 (d, J = 8.7 Hz, 1H), 5.22 (quintet, J = 6.3 Hz, 1H), 3.87 (s,
587 N4-(4-Chloro-3-methoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5- 1H
NMR (DMSO-d6): d 9.44 (bs, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.40 (d,
+ + - fluoro-N4-methyl-2,4-pyrimidinediamine J = 8.1 Hz, 1H), 7.15
(d, J = 2.1 Hz, 1H), 6.95 (d, J = 1.2 Hz, 2H), 6.90 (dd, J = 2.1
and 8.4 Hz, 1H), 6.12-6.08 (m, 1H), 3.82 (s, 3H), 3.69 (s, 6H),
3.49 (s, 3H); LCMS: purity: 96%; MS (m 588
N4-(4-Chloro-3-methoxyphenyl)-N2-(3,5-dimethylphenyl)-5- 1H NMR
(DMSO-d6): d 9.35 (bs, 1H), 8.03 (d, J = 6.0, 1H), 7.41 (d, J =
8.4, + - fluoro-N4-methyl-2,4-pyrimidinediamine 1H), 7.26-7.23 (m,
2H), 7.16 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 2.1 and 8.7 Hz, 1H),
6.58-6.55 (m, 1H), 3.82 (s, 3H), 3.49 (s, 3H), 2.19 (s, 6H); LCMS:
purity: 91%; MS (m/e): 387 (MH+ 589
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(N- 1H NMR
(DMSO-d6): d 9.34 (s, 1H), 8.00 (d, J = 5.4, 1H), + + -
methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.93-8.00 (m, 1H),
7.44 (t, J = 1.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (dd, J =
1.2 pyrimidinediamine and 8.4 Hz, 1H), 7.15-7.12 (m, 1H), 7.09 (d,
J = 8.4 Hz, 1H), 6.87 (dd, J = 2.1 and 9.0 Hz, 1H), 6.47 (dd, J =
2.7 590 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(indol-5-yl)-N4-
1H NMR (DMSO-d6): d 10.84 (s, 1H), 9.010 (s, 1H), 7.96 (d, J = 5.4
Hz, + + - methyl-2,4-pyrimidinediamine 1H), 7.87-7.84 (m, 1H), 7.39
(d, J = 8.1 Hz, 1H), 7.27-7.19 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H),
6.87 (dd, J = 2.4 and 8.7 Hz, 1H), 6.29-6.25 (m, 1H), 3.82 (s, 3H),
3.47 (s, 3H); LCMS: puri 591
N4-(4-Chloro-3,5-dimethylphenyl)-N2-(3,5-dimethoxyphenyl)- 1H NMR
(DMSO-d6): d 9.51 (bs, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.19 (s, + +
- 5-fluoro-N4-methyl-2,4-pyrimidinediamine 2H), 6.93 (d, J = 1.8
Hz, 2H), 6.12 (t, J = 2.4 Hz, 1H), 3.70 (s, 6H), 3.46 (s, 3H), 2.32
(s, 6H); LCMS: purity: 98%; MS (m/e): 418 (MH+). 592
N4-(4-Chloro-3,5-dimethylphenyl)-N2-(3,5-dimethylphenyl)-5- 1H NMR
(DMSO-d6): d 9.49 (bs, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.24 (s, - -
fluoro-N4-methyl-2,4-pyrimidinediamine 2H), 7.20 (s, 2H), 6.60 (s,
1H), 3.45 (s, 3H), 2.32 (s, 6H), 2.19 (s, 6H); LCMS: purity: 98%;
MS (m/e): 386 (MH+). 593
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR
(DMSO-d6): d 9.32 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), + + -
(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.00-7.92 (m, 1H),
7.44 (t, J = 2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.16 (s, 2H),
pyrimidinediamine 7.10 (t, J = 8.1 Hz, 1H), 6.47 (dd, J = 2.4 and
7.8 Hz, 1H), 4.39 (s, 2H), 3.44 (s, 3H), 2.64 (d, J = 4.5 Hz, 3H),
2.32 ( 594
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2-(indol-5-yl)-N4- 1H
NMR (DMSO-d6): d 10.84 (s, 1H), 8.98 (s, 1H), 7.94 (d, J = 5.7 Hz,
+ + + methyl-2,4-pyrimidinediamine 1H), 7.84 (s, 1H), 7.29-7.19 (m,
3H), 7.15 (s, 2H), 6.26 (t, J = 2.1 Hz, 1H), 3.42 (s, 3H), 2.32 (s,
6H); LCMS: purity: 94%; MS (m/e): 397 (MH+). 595
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2-(2- 1H NMR (DMSO-d6):
d 9.43 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.01 (d, - -
methoxycarbonyl-benzofuran-5-yl)-N4-methyl-2,4- J = 5.4 Hz, 1H),
7.68-7.61 (m, 2H), 7.55 (d, J = 9.3 Hz, 1H), 7.17 (s,
pyrimidinediamine 2H), 3.87 (s, 3H), 3.45 (s, 3H), 2.32 (s, 6H),;
LCMS: purity: 97%; MS (m/e): 457 (MH+). 596
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR
(DMSO-d6): d 9.66 (s, 1H), 8.11 (d, J = 0.90 Hz, 1H), 8.04 (d, - -
(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine J = 5.4 Hz, 1H), 7.81
(s, 4H), 7.28 (d, J = 0.6 Hz, 1H), 7.18 (s, 2H), 3.46 (s, 3H), 2.33
(s, 6H); LCMS: purity: 89%; MS (m/e): 425 (MH+). 597
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR
(DMSO-d6): d 9.71 (s, 1H), 8.40 (s, 1H), 8.24-8.18 (m, 1H), + -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.06 (d, J = 6.0 Hz,
1H), 7.59-7.53 (m, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 2H), 3.49 (s,
3H), 2.32 (s, 6H); LCMS: purity: 96%; MS (m/e): 425 (MH+). 598
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR
(DMSO-d6): d 9.64 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 5.7 Hz, + -
(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1H), 7.76 (d, J = 8.7
Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.49 (s, 1H), 7.19 (s, 2H), 3.46
(s, 3H), 2.32 (s, 6H); LCMS: purity: 96%; MS (m/e): 425 (MH+). 599
N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2-(indol-6-yl)-N4- 1H
NMR (DMSO-d6): d 11.00 (s, 1H), 9.58 (bs, 1H), 8.00 (d, J = 6.0 Hz,
+ - methyl-2,4-pyrimidinediamine 1H), 7.89 (s, 1H), 7.41 (d, J =
8.4 Hz, 1H), 7.24-7.18 (m, 3H), 7.11 (dd, J = 1.8 and 8.4 Hz, 1H),
6.35-6.31 (m, 1H), 3.47 (s, 3H), 2.33 (s, 6H); LCMS: purity: 95%;
MS (m/e): 397 (MH+). 600 N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d
9.94 (bs, 1H), 9.65 (bs, 1H), 8.18 (d, J = 4.2 Hz, + + -
methylamino)carbonylmethyleneoxyphenyl]-N2-(3,5- 1H), 7.93-7.84 (m,
1H), 7.74 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.7
dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine and 9.0 Hz, 1H),
7.12 (s, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 4.55 (s, 2H),
2.66 (d, J = 4.8 Hz, 3H), 2.18 (s, 601 N4-[3-Chloro-4-(N- 1H NMR
(DMSO-d6): d 9.52 (bs, 1H), 9.30 (bs, 1H), 8.11 (d, J = 3.9 Hz, + +
- methylamino)carbonylmethyleneoxyphenyl]-N2-(3,5- 1H), 7.92-7.85
(m, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.7
dimethoxylphenyl)-5-fluoro-2,4-pyrimidinediamine and 8.7 Hz, 1H),
6.96 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 1.8 Hz, 2H), 6.10 (t, J =
2.4 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 6H) 602
N2-(3-Chloro-4-methoxyphenyl)-N4-[3-chloro-4-(N- 1H NMR (DMSO-d6):
d 9.45 (bs, 1H), 9.25 (bs, 1H), 8.03 (d, J = 3.3 Hz, + + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 1H),
7.86-7.78 (m, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz,
pyrimidinediamine 1H), 7.58 (dd, J = 2.7 and 9.3 Hz, 1H), 6.96 (d,
J = 9.3 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H), 4.48 (s, 2H), 3.73 (s,
3H) 603 N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4-(N- 1H NMR
(DMSO-d6): d 9.45 (bs, 1H), 9.2 = 8 (bs, 1H), 8.11 (d, J = 3.9 Hz,
+ - - methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 1H),
7.92-7.87 (m, 1H), 7.75 (d, J = 2.4, 1H), 7.68 (dd, J = 2.7 and
pyrimidinediamine 9.3 Hz, 1H), 7.40 (s, 2H), 6.99 (d, J = 8.7 Hz,
1H), 4.54 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H), 2.22 (s, 6H),; LCMS:
pur 604 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4-
1H NMR (DMSO-d6): d 9.42 (s, 1H), 8.46-8.43 (m, 1H), 8.39-8.37 (m,
+ - (oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.00 (d, J =
5.4 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H),
7.17 (s, 2H), 3.45 (s, 3H), 2.32 (s, 6H); LCMS: purity: 96%; MS
(m/e): 424 (MH+). 605 N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 10.80
(s, 1H), 9.26 (s, 1H), 9.07 (s, 1H), + + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-(indol- 8.06
(s, J = 3.9 Hz, 1H), 7.93-7.75 (m, 4H), 7.36 (d, J = 8.4 Hz, 1H),
6-yl)-2,4-pyrimidinediamine 7.22-7.15 (m, 2H), 6.95 (d, J = 8.7 Hz,
1H), 6.33-6.27 (m, 1H), 4.54 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H);
LCMS: purity: 96%; M 606
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR
(DMSO-d6): d 9.44 (s, 1H), 8.44 (d, J = 0.90 Hz, 1H), 8.38 (d, + +
+ (oxazol-4-yl)phenyl]-2,4-pyrimidinediamine J = 0.90 Hz, 1H), 8.02
(d, J = 5.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz,
2H), 7.41 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.92-6.86
(m, 1H), 3.83 (s, 3H), 3.49 (s, 3 607
N4-(4-Chloro-3-methoxyphenyl)-N2-[4-chloro-3-(N- 1H NMR (DMSO-d6):
d 9.70 (bs, 2H), 8.23-8.18 (m, 1H), 8.15 (d, J = 4.2 Hz, + + -
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 1H),
7.71 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 2.7 and 9.0 Hz, 1H), 7.45
(dd, J = 2.4 and 8.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.28 (d, J
= 8.7 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 3.73 (s 608
N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 9.53 (bs, 1H), 9.49 (bs,
1H), 8.28-8.21 (m, + -
methylamino)carbonylmethyleneoxyphenyl]-N2-[4-chloro-3-(N- 1H),
8.13 (d, J = 3.9 Hz, 1H), 7.93-7.87 (m, 1H), 7.77-7.64 (m, 4H),
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 7.28 (d,
J = 8.7 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.59 (s, 2H), 2.70 (d, J
= 4.8 Hz, 3H), 2.67 (d, J = 4.5 Hz, 3H); LCMS: pu 609
N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-(4-chloro- 1H NMR
(DMSO-d6): d 9.84 (s, 1H), 9.59 (s, 1H), 8.35-8.27 (m, 2H), + + -
3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine 8.23 (d, J
= 3.9 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H),
7.67-7.60 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 2.71 (d, J = 4.5 Hz,
3H); LCMS: purity: 92%; MS (m/e): 475 (MH+). 610
N4-(4-Chloro-3,5-dimethylphenyl)-N2-[4-chloro-3-(N- 1H NMR
(DMSO-d6): d 9.55 (s, 1H), 8.30-8.24 (m, 1H), 8.01 (d, J = 6.6 Hz,
- - methylamino)carbonylphenyl]-5-fluoro-N4-methyl-2,4- 1H), 7.86
(d, J = 2.7 Hz, 1H), 7.68 (dd, J = 2.7 and 9.0 Hz, 1H),
pyrimidinediamine 7.27 (d, J = 8.7 Hz, 1H), 7.16 (s, 2H), 3.42 (s,
3H), 2.72 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LCMS: purity: 98%; MS
(m/ 611 N4-(4-Chloro-3-methoxyphenyl)-N2-[3-chloro-4-(N- 1H NMR
(DMSO-d6): d 9.57 (s, 1H), 9.54 (s, 1H), 8.19 (d, J = 3.6 Hz, + + -
methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 1H),
8.15-8.08
(m, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 2.4 and 8.7 Hz,
1H), 7.47 (dd, J = 2.45 and 8.7 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H),
7.34 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.4 Hz 612
N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(4-chloro- 1H NMR
(DMSO-d6): d 9.83 (s, 1H), 9.65 (s, 1H), 8.33-8.26 (m, 1H), + + -
3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine 8.25 (d, J
= 3.6 Hz, 1H), 8.16-8.11 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.87
(d, J = 1.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 1.8
and 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 2.72 (d, 613
N4-(4-Chloro-3,5-dimethylphenyl)-N2-[3-chloro-4-(N- 1H NMR
(DMSO-d6): d 9.66 (s, 1H), 8.17-8.09 (m, 1H), 8.05 (d, J = 5.4 Hz,
+ - methylamino)carbonylphenyl]-5-fluoro-N4-methyl-2,4- 1H), 7.94
(d, J = 2.1 Hz, 1H), 7.54 (dd, J = 2.1 and 8.4 Hz, 1H),
pyrimidinediamine 7.28 (d, J = 8.1 Hz, 1H), 7.18 (s, 2H), 3.44 (s,
3H), 2.71 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LCMS: purity: 99%; MS
(m/ 614 N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-N2- 1H
NMR (DMSO-d6): d 10.28 (s, 1H), 10.05 (s, 1H), 8.26 (d, J = 4.8 Hz,
+ + + (3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.74
(d, J = 2.7 Hz, 1H), 7.57 (dd, J = 2.7 and 8.7 Hz, 1H), 7.10-7.01
(m, 3H), 6.69 (s, 1H), 4.93 (s, 2H), 3.70 (s, 3H), 2.17 (s, 6H);
LCMS: purity: 98%; MS (m/e): 431 (MH+). 615
N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-N2- 1H NMR
(DMSO-d6): d 9.75 (s, 1H), 9.53 (s, 1H), 8.15 (d, J = 4.5 Hz, + + +
(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.80 (d,
J = 2.7 Hz, 1H), 7.66 (dd, J = 2.7 and 9.0 Hz, 1H), 7.00 (d, J =
9.0 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.14 (t, J = 2.1 Hz, 1H),
4.90 (s, 2H), 3.71 (s, 3H), 3.64 (s, 6H); LCMS: 616
N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-N2-(3- 1H NMR
(DMSO-d6): d 9.63 (s, 1H), 9.41 (s, 1H), 8.12 (d, J = 4.2 Hz, + + +
chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.76
(d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 2.4
and 9.0 Hz, 1H), 7.44 (dd, J = 2.7 and 8.7 Hz, 1H), 7.04 (d, J =
8.7 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.90 (s, 2H), 617
N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4- 1H NMR (DMSO-d6):
d 9.64 (s, 1H), 9.45 (s, 1H), 8.14 (d, J = 4.2 Hz, + + +
(methoxycarbonyl)methyleneoxyphenyl]-5-fluoro-2,4- 1H), 7.75 (d, J
= 2.4 Hz, 1H), 7.61 (dd, J = 2.4 and 9.0 Hz, 1H), 7.38 (s,
pyrimidinediamine 2H), 7.02 (d, J = 9.0 Hz, 1H), 4.91 (s, 2H), 3.70
(s, 3H), 2.21 (s, 6H); LCMS: purity: 95%; MS (m/e): 465 (M+). 618
N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-5- 1H NMR
(DMSO-d6): d 10.86 (s, 1H), 9.23 (s, 1H), 8.94 (s, 1H), + + -
fluoro-N2-(indol-5-yl)-2,4-pyrimidinediamine 8.03 (d, J = 3.9 Hz,
1H), 7.83 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.68 (dd, J = 2.4 and
9.0 Hz, 1H), 7.25-7.21 (m, 3H), 6.93 (d, J = 9.0 Hz, 1H), 6.27 (t,
J = 2.4 Hz, 1H), 4.89 (s, 2H), 3.71 (s, 3 619
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 9.63 (bs, 1H), 9.34 (bs, 1H), 8.11 (d, J = 4.2 Hz, + +
+ dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.72 (d, J =
2.7 Hz, 1H), 7.64 (dd, J = 2.7 and 9.0 Hz, 1H), 7.12 (d, J = 8.7
Hz, 1H), 6.58 (s, 1H), 4.05 (t, J = 5.1 Hz, 2H), 3.73 (t, J = 5.1
Hz, 2H), 2.16 (s, 6H),; LCMS: purity: 9 620
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2-(3,5- 1H NMR
(DMSO-d6): d 9.29 (s, 1H), 9.13 (s, 1H), 8.08 (d, J = 3.6 Hz, + + +
dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.75 (d, J =
2.7 Hz, 1H), 7.71 (dd, J = 2.7 and 8.7 Hz, 1H), 7.08 (d, J = 9.0
Hz, 1H), 6.90 (d, J = 2.1 Hz, 2H), 6.05 (t, J = 2.1 Hz, 1H), 4.89
(t, J = 5.1 Hz, 1H), 4.05 (t, J = 5.1 Hz, 2H 621
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2-(3-chloro-4- 1H NMR
(DMSO-d6): d 9.29 (s, 1H), 9.15 (s, 1H), 8.06 (d, J = 3.6 Hz, + + -
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.74 (d, J = 2.1
Hz, 2H), 7.63 (dd, J = 2.7 and 9.0 Hz, 1H), 7.46 (dd, J = 2.7 and
9.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H),
4.87 (t, J = 5.4 Hz, 1H), 4.05 (t, J = 5 622
N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4-(2- 1H NMR
(DMSO-d6): d 9.31 (s, 1H), 9.18 (s, 1H), 8.08 (d, J = 3.9 Hz, + + -
hydroxyethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 1H), 7.72
(d, J = 2.7 Hz, 1H), 7.63 (dd, J = 2.4 and 9.0 Hz, 1H), 7.42 (s,
2H), 7.12 (d, J = 9.0 Hz, 1H), 4.87 (t, J = 5.7 Hz, 1H), 4.04 (t, J
= 5.1 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 2.20 (s, 623
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.84 (s, 1H), 9.17 (s, 1H), 8.90 (s, 1H), + + +
(indol-5-yl)-2,4-pyrimidinediamine 8.01 (d, J = 3.9 Hz, 1H),
7.82-7.76 (m, 2H), 7.67 (dd, J = 3.0 and 9.3 Hz, 1H), 7.25-7.21 (m,
3H), 7.03 (d, J = 9.0 Hz, 1H), 6.28-6.25 (m, 1H), 4.87 (t, J = 5.4
Hz, 1H), 4.04 (t, J = 5.1 Hz, 2H), 624
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2-(4-chloro-3- 1H NMR
(DMSO-d6): d 9.49 (s, 1H), 9.42 (s, 1H), 8.12 (d, J = 3.9 Hz, + + -
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.80 (d, J = 2.4
Hz, 1H), 7.59 (dd, J = 2.7 and 9.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.30
(dd, J = 2.7 and 8.4 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.12 (d, J
= 8.7 Hz, 1H), 4.06 (t, J = 4.8 Hz, 625 N4-[3-Chloro-4-(N- 1H NMR
(DMSO-d6): d 10.84 (s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), + + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-(indol- 8.02
(d, J = 3.9 Hz, 1H), 7.90-7.82 (m, 2H), 7.73 (dd, J = 2.4 and 9.0
Hz, 5-yl)-2,4-pyrimidinediamine 1H), 7.26-7.19 (m, 3H), 6.93 (d, J
= 8.7 Hz, 1H), 6.28 (t, J = 2.4 Hz, 1H), 4.52 (s, 2H), 2.67 (d, J =
4.5 Hz, 3H); LCMS 626
2-Chloro-N4-(4-chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl- 1H
NMR (DMSO-d6): d 8.17 (d, J = 5.1 Hz, 1H), 7.23 (s, 2H), 3.38 (s, -
+ 4-pyrimidineamine 3H), 2.32 (s, 6H); LCMS: purity: 98%; MS (m/e):
301 (MH+). 627 2-Chloro-5-fluoro-N4-methyl-N4-[3,4- 1H NMR
(DMSO-d6): d 7.94 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 9.6 Hz, - -
(tetrafluoroethylenedioxy)phenyl]-4-pyrimidineamine 1H), 7.17 (d, J
= 9.6 Hz, 1H), 7.05-7.00 (m, 2H), 3.50 (s, 3H); LCMS: purity: 92%;
MS (m/e): 368 (MH+). 628
2-Chloro-N4-[3,4-(difluoromethylenedioxy)phenyl]-5-fluoro-N4- 1H
NMR (DMSO-d6): d 7.82 (d, J = 4.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, - -
methyl-4-pyrimidineamine 1H), 6.90-6.83 (m, 2H), 3.40 (s, 3H);
LCMS: purity: 100%; MS (m/e): 318 (MH+). 629
N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-(indol-6-yl)- 1H
NMR (DMSO-d6): d 10.86 (s, 1H), 9.67 (s, 1H), 9.14 (s, 1H), + + -
2,4-pyrimidinediamine 8.44 (dd, J = 2.4 and 9.0 Hz, 1H), 8.15 (d, J
= 3.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J =
9.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 2.1 Hz, 1H),
7.14 (dd, J = 1.8 a 630
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4- 1H NMR
(DMSO-d6): d 10.85 (s, 1H), 9.35 (s, 1H), 9.04 (s, 1H), + + -
pyrimidinediamine 8.10 (d, J = 3.6 Hz, 1H), 7.79 (s, 1H), 7.62-7.57
(m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 7.19
(t, J = 2.7 Hz, 1H), 7.15 (dd, J = 1.8 and 8.4 Hz, 1H), 6.34-6.30
(m, 1H), 3.67 631
N4-(3-Chloro-4-methoxycarbonylmethyleneoxyphenyl)-5- 1H NMR
(DMSO-d6): d 10.78 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H), + + +
fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine 8.05 (d, J = 3.6 Hz,
1H), 7.85 (d, J = 2.7 Hz, 1H), 7.79-7.73 (m, 2H), 7.36 (d, J = 8.4
Hz, 1H), 7.19 (dd, J = 2.1 and 8.7 Hz, 1H), 7.16 (t, J = 3.0 Hz,
1H), 6.95 (d, J = 9.0 Hz, 1H), 6.32-6.28 (m, 632
N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.79 (s, 1H), 9.19 (d, J = 1.2 Hz, 1H), 9.01 (s, + +
- (indol-6-yl)-2,4-pyrimidinediamine 1H), 8.04 (d, J = 3.6 Hz, 1
H), 7.84 (d, J = 2.7, 1 H), 7.79-7.73 (m, 2 H), 7.36 (d, J = 8.4
Hz, 1H), 7.19 (dd, J = 1.8 and 8.4 Hz, 1H), 7.16 (t, J = 2.4 Hz,
1H), 7.05 (d, J = 9.3 Hz, 1H), 633
5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-[3,4- 1H NMR (DMSO-d6): d
9.76 (s, 1H), 9.63 (s, 1H), 8.33-8.29 (m, 1H), + -
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.22 (d, J
= 3.6 Hz, 1H), 8.16-8.13 (m, 1H), 7.78-7.74 (m, 1H), 7.62 (dd, J =
2.4 and 9.0 Hz, 1H), 7.58-7.53 (m, 1H), 7.42-7.31 (m, 3H),; LCMS:
purity: 92%; MS (m/e): 478 (MH+). 634
5-Fluoro-N4-methyl-N2-[3-(oxazol-2-yl)phenyl]-N4-[3,4- 1H NMR
(DMSO-d6): d 9.67 (s, 1H), 8.57 (t, J = 1.8 Hz, 1H), - + -
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.18-8.16
(m, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.72-7.66 (m, 1H), 7.60 (d, J =
1.8 Hz, 1H), 7.54-7.47 (m, 2H), 7.39-7.32 (m, 3H), 3.53 (s, 3H);
LCMS: purity: 96%; MS (m/e): 492 (MH+). 635 N2-[3,5-Dimethyl-4-(N-
1H NMR (DMSO-d6): d 9.02 (s, 1H), 8.12-8.06 (m, 1H), 7.88 (d, J =
5.7 Hz, + + + methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4- 1H),
7.34 (s, 2H), 6.83 (d, J = 6.9 Hz, 1H), 6.82 (s, 1H),
ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 6.73 (dd, J = 3.0 and
9.0 Hz, 1H), 4.24 (s, 4H), 4.11 (s, 2H), 3.38 (s, 3H),
pyrimidinediamine 2.69 (d, J = 4.8 Hz, 3H), 2.16 (s, 6H); LCMS: pu
636 N2-[3,5-Dimethyl-4-(N- 1H NMR (DMSO-d6): d 9.15 (s, 1H),
8.12-8.05 (m, 1H), 8.02 (d, J = 5.7 Hz, + + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 1H), 8.02 (d,
J = 5.7 Hz, 1H), 7.55 (dd, J = 0.9 and 2.7 Hz, 1H),
methyl-N4-[3,4-(tetrafluoroethylenedioxy)phenyl]-2,4- 7.48 (d, J =
9.3 Hz, 1H), 7.31 (s, 2H), 7.27 (dd, J = 0.9 and 2.1 Hz, 1H),
pyrimidinediamine 4.11 (s, 2H), 3.46 (s, 3H), 2.69 (d, J = 4.8 637
N2-[3,5-Dimethyl-4-(N- 1H NMR (DMSO-d6): d 9.59 (s, 1H), 9.14 (s,
1H), 8.16-8.08 (m, 3H), + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-[3,4- 7.61 (dd,
J = 2.7 and 9.0 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 (s, 2H),
(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 4.12 (s,
2H), 2.69 (d, J = 4.8 Hz, 3H), 2.15 (s, 6H); LCMS: purity: 99%; MS
(m/e): 526 (MH+). 638 N2-[3,5-Dimethyl-4-(N- 1H NMR (DMSO-d6): d
9.07 (s, 1H), 8.13-8.05 (m, 1H), 7.94 (d, J = 5.7 Hz, + + +
methylamino)carbonylmethyleneoxyphenyl]-N4-(3,5- 1H), 7.35 (s, 2H),
6.44 (dd, J = 0.6 and 2.4 Hz, 2H), 6.39 (t, J = 2.4 Hz,
dimethoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H), 4.16
(s, 2H), 3.72 (s, 6H), 3.43 (s, 3H), 2.69 (d, J = 4.8 Hz, 3H), 2.16
(s, 6H); LCMS: purity: 99%; MS 639
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.60 (s, 1H), 9.45 (s, 1H), 9.09 (s, 1H), + + -
[1-(methoxycarbonylmethylene)indol-6-yl]-2,4- 8.04 (d, J = 3.6 Hz,
1H), 7.57 (s, 1H), 7.40-7.33 (m, 2H), 7.31-7.24 (m, 2H),
pyrimidinediamine 7.20 (d, J = 3.3 Hz, 1H), 6.81 (d, J = 8.7 Hz,
1H), 3.35 (d, J = 2.4 Hz, 1H), 4.91 (s, 2H), 3.63 (s, 3H), 1.40 (s,
6H 640 N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 9.42 (s, 1H), 9.24
(s, 1H), 8.07 (d, J = 3.9 Hz, + + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- 1H),
7.92-7.84 (m, 2H), 7.71 (dd, J = 2.7 and 9.3 Hz, 1H), 7.55 (s, 1H),
(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 7.41
(d, J = 8.4 Hz, 1H), 7.29 (dd, J = 1.5 and 8.4 Hz, 1H), 7.20 (d, J
= 3.3 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.36 641
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d
9.34 (s, 1H), 9.10 (s, 1H), 8.09 (d, J = 3.6 Hz, + + +
(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 1H),
7.62-7.59 (m, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4 and
8.4 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.27-7.22 (m, 2H), 7.20 (d,
J = 3.3 Hz, 1H), 6.36 (dd, J = 0.6 and 3.0 Hz, 1H), 642
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d
9.19 (s, 1H), 9.14 (s, 1H), 8.02 (d, J = 3.9 Hz, + + -
(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 1H),
7.63 (s, 1H), 7.40-7.31 (m, 2H), 7.30-7.17 (m, 3H), 6.74 (d, J =
9.0 Hz, 1H), 6.35 (d, J = 2.7 Hz, 1H), 4.90 (s, 2H), 4.21 (s, 4H),
3.63 (s, 3H); LCMS: purity: 93%; MS (m/e): 450 (MH+) 643
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.56 (s, 1H), 9.20 (s, 1H), 8.79 (s, 1H), + + -
[1-(methoxycarbonylmethylene)indol-5-yl]-2,4- 8.00 (d, J = 3.6 Hz,
1H), 7.86 (s, 1H), 7.33 (dd, J = 2.1 and 8.7 Hz, 1H),
pyrimidinediamine 7.27-7.16 (m, 4H), 6.83 (d, J = 8.7 Hz, 1H), 6.27
(d, J = 3.0 Hz, 1H), 5.05 (s, 2H), 3.66 (s, 3H), 1.40 (s, 6H);
LCMS: p 644 N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 9.22 (s, 1H),
8.96 (s, 1H), 8.03 (d, J = 3.9 Hz, + + -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- 1H),
7.90-7.72 (m, 4H), 7.28-7.23 (m, 3H), 6.94 (d, J = 8.7 Hz, 1H),
(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 6.32
(d, J = 3.0 Hz, 1H), 5.07 (s, 2H), 4.53 (s, 2H), 3.67 (s, 3H), 2.67
(d, J = 4.5 Hz, 3H),; LCMS: purity: 90%; MS (m 645
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d
9.32 (s, 1H), 8.96 (s, 1H), 8.07 (d, J = 3.6 Hz, + + -
(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H),
7.84 (s, 1H), 7.55-7.47 (m, 2H), 7.28-7.17 (m, 4H), 6.29 (d, J =
3.0 Hz, 1H), 5.08 (s, 2H), 3.67 (s, 3H), 3.64 (s, 3H); LCMS:
purity: 96%; MS (m/e): 457 (MH+). 646
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d
9.18 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 3.0 Hz, + + -
(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H),
7.82-7.76 (m, 2H), 7.70 (dd, J = 2.1 and 9.0 Hz, 1H), 7.27-7.21 (m,
3H), 7.03 (d, J = 9.0 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 5.06 (s,
2H), 3.83 (s, 3H), 3.66 (s, 3H); LCMS: purity: 98% 647
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d
10.18 (s, 1H), 9.99 (s, 1H), 8.16 (d, J - 4.5 Hz, + + -
(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H),
7.74 (s, 1H), 7.46-7.18 (m, 3H), 7.34-7.18 (m, 3H), 6.83 (d, J =
8.1 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.29 (s, 4H),
3.74 (s, 3H); LCMS: purity: 92%; MS (m/e): 450 (MH+ 648
N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 9.25 (s, 1H), 9.07 (s, 1H),
8.04 (d, J = 3.6 Hz, + + - +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1-(N- 1H),
7.90-7.83 (m, 3H), 7.77-7.73 (m, 1H), 7.55-7.52 (m, 1H), 7.39 (d,
methylamino)carbonylmethyleneindol-6-yl]-2,4- J = 9.0 Hz, 1H),
7.32-7.26 (m, 1H), 7.16 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 9.3 Hz,
pyrimidinediamine 1H), 6.33 (d, J = 3.0 Hz, 1H), 4.62 ( 649
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR (DMSO-d6): d
9.06 (s, 1H), 9.02 (s, 1H), 7.99 (d, J = 3.9 Hz, + + -
methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 7.88-7.82 (m,
1H),
7.58 (s, 1H), 7.39-7.33 (m, 2H), 7.32-7.25 (m, pyrimidinediamine
2H), 7.16 (d, J = 3.3 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 6.33 (d, J
= 3.3 Hz, 1H), 4.63 (s, 2H), 4.19 (s, 4H), 2.58 (d 650
5-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyrid-5-yl]-N2-[1-(N- 1H NMR
(DMSO-d6): d 9.26 (s, 1H), 8.98 (s, 1H), 8.51 (s, 1H), +
methylamino)carbonylmethyleneindol-5-yl]-2,4- 8.07 (dd, J = 2.4 and
9.0 Hz, 1H), 8.03 (d, J = 3.9 Hz, 1H), 7.98-7.92 (m,
pyrimidinediamine 1H), 7.87 (s, 1H), 7.24-7.14 (m, 3H), 6.76 (d, J
= 9.0 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 4.84 (t, J = 5.4 Hz, 1H),
4.72 ( 651
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 9.55 (s, 1H), 9.09 (s, 1H), 8.15-7.99 (m, 2H), +
methylamino)carbonylmethyleneindol-5-yl]-2,4- 8.02-7.95 (m, 1H),
7.89 (dd, J = 1.5 and 9.6 Hz, 1H), 7.75 (s, 1H), pyrimidinediamine
7.40 (d, J = 9.0 Hz, 1H), 7.27-7.21 (m, 3H), 6.30 (d, J = 2.7 Hz,
1H), 4.73 (s, 2H), 2.61 (d, J = 4.5 Hz, 3H); LCMS: purity 652
N4-[3-Chloro-4-(N- 1H NMR (DMSO-d6): d 9.88 (s, 1H), 9.70 (s, 1H),
8.12-8.03 (m, 2H), + +
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1-(N-
7.94-7.87 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69-7.63 (m, 2H),
methylamino)carbonylmethyleneindol-5-yl]-2,4- 7.35-7.27 (m, 2H),
7.17 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.35 (d,
pyrimidinediamine J = 3.0 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 2.
653 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 10.22 (s, 1H), 9.91 (s, 1H), 8.16 (d, J = 4.8 Hz, +
methylamino)carbonylmethyleneindol-5-yl]-2,4- 1H), 8.12-8.05 (m,
1H), 7.70-7.66 (m, 1H), 7.52-7.48 (m, 1H), 7.42 (d,
pyrimidinediamine J = 7.8 Hz, 1H), 7.37-7.28 (m, 3H), 7.16-7.10 (m,
1H), 6.35 (d, J = 2.7 Hz, 1H), 4.79 (s, 2H), 3.63 (s, 3H), 2.62 (d,
654 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 10.21 (s, 1H), 9.94 (s, 1H), 8.16-8.03 (m, 2H), +
methylamino)carbonylmethyleneindol-5-yl]-2,4- 7.79-7.74 (m, 1H),
7.65-7.58 (m, 2H), 7.37-7.30 (m, 2H), 7.14 (d, J = 8.4 Hz,
pyrimidinediamine 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 3.0
Hz, 1H), 4.78 (s, 2H), 3.84 (s, 3H), 2.61 (d, J = 4.5 Hz, 3H); LC
655 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 10.19 (bs, 1H), 10.04 (bs, 1H), 8.12-8.03 (m, +
methylamino)carbonylmethyleneindol-5-yl]-2,4- 2H), 7.66-7.61 (m,
1H), 7.36-7.30 (m, 2H), 7.27-7.09 (m, 3H), 6.78 (d,
pyrimidinediamine J = 8.4 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 4.79
(s, 2H), 4.23 (s, 4H), 2.61 (d, J = 4.2 Hz, 3H); LCMS: purity: 99%;
MS ( 656 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2-
1H NMR (DMSO-d6): d 9.46 (s, 1H), 9.07 (s, 1H), 8.24-8.17 (m, 1H),
+ [1-(N-methylamino)carbonylmethyleneindol-5-yl]-2,4- 8.11 (d, J =
3.0 Hz, 1H), 8.00-7.94 (m, 1H), 7.94-7.86 (m, 2H), 7.77 (s,
pyrimidinediamine 1H), 7.31-7.22 (m, 4H), 6.33 (d, J = 3.3 Hz, 1H),
4.73 (s, 2H), 2.73 (d, J = 4.8 Hz, 3H), 2.60 (d, J = 4.8 Hz, 3H);
LC 657 2-Chloro-5-fluoro-N4-(2-methoxypyrid-5-yl)-N4-methyl-4- 1H
NMR (DMSO-d6): d 8.21 (d, J = 3.0 Hz, 1H), 8.15 (d, J = 5.7 Hz, - -
pyrimidineamine 1H), 7.78 (dd, J = 2.7 and 8.7 Hz, 1H), 6.87 (d, J
= 8.7 Hz, 1H), 3.86 (s, 3H), 3.38 (s, 3H); LCMS: purity: 95%; MS
(m/e): 269 (MH+). 658
2-Chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 8.25 (d, J = 5.4 Hz, 1H), 7.97-7.94 (m, 1H), - -
methyl-4-pyrimidineamine 7.78-7.72 (m, 2H), 3.45 (s, 3H); LCMS:
purity: 96%; MS (m/e): 341 (MH+). 659
2-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-N4-methyl- 1H NMR
(DMSO-d6): d 8.18 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, - -
4-pyrimidineamine 1H), 7.24 (s, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.82
(s, 1H), 3.31 (s, 3H); LCMS: purity: 99%; MS (m/e): 303 (MH+). 660
2-Chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-methyl- 1H NMR
(DMSO-d6): d 8.14 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 2.7 Hz, - -
4-pyrimidineamine 1H), 7.34 (dd, J = 2.4 and 8.7 Hz, 1H), 7.15 (d,
J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.36 (s, 3H); LCMS: purity: 96%; MS
(m/e): 303 (MH+). 661 2-Chloro-N4-[3-chloro-4-(N- 1H NMR (DMSO-d6):
d 8.15 (d, J = 5.4 Hz, 1H), 7.94-7.87 (m, 1H), - -
methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 7.58 (d, J =
2.4 Hz, 1H), 7.32 (dd, J = 2.4 and 8.7 Hz, 1H), 7.02 (d, J = 9.0
Hz, methyl-4-pyrimidineamine 1H), 4.60 (s, 2H), 3.36 (s, 3H), 2.66
(d, J = 4.8 Hz, 3H),; LCMS: purity: 90%; MS (m/e): 360 (MH+). 662
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 10.22 (s, 1H), 9.88 (s, 1H), 8.22 (d, J = 3.9 Hz, + +
- methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 8.14 (d, J =
2.7 Hz, 1H), 8.02-7.95 (m, 1H), 7.84-7.78 (m, 1H),
pyrimidinediamine 7.49 (d, J = 8.1 Hz, 1H), 7.45-7.37 (m, 2H), 7.27
(d, J = 2.7 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.18 (d, J = 8.4 Hz,
1H) 663 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR
(DMSO-d6): d 10.13 (s, 1H), 9.90 (s, 1H), 8.10 (d, J = 4.5 Hz, + -
methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 7.91 (d, J = 3.9
Hz, 1H), 7.49-7.34 (m, 4H), 7.23 (d, J = 3.3 Hz, pyrimidinediamine
1H), 7.17 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.37 (d, J
= 3.0 Hz, 1H), 4.62 (s, 2H), 3.52 (s, 3H), 2.51 (d, 664
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(N- 1H NMR (DMSO-d6):
d 10.21 (s, 1H), 10.04 (s, 1H), 8.14 (d, J = 5.1 Hz, + + -
methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 7.98-7.92 (m,
1H), 7.84 (d, J = 2.7 Hz, 1H), 7.60 (dd, J = 2.4 pyrimidinediamine
and 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J
= 3.3 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.01 (d, J= 665
N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR
(DMSO-d6): d 9.50 (s, 1H), 9.19 (s, 1H), 8.28-8.20 (m, 1H), + -
[1-(N-methylamino)carbonylmethyleneindol-6-yl]-2,4- 8.12 (d, J =
3.3 Hz, 1H), 7.97-7.84 (m, 3H), 7.53 (s, 1H), 7.42 (d, J = 8.7 Hz,
pyrimidinediamine 1H), 7.32-7.25 (d, J = 3.3 Hz, 1H), 6.35 (d, J =
3.0 Hz, 1H), 4.63 (s, 2H), 2.74 (d, J = 4.5 Hz, 3H), 2.58 (d, J 666
2-Chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4- 1H NMR
(DMSO-d6): d 9.94 (s, 1H), 8.28 (dd, J = 0.6 and 3.6 Hz, 1H), - -
pyrimidineamine 7.75 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 2.4 and 8.7
Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H); LCMS: purity: 96%;
MS (m/e): 288 (M+). 667
5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-(3,4,5- 1H NMR (DMSO-d6): d
9.38 (s, 1H), 9.28 (s, 1H), 8.28 (s, 1H), +
trimethoxyphenyl)-2,4-pyrimidinediamine 8.14-8.10 (m, 2H), 7.87 (d,
J = 7.2 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.34-7.27 (m, 2H), 7.06
(s, 2H), 3.70 (s, 6H), 3.63 (s, 3H); LCMS: purity: 98%; MS (m/e):
438 (MH+). 668 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2,3,4- 1H
NMR (DMSO-d6): d 9.10 (s, 1H), 7.96 (d, J = 3.9 Hz, 1H), 7.75 (s, +
trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.50 (d, J = 8.7 Hz,
1H), 7.26 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 2.4 Hz, 1H), 6.74-6.64
(m, 2H), 4.25-4.18 (m, 4H), 3.77 (s, 3H), 3.75 (s, 3H), 3.74 (s,
3H); LCMS: purity: 99%; MS (m/ 669
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR (DMSO-d6):
d 9.26 (s, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86 (s, -
trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.81 (d, J = 2.7 Hz,
1H), 7.54 (dd, J = 2.4 and 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H),
7.03 (d, J = 9.0 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H),
3.76 (s, 3H), 3.74 (s, 3H), 3.73 670
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR (DMSO-d6):
d 816 (d, J = 4.8 Hz, 1H), 7.56-7.51 (m, 1H), -
trimethoxyphenyl)-2,4-pyrimidinediamine 7.36-7.24 (m, 4H), 6.74 (d,
J = 9.3 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.68 (s,
3H),; LCMS: purity: 95%; MS (m/e): 436 (MH+). 671
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR
(DMSO-d6): d 8.20 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 2.7 Hz, +
trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.73-7.66 (m, 1H),
7.45 (d, J = 9.6 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.75 (d, J =
9.0 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H); LCMS:
purity: 95%; MS (m/e): 490 (MH+). 672
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.73 (s, 1H), 10.44 (s, 1H), 8.21 (d, J = 4.8 Hz, +
(2,3,4-trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.43-7.32 (m,
1H), 7.27-7.13 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 9.6
Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 1.41 (s, 6H);
LCMS: purity: 98%; MS (m/e): 470 (MH 673
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.14 (s, 1H), 9.98 (s, 1H), 9.63 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 8.17 (d, J = 3.9
Hz, 1H), 7.62-7.52 (m, 3H), 7.36-7.25 (m, 4H), 6.87 (s, 2H),
Benzenesulfonic Acid Salt 3.66 (s, 6H), 3.61 (s, 3H), 1.43 (s, 6H).
674 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H
NMR (DMSO-d6): d 11.13 (s, 1H), 9.95 (s, 1H), 9.62 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 8.18 (d, J = 3.9
Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H),
Methanesulfonic Acid Salt 6.88 (s, 2H), 3.66 (s, 6H), 3.61 (s, 3H),
2.33 (s, 3H), 1.43 (s, 6H). 675
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.12 (s, 1H), 9.89 (s, 1H), 9.57 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine p-Toluene 8.17
(d, J = 3.9 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.8 Hz,
2H), Sulfonic Acid Salt 7.31 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.8
Hz, 2H), 6.89 (s, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 2.28 (s, 3H),
1.43 (s, 6 676
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.12 (s, 1H), 9.81 (s, 1H), 9.53 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 4- 8.16 (d, J =
4.2 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H),
Hydroxybenzenesulfonic Acid Salt 7.31 (d, J = 8.7 Hz, 1H), 6.90 (s,
2H), 6.64 (d, J = 8.7 Hz, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 1.43 (s,
6H). 677
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.72 (s, 1H), 9.47 (s, 1H), +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 2,4,6- 8.15 (d, J
= 4.2 Hz, 1H), 7.62-7.56 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.91
(s, Trimethylbenzenesulfonic Acid Salt 2H), 6.72 (s, 2H), 3.66 (s,
6H), 3.61 (s, 3H), 2.48 (s, 6H), 2.16 (s, 3H), 1.43 (s, 6H). 678
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.08 (s, 2H), 9.46 (s, 2H), 9.30 (s, 2H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 0.5 8.91 (s, 1H),
8.70 (d, J = 5.4 Hz, 1H), 8.37 (dd, J = 1.5 and 7.8 Hz, 1H),
Pyridine-3-sulfonic Acid Salt 8.13 (d, J = 3.6 Hz, 2H), 7.80-7.74
(m, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.97
(s, 4H), 3.66 (s, 1 679
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.08 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine p- 8.13 (d, J =
3.3 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H),
Ethylbenzenesulfonic Acid Salt 7.31 (d, J = 8.1 Hz, 1H), 7.12 (d, J
= 7.8 Hz, 2H), 6.97 (s, 2H), 3.65 (s, 6H), 3.59 (s, 3H), 2.57 (q, J
= 7.8 Hz, 2H), 680
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.08 (s, 2H), 9.54 (s, 2H), 9.35 (s, 2H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 0.5 1,2- 8.14 (d,
J = 3.9 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz,
2H), Ethanedisulfonic Acid Salt 6.95 (s, 4H), 3.66 (s, 12H), 3.60
(s, 6H), 2.62 (s, 4H), 1.43 (s, 12H). 681
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.11 (s, 1H), 9.83 (s, 1H), 9.54 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1R)-10- 8.17 (d,
J = 3.9 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.4 Hz,
1H), Camphorsulfonic Acid Salt 6.99 (s, 2H), 3.66 (s, 6H), 3.61 (s,
3H), 2.86 (d, J = 14.7 Hz, 1H), 2.67 (t, J = 9.9 Hz, 1H), 2.38 (d,
J = 14.7 Hz, 1H) 682
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.08 (s, 1H), 9.55 (s, 1H), 9.36 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1S)-10- 8.14 (d,
J = 3.9 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.4 Hz,
1H), Camphorsulfonic Acid Salt 6.94 (s, 2H), 3.66 (s, 6H), 3.60 (s,
3H), 2.85 (d, J = 14.7 Hz, 1H), 2.68 (t, 11.4 Hz, 1H), 2.36 (d, J =
14.7 Hz, 1H), 683
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.04 (s, 1H), 9.08-8.90 (m, 2H), 8.07 (d, J = 3.3 Hz,
+ + N2-[1-(N-methylamino)carbonylmethyleneindol-5-yl]-2,4- 1H),
7.99-7.89 (m, 1H), 7.81-7.96 (m, 1H), 7.70-7.64 (m, 1H),
pyrimidinediamine 7.29-7.20 (m, 4H), 6.29 (d, J = 3.0 Hz, 1H), 4.73
(s, 2H), 2.61 (d, J = 4.5 Hz, 3H), 1.42 (s, 6H),; LCMS: purity:
99%; 684
N2-(4-Chloro-3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H- 1H NMR
(DMSO-d6): d 11.13 (s, 1H), 9.68 (s, 1H), 9.46 (s, 1H), +
5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- 8.17 (d,
J = 3.6 Hz, 1H), 7.51-7.35 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 2.28
(s, Toluenesulfonic Acid Salt 3H), 2.22 (s, 6H), 1.43 (s, 6H). 685
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.31 (s, 1H), 9.89 (s, 1H), 9.66 (s, 1H), + +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine Hydrogen 8.18 (d,
J = 4.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz,
1H), Chloride Salt 6.89 (s, 2H), 3.65 (s, 6H), 3.61 (s, 3H), 1.43
(s, 6H) 686
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5- 1H NMR
(DMSO-d6): d 11.07 (s, 1H), 9.32 (s, 1H), 9.27 (s, 1H), + +
dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.13 (d, J
= 3.3 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J = 8.7 Hz, 1H), 7.35 (d, J =
8.7 Hz, 1H), 1.43 (s, 6H); LCMS: purity: 92%; MS (m/e): 467
(MH.sup.+). 687
N2,N4-Bis(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 9.49 (bs, 2H), 8.18 (d, J = 3.3 Hz, 1H), 7.93 (d, +
fluoro-2,4-pyrimidinediamine J = 8.7 Hz, 1H), 7.74 (d, J = 8.4 Hz,
1H), 7.37 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.34 (s,
3H), 3.33 (s, 3H), 1.44 (s, 6H), 1.41 (s, 6H); LCMS: purity: 98%;
MS (m/e): 509 (MH.sup.+). 688
N2,N4-Bis(2,2-dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H NMR
(DMSO-d6): d 9.55 (s, 1H), 9.49 (s, 1H), 8.19 (d, J = 2.7 Hz, -
pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.97 (d, J = 8.7
Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38
(d, J = 8.7 Hz, 1H), 4.81 (s, 2H), 4.80 (s, 2H), 3.67 (s,
3H), 3.66 (s, 3H), 1.48 (s, 6H), 1.45 (s, 6H 689
5-Fluoro-N4-(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-N2- 1H
NMR (DMSO-d6): d 9.42 (s, 1H), 9.13 (s, 1H), 8.14 (d, J = 3.6 Hz, +
(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.80 (d, J =
8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz. 1H), 7.03 (s, 2H), 3.66 (s, 6H),
3.60 (s, 3H), 1.44 (s, 6H); LCMS: purity: 97%; MS (m/e): 485
(MH.sup.+). 690 N4-(2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H
NMR (DMSO-d6): d 9.46 (s, 1H), 9.15 (s, 1H), 8.15 (d, J = 3.6 Hz, +
pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-
1H), 7.86 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.04 (s,
2H), pyrimidinediamine 4.80 (s, 2H), 3.67 (s, 6H), 3.66 (s, 3H),
3.60 (s, 3H), 1.47 (s, 6H); LCMS: purity: 96%; MS (m/e): 543
(MH.sup.+). 691 N4-(2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H
NMR (DMSO-d6): d 9.27 (s, 1H), 8.22 (d, J = 4.8 Hz, 1H), 7.42 (d, +
pyrid[1,4]oxazin-6-yl)-5-fluoro-N4-carbomethoxymethyl-N2- J = 8.4
Hz, 1H), 6.98 (s, 2H), 6.81 (dd, J = 3.3 and 8.4 Hz, 1H), 4.83 (s,
(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 2H), 4.63 (s, 2H),
3.72 (s, 6H), 3.63 (s, 3H), 3.59 (s, 3H), 3.57 (s, 3H), 1.47 (s,
6H); LCMS: purity: 99%; MS (m 692
N2-[3,5-Dimethoxy-4-(2-(N-morpholino)ethyloxo)phenyl]-N4- 1H NMR
(DMSO-d6): d 11.04 (s, 1H), 9.14 (s, 1H), 9.09 (s, 1H), + +
(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.11
(d, J = 3.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz,
1H), pyrimidinediamine 7..02 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H),
3.65 (s, 6H), 3.58-3.53 (m, 4H), 2.58 (t, J = 6.0 Hz, 2H),
2.47-2.42 (m, 4H), 693
N2,N4-Bis(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 11.07 (s, 1H), 10.91 (s, 1H), 9.27 (s, 1H), +
fluoro-2,4-pyrimidinediamine 9.12 (s, 1H), 8.13 (d, J = 3.3 Hz,
1H), 7.69 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.32 (d, J
= 8.4 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 1.43 (s, gH), 1.39 (s,
6H); LCMS: purity: 99%; MS 694
N4-(3-Chloro-4-methoxyphenyl)-N2-(1-ethylindazol-5-yl)-5- 1H NMR
(DMSO-d6): d 10.36 (s, 1H), 10.21 (s, 1H), 8.24 (d, 1H, J = 4.9
Hz), + + - fluoro-2,4-pyrimidinediamine 7.92 (s, 1H), 7.83 (s, 1H),
7.74 (d, 1H, J = 2.6 Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (app dd,
1H, J = 2.3 and 9.1 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.09
(d, 1H, J = 9.1 Hz), 4.40 (qt, 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.38
(t, 3H, J = 7.0 Hz). LCMS: ret. time: 9.30 min.; purity: 97%; MS
(m/e): 414 (MH+) 695
N4-(3,4-Dichlorophenyl)-N2-(1-ethylindazol-5-yl)-5-fluoro-2,4-
.sup.1H NMR (DMSO-d6): d 10.28 (s, 1H), 10.02 (s, 1H), 8.28 (d, 1H,
J = 4.7 Hz), - - pyrimidinediamine 8.02 (d, 1H, J = 2.3 Hz), 7.94
(s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H, J = 9.1 Hz), 7.52
(d, 1H, J = 8.8 Hz), 7.42 (dd, 1H, J = 2.3 and 8.8 Hz), 4.41 (qt,
2H, J = 7.0 Hz 696
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(1- .sup.1H NMR
(DMSO-d6): d 10.77 (s, 1H), 10.39 (s, 1H), 10.21 (s, 1H), + + + +
ethylindazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J =
5.3 Hz), 7.89 (s, 2H), 7.61 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J =
8.8 Hz), 7.20 (dd, 2H, J = 2.3 and 8.2 Hz), 6.81 (d, 1H, J = 8.2
Hz), 4.39 (qt, 2H, J = 7.0 Hz), 1.37 (s, 6 697
N2-(1-Ethylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.26 (d, 1H, J = 4.9
Hz), + + - methoxyphenyl)-2,4-pyrimidinediamine 7.89 (s, 2H), 7.63
(d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.37 (d, 1H, J = 9.0
Hz), 7.31-7.23 (m, 1H), 7.19 (dd, 1H, J = 8.8 and 11.8 Hz), 4.41
(qt, 2H, J = 7.0 Hz), 3.60 698
N4-(3-Chloro-4-methoxyphenyl)-N2-(1-ethylindazol-6-yl)-5- .sup.1H
NMR (DMSO-d6): d 10.44 (s, 1H), 10.40 (s, 1H), 8.32 (d, 1H, J = 4.9
Hz), + + - fluoro-2,4-pyrimidinediamine 7.92 (s, 1H), 7.78 (app t,
2H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.58-7.52 (dt, 1H, J =
2.6 and 9.1 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.10 (d, 1H, J = 9.1
Hz), 4.11 (qt, 2H, J 699
N4-(3,4-Dichlorophenyl)-N2-(1-ethylindazol-6-yl)-5-fluoro-2,4-
.sup.1H NMR (DMSO-d6): d 9.92 (s, 1H), 9.78 (s, 1H), 8.27 (d, 1H, J
= 4.1 Hz0, + + pyrimidinediamine 8.08 (app d, 1H, J = 2.6 Hz), 7.93
(s, 1H), 7.91 (s, 1H), 7.76 (dt, 1H, J = 2.6 and 8.1 Hz), 7.62 (d,
1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.23 (d, 1H, J = 8.5
Hz), 4.14 (qt, 2 700
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(1- .sup.1H NMR
(DMSO-d6): d 10.75 (s, 1H), 10.18 (s, 2H), 8.25 (d, 1H, J = 4.7
Hz), + + + ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.94
(s, 1H), 7.84 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.27-7.17 (m, 3H),
6.86 (d, 1H, J = 8.5 Hz), 4.14 (qt, 2H, J = 7.0 Hz), 1.38 (s, 6H),
1.28 (t, 3H, J = 7.0 Hz). LCMS: ret. t 701
N2-(1-Ethylindazol-6-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.18 (s, 2H), 8,26 (d, 1H, J = 4.7 Hz), 7.93 (s, + +
methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.90 (s, 1H), 7.62 (d,
1H, J = 8.5 Hz), 7.50-7.46 (m, 1H), 7.30-7.27 (m, 1H), 7.19-7.13
(m, 2H), 4.09 (qt, 2H, J = 7.0 Hz), 3.60 (s, 3H), 1.27 (t, 3H, J =
7.0 Hz). LCMS: ret. time 702
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-n- .sup.1H NMR
(DMSO-d6): d 10.39 (s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = 4.7
Hz), + propylindazol-5-yl)-2,4-pyrimidinediamine 7.92 (s, 1H), 7.82
(s, 1H), 7.75 (d, 1H, J = 2.7 Hz), 6.66 (d, 1H, J = 9.1 Hz), 7.54
(dt, 1H, J = 2.3 and 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.33 (t,
2H, J = 7.0 Hz), 3.83 (s, 3H) 703
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-n-propylindazol-5-yl)-
.sup.1H NMR (DMSO-d6): d 10.21 (s, 1H), 9.93 (s, 1H), 8.26 (d, 1H,
J = 4.4 Hz), + 2,4-pyrimidinediamine 8.01 (d, 1H, J = 2.6 Hz), 7.94
(s, 1H), 7.87 (s, 1H), 7.69 (dd, 1H, J = 1.8 and 8.8 Hz), 7.65 (d,
1H, J = 9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 9.1
Hz), 4.34 (t, 2H, 704
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.75 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H,
J = 4.9 Hz), + + (1-n-propylindazol-5-yl)-2,4-pyrimidinediamine
7.94 (s, 1H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.27-7.17 (m,
3H), 6.86 (d, 1H, J = 8.8 Hz), 4.06 (t, 2H, J = 7.0 Hz), 1.72 (qt,
2H, J = 7.0 Hz), 1.38 (s, 6H), 0.71 (t, 3H, 705
5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(1-n- .sup.1H NMR
(DMSO-d6): d 10.46 (s, 1H), 10.35 (s, 1H), 8.28 (d, 1H, J = 4.9
Hz), + propylindazol-5-yl)-2,4-pyrimidinediamine 7.90 (s, 1 H),
7.87 (s, 1H), 7.63 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 2.3 and
8.8 Hz), 7.27-7.22 (m, 1H), 7.14 (dd, 1H, J = 1.8 and 11.1 Hz),
4.34 (t, 2H, J = 7.0 Hz), 3.60 (s, 706
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-n- .sup.1H NMR
(DMSO-d6): d 10.51 (s, 1H), 10.44 (s, 1H), 8.33 (d, 1H, J = 4.9
Hz), + + propylindazol-6-yl)-2,4-pyrimidinediamine 7.96 (s, 1H),
7.77 (d, 1H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J
= 2.6 and 8.8 Hz), 7.16 (dd, 1H, J = 2.6 and 8.8 Hz), 4.03 (t, 2H,
J = 7.0 Hz), 3.83 (s, 3H), 1.6 707
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-n-propylindazol-6-yl)-
.sup.1H NMR (DMSO-d6): d 10.15 (s, 1H), 10.02 (s, 1H), 8.30 (d, 1H,
J = 4.4 Hz), + + 2,4-pyrimidinediamine 8.06 (d, 1H, J = 2.6 Hz),
7.93 (s, 1H), 7.89 (s, 1H), 7.73 (dd, 1H, J = 2.6 and 8.5 Hz), 7.65
(d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J = 8.8
Hz), 4.07 (t, 2H, 708
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.77 (s, 1H), 10.37 (s, 1H), 10.16 (s,
1H), + + (1-n-propylindazol-6-yl)-2,4-pyrimidinediamine 8.21 (d,
1H, J = 5.3 Hz), 7.89 (s, 1H), 7.87 (s, 1H), 7.61 (d, 1H, J = 8.8
Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz),
8.87 (d, 1H, J = 8.8 Hz), 4.31 (t, 2H, J = 7.0 Hz) 709
5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(1-n- .sup.1H NMR
(DMSO-d6): d 10.40 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J = 5.0
Hz), + propylindazol-6-yl)-2,4-pyrimidinediamine 7.96 (s, 1H), 7.84
(s, 1H), 7.64 (d, 1H, J = 8.5 Hz), 7.47 (dt, 1H, J = 1.8 and 8.5
Hz), 7.26-7.22 (m, 2H), 7.15 (dd, 1H, J = 11.8 and 8.8 Hz), 4.02
(t, 2H, J = 7.0 Hz), 3.55 (s, 710
N2-(1-n-Butylindazol-5-yl)-N4-(3-chloro-4-methoxyphenyl)-5- .sup.1H
NMR (DMSO-d6): d 10.40 (s, 1H), 10.27 (s, 1H), 7.92 (s, 1H), +
fluoro-2,4-pyrimidinediamine 7.82 (s, 1H), 7.75 (d, 1H, J = 2.3
Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz),
7.39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.36 (t, 2H, J
= 7.3 Hz), 3.83 (s, 3H) 711
N2-(1-n-Butylindazol-5-yl)-N4-(3,4-dichlorophenyl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 10.43 (s, 1H), 10.20 (s, 1H), 8.32 (d, 1H,
J = 4.7 Hz), + 2,4-pyrimidinediamine 8.00 (d, 1H, J = 2.3 Hz), 7.95
(s, 1H), 7.83 (s, 1H), 7.67 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J =
8.8 Hz), 7.41 (dd, 1H, J = 2.3 and 8.8 Hz), 4.38 (t, 2H, J = 7.3
Hz), 1.79 (q, 2H, 712
N2-(1-n-Butylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H NMR
(DMSO-d6): d 10.75 (s, 1H), 10.28 (s, 1H), 10.05 (s, 1H), + +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.19 (d, 1H, J
= 4.9 Hz), 7.89 (s, 2H), 7.60 (d, 1H, J = 9.1 Hz), 7,38 (d, 1H, J =
9.1 Hz), 7.20 (dd, 1H, J = 1.8 and 9.1 Hz), 7.16 (s, 1H), 6.86 (d,
1H, J = 9.1 Hz), 4.35 (t, 2H, J = 7.3 Hz) 713
N2-(1-n-Butylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.27 (d, 1H, J = 4.9
Hz), + + methoxyphenyl)-2,4-pyrimidinediamine 7.89 (s, 1H), 7.87
(s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8
Hz), 7.36 (dd, 1H, J = 1.8 and 9.1 Hz), 7.28-7.23 (m, 1H), 7.13
(dd, 1H, J = 11.3 and 9.1 Hz0, 714
N2-(1-n-Butylindazol-6-yl)-N4-(3-chloro-4-methoxyphenyl)-5- .sup.1H
NMR (DMSO-d6): d 10.27 (s, 2H), 8.30 (d, 1H, J = 4.7 Hz), 7.94 (s,
+ fluoro-2,4-pyrimidinediamine 1H), 7.82 (s, 1H), 7.77 (d, 1H, J =
2.6 Hz), 7.65 (d, 1H, J = 8.8 Hz), 7.56 (dd, 1H, J = 2.6 and 8.8
Hz), 7.16 (d, 1H, J = 8.8 Hz0, 7.11 (d, 1H, J = 8.8 Hz), 4.06 (t,
2H, J = 7.3 Hz), 3 715
N2-(1-n-Butylindazol-6-yl)-N4-(3,4-dichlorophenyl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 10.21 (s, 1H), 10.09 (s, 1H), 8.32 (d, 1H,
J = 4.4 Hz), + 2,4-pyrimidinediamine 8.05 (d, 1H, J = 2.3 Hz), 7.94
(s, 1H), 7.86 (s, 1H0, 7.72 (d, 1H, J = 8.8 Hz), 7.66 (d, 1H, J =
8.8 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 4.11
(t, 2H, J = 7.3 716
N2-(1-n-Butylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H NMR
(DMSO-d6): d 11.77 (s, 1H), 10.40 (s, 1H), 10.36 (s, 1H), + +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.29 (d, 1H, J
= 4.9 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz),
7.23 (s, 2H), 7.18 (d, 1H, J = 8.8 Hz), 6.85 (d, 1H, J = 8.8 Hz),
4.10 (t, 2H, J = 7.3 Hz), 1.67 (q, 2H, J = 7 717
N2-(1-n-Butylindazol-6-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.42 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J = 4.7
Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.96 (s, 1H), 7.84 (s,
1H), 7.64 (d, 1H, J = 8.8 Hz), 7.50-7.46 (m, 1H), 7.27-7.22 (m,
1H), 7.16 (app t, 1H, J = 11.8 and 8.8 Hz), 4.06 (t, 2H, J = 7.3
Hz), 3.54 (s, 3H), 1.65 (q, 718
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.19
(s, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz), +
(cyclohexylmethyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.90
(s, 1H), 7.84 (s, 1H), 7.76 (d, 1H, J = 2.6 Hz), 7.62 (d, 1H, J =
9.1 Hz), 7.56 (dd, 1H, J = 2.6 and 9.1 Hz), 7.39 (dd, 1H, J = 1.8
and 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.2 719
N2-[1-(Cyclohexylmethyl)indazol-5-yl]-N4-(3,4-dichlorophenyl)-
.sup.1H NMR (DMSO-d6): d 9.69 (s, 1H), 9.38 (s, 1H), 8.17 (d, 1H, J
= 3.8 Hz), + 5-fluoro-2,4-pyrimidinediamine 8.07 (app d, 1H, J =
2.6 Hz), 7.92 (s, 1H), 7.88 (s, 1H0, 7.78 (d, 1H, J = 8.8 Hz), 7.58
(d, 1H, J = 9.1 Hz0, 7.49-7.44 (m, 2H), 4.19 (d, 2H, J = 7.3 Hz),
1.91-1.84 (m, 1H), 1.62 (m 720
N2-[1-(Cyclohexylmethyl)indazol-5-yl]-N4-(2,2-dimethyl-3-oxo-
.sup.1H 7.90 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J = 9.1 Hz), 7.37
(dd, 1H, J = 2.3 +
4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine and 8.8
Hz), 7.23 (dd, 1H, J = 2.3 and 9.1 Hz), 7.17 (s, 1H), 6.84 (d, 1H,
J = 9.1 Hz), 4.19 (d, 2H, J = 7.3 Hz), 1.91-1.84 (m, 1H), 1.62 (br
s, 3H), 1.47-1.38 (m, 2H), 1.36 (s 721
N2-[1-(Cyclohexylmethyl)indazol-5-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.31 (s, 1H), 10.13 (s, 1H), 8.25 (d, 1H,
J = 4.9 Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.89 (s, 1H),
7.87 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.6 and
8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 9.1 Hz), 7.29-7.25 (s, 1H), 7.12
(dd, 1H, J = 8.8 and 11.4 Hz), 722
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.12
(s, 2H), 8.26 (d, 1H, J = 4.7 Hz), 7.93 (s, + +
(cyclohexylmethyl)indazol-6-yl]-5-fluoro-2,4-pyrimidinediamine 1H),
7.85 (s, 1H), 7.78 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J = 8.8 Hz),
7.58 (dd, 1H, J = 2.6 and 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.11
(d, 1H, J = 8.8 Hz), 3.90 (d, 2H, J = 7.3 Hz), 3 723
N2-[1-(Cyclohexylmethyl)indazol-6-yl]-N4-(3,4-dichlorophenyl)-
.sup.1H NMR (DMSO-d6): d 10.05 (s, 1H), 9.91 (s, 1H), 8.29 (d, 1H,
J = 4.1 Hz0, - 5-fluoro-2,4-pyrimidinediamine 8.05 (d, 1H, J = 2.3
Hz), 7.92 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H, J = 2.3 and 8.8 Hz),
7.63 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J
= 8.8 Hz), 3.93 (d, 2H, 724
N2-[1-(Cyclohexylmethyl)indazol-6-yl]-N4-(2,2-dimethyl-3-oxo-
.sup.1H NMR (DMSO-d6): d 10.73 (s, 1H), 10.07 (s, 1H), 10.01 (s,
1H), + 4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.22
(d, 1H, J = 4.7 Hz), 7.91 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H, J =
8.8 Hz0, 7.26 (dd, 1H, J = 2.3 and 8.5 Hz), 7.22-7.19 (app m, 2H),
6.85 (d, 1H, J = 8.5 Hz), 3.93 (d, 2H, J = 7.3 Hz), 1
725 N2-[1-(Cyclohexylmethyl)indazol-6-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.24 (s, 2H), 8.29 (d, 1H, J = 4.7 Hz),
7.95 (s, + methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.86 (s, 1H),
7.63 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz),
7.28-7.24 (m, 1H), 7.19-7.12 (m, 2H), 3.91 (d, 2H, J = 7.3 Hz),
3.55 (s, 3H), 1.75-1.73 (m, 1H), 1.54 (br 726
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.40
(s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = 5.3 Hz), +
(cyclobutylmethyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.91
(s, 1H), 7.81 (s, 1H), 7.75 (d, 1H, J = 2.6 Hz), 7.68 (d, 1H, J =
9.1 Hz), 7.55 (dd, 1H, J = 2.6 and 2.6 and 8.8 Hz), 7.38 (d, 1H, J
= 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.39 727
N2-[1-(Cyclobutylmethyl)indazol-5-yl]-N4-(3,4-dichlorophenyl)-
.sup.1H NMR (DMSO-d6): d 10.32 (s, 1H), 10.06 (s, 1H), 8.29 (d, 1H,
J = 4.7 Hz), + 5-fluoro-2,4-pyrimidinediamine 8.00 (s, 1H), 7.93
(s, 1H), 7.84 (s, 1H), 7.68 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J =
8.8 Hz), 7.41 (d, 1H, J = 8.8 Hz), 4.40 (d, 2H), 2.86-2.76 (m, 1H),
1.96-1.75 (m, 6H). LCMS: 728
N2-[1-(Cyclobutylmethyl)indazol-5-yl]-N4-(2,2-dimethyl-3-oxo-
.sup.1H NMR (DMSO-d6): d 10.79 (s, 1H), 10.40 (s, 1H), 10.25 (s,
1H), + 4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.23
(d, 1H, J = 4.9 Hz), 7.88 (s, 1H0, 7.86 (s, 1H0, 7.64 (d, 1H, J =
8.8 Hz), 7.37 (d, 1H, J = 9.1 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 6.86
(d, 1H, J = 9.1 Hz), 4.37 (d, 1H, J = 7.0 Hz), 2.83-2 729
N2-[1-(Cyclobuylmethyl)indazol-5-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.48 (s, 1H), 10.36 (s, 1H), 8.29 (d, 1H,
J = 5.3 Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.88 (s, 1H),
7.86 (s, 1H0, 7.67 (d, 1H, J = 8.0 Hz), 7.43 (dd, 1H, J = 2.3 and
8.0 Hz), 7.35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.23 (m, 1H), 7.14
(dd, 1H, J = 9.1 and 11.8 Hz), 730
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.35
(s, 2H), 8.31 (d, 1H, J = 4.7 Hz), 7.94 (s, +
(cyclobutylmethyl)indazol-6-yl]-5-fluoro-2,4-pyrimidinediamine 1H0,
7.86 (s, 1H), 7.78 (d, 1H, J = 2.3 Hz), 7.66 (d, 1H, J = 8.8 Hz),
7.57 (dd, 1H, J = 2.3 and 8.8 Hz0, 7.16 (d, 1H, J = 8.8 Hz), 7.12
(d, 1H, J = 8.8 Hz), 4.09 (d, 2H, J = 7.3 Hz), 3 731
N2-[1-(Cyclobutylmethyl)indazol-6-yl]-N4-(3,4-dichlorophenyl)-
.sup.1H NMR (DMSO-d6): d 10.27 (s, 1H), 10.16 (s, 1H), 8.30 (d, 1H,
J = 4.4 Hz), + 5-fluoro-2,4-pyrimidinediamine 7.99 (d, 1H, J = 2.3
Hz), 7.88 (s, 1H), 7.85 (s, 1H), 7.67 (dd, 1H, J = 2.3 and 8.8 Hz),
7.60 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J
= 8.8 Hz), 4.07 (d, 2H, 732
N2-[1-(Cyclobutylmethyl)indazol-6-yl]-N4-(2,2-dimethyl-3-oxo-
.sup.1H NMR (DMSO-d6): d 10.81 (s, 1H), 10.63 (s, 1H), 10.55 (s,
1H), + 4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.33
(d, 1H, J = 5.3 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H, J =
8.8 Hz), 7.24-7.21 (m, 2H), 7.17 (d, 1H, J = 8.5 Hz), 6.86 (d, 1H,
J = 8.5 Hz), 4.12 (d, 2H, J = 7.0 Hz), 2.71-2.61 (m, 733
N2-[1-(Cyclobuylmethyl)indazol-6-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.67 (s, 1H), 10.58 (s, 1H), 8.38 (d, 1H,
J = 5.3 Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.96 (s, 1H),
7.85 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.3 and
8.5 Hz), 7.23-7.11 (m, 3H), 4.07 (d, 2H, J = 7.0 Hz), 3.51 (s, 3H),
2.67-2.57 (m, 6H). LCMS: ret. 734
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.05
(s, 1H), 9.91 (s, 1H), 8.31 (d, 1H, J = 5.2 Hz), +
(cyclopropylmethyl)indazol-5-yl]-5-fluoro-2,4- 7.96 (s, 1H), 7.87
(s, 1H), 7.80 (s, 1H), 7.72 (d, 1H, J = 8.8 Hz), pyrimidinediamine
7.60 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 9.1 Hz), 7.14 (d, 1H, J
= 8.8 Hz), 4.31 (d, 2H, J = 7.0 Hz), 3.48 (s, 735
N2-[1-(Cyclopropylmethyl)indazol-5-yl]-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 10.39 (s, 1H), 10.14 (s, 1H), 8.31 (d, 1H, J = 4.7
Hz), + dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 8.05 (d, 1H,
J = 2.3 Hz), 7.98 (s, 1H), 7.89 (s, 1H), 7.73 (d, 1H, J = 9.1 Hz),
7.54 (d, 1H, J = 8.8 Hz), 7.45 (dd, 1H, J = 2.3 and 8.8 Hz), 4.32
(d, 2H, J = 7.0 Hz), 1.34-1.24 (m 736
N2-[1-(Cyclopropylmethyl)indazol-5-yl]-N4-(2,2-dimethyl-3- .sup.1H
NMR (DMSO-d6): d 10.85 (s, 1H), 10.46 (s, 1H), 10.29 (s, 1H), + +
oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.23
(d, 1H, J = 5.3 Hz), 7.95 (s, 1H), 7.94 (s, 1H0, 7.71 (d, 1H, J =
9.1 Hz), 7.42 (dd, 1H, J = 2.3 and 9.1 Hz), 7.27 (d, 1H, J = 8.5
Hz), 7.25 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 4.32 (d, 737
N2-[1-(Cyclopropylmethyl)indazol-5-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.43 (s, 1H), 10.27 (s, 1H), 8.31 (d, 1H,
J = 4.3 Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.95 (s, 1H),
7.94 (s, 1H), 7.71 (d, 1H, J = 9.1 Hz), 7.48 (dd, 1H, J = 2.3 and
8.8 Hz), 7.41 (dd, 1H, J = 2.3 and 9.1 Hz), 7.31-7.29 (m, 1H), 7.30
(dd, 1H, J = 8.8 and 11.1 Hz), 738
N4-(3-Chloro-4-methoxyphenyl)-N2-[1- .sup.1H NMR (DMSO-d6): d 10.28
(s, 2H), 8.31 (d, 1H, J = 4.3 Hz), 7.95 (s, +
(cyclopropylmethyl)indazol-6-yl]-5-fluoro-2,4- 1H), 7.96 (s, 2H),
7.87 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.69 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.58 (dd, 1H, J = 2.6 and 9.1 Hz), 7.19 (dd, 1H,
J = 1.8 and 8.8 Hz), 7.11 (d, 1H, J = 9.1 Hz), 4.32 739
N2-[1-(Cyclopropylmethyl)indazol-6-yl]-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 10.21 (s, 1H), 10.10 (s, 1H), 8.32 (d, 1H, J = 4.3
Hz), + dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 8.04 (d, 1H,
J = 2.6 Hz), 7.93 (s, 1H), 7.91 (s, 1H), 7.71 (dd, 1H, J = 2.6 and
8.8 Hz), 7.65 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.20
(d, 1H, J = 8.8 Hz), 4.32 (d, 2H, 740
N2-[1-(Cyclopropylmethyl)indazol-6-yl]-N4-(2,2-dimethyl-3- .sup.1H
NMR (DMSO-d6): d 10.82 (s, 1H), 10.22 (s, 1H), 10.16 (s, 1H), + +
oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.31
(d, 1H, J = 4.7 Hz), 8.00 (d, 1H, J = 0.8 Hz), 7.97 (s, 1H), 7.34
(d, 1H, J = 8.8 Hz), 7.35-7.27 (m, 3H), 6.92 (d, 1H, J = 8.5 Hz),
4.32 (d, 2H, J = 7.0 Hz), 1.36 (s, 6H), 1.33-1.17 (m, 741
N2-[1-(Cyclopropylmethyl)indazol-6-yl)-5-fluoro-N4-(4-fluoro-3-
.sup.1H NMR (DMSO-d6): d 10.23 (s, 2H), 8.31 (d, 1H, J = 4.9 Hz),
7.95 (s, + methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.91 (s, 1H),
7.65 (d, 1H, J = 8.8 Hz), 7.48 (dd, 1H, J = 2.3 and 8.8 Hz),,
7.29-7.24 (m, 1H), 7.20-7.13 (m, 3H), 4.09 (d, 2H, J = 6.7 Hz),
3.65 (s, 3H), 1.33-1.17 (m, 1H), 0.55-0 742
N4-(3-Chloro-4-methoxyphenyl)-N2-(1-cyclohexylindazol-5-yl)-
.sup.1H NMR (DMSO-d6): d 10.35 (s, 1H), 10.20 (s, 1H), 8.24 (d, 1H,
J = 5.3 Hz), + + 5-fluoro-2,4-pyrimidinediamine 7.92 (s, 1H), 7.81
(s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.71 (d, 1H, J = 8.1 Hz), 7.55
(dd, 1H, J = 2.6 and 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz),
7.09 (d, 1H, J = 8.1 Hz), 4.5 743
N2-(1-Cyclohexylindazol-5-yl)-N4-(3,4-dichlorophenyl)-5- .sup.1H
NMR (DMSO-d6): d 10.26 (s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.9
Hz), + fluoro-2,4-pyrimidinediamine 7.96 (s, 1H), 7.89 (s, 1H),
7.80 (s, 1H), 7.66 (d, 1H, J = 8.1 Hz), 7.61 (app s, 1H), 7.45 (d,
1H, J = 9.1 Hz), 7.34 (d, 1H, J = 9.1 Hz), 4.53-4.49 (m, 1H),
1.87-1.78 (m, 6H), 1.67 744
N2-(1-Cyclohexylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.80 (s, 1H), 10.36 (s, 1H), 10.15 (s, 1H), + +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.21 (d, 1H, J
= 4.9 Hz), 7.89 (s, 1H), 7.86 (s, 1H), 7.64 (d, 1H, J = 9.4 Hz),
7.36 (dd, 1H, J = 2.3 and 8.8 Hz), 7.18 (d, 1H, J = 2.3 Hz), 6.86
(d, 1H, J = 9.4 Hz), 4.53-4.49 (m, 1H), 1.89 745
N2-(1-Cyclohexylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.26 (s, 1H), 10.07 (s, 1H), 8.22 (d, 1H, J = 5.0
Hz), + methoxyphenyl)-2,4-pyrimidinediamine 7.90 (s, 1H), 7.89 (s,
1H), 7.67 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.5 Hz), 7.34 (dd,
1H, J = 1.8 and 8.8 Hz), 7.28-7.24 (m, 1H), 7.15 (dd, 1H, J = 8.8
and 11.1 Hz), 4.53-4.4 746
N4-(3-Chloro-4-methoxyphenyl)-N2-(1-cyclohexylindazol-6-yl)-
.sup.1H NMR (DMSO-d6): d 10.21 (s, 1H), 10.19 (s, 1H), 8.28 (d, 1H,
J = 4.9 Hz), + 5-fluoro-2,4-pyrimidinediamine 7.95 (s, 1H), 7.86
(d, 1H, J = 2.6 Hz), 7.84 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz), 7.59
(dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8 and 8.5 Hz),
7.06 (d, 1H, J = 9.1 Hz), 4.19 747
N2-(1-Cyclohexylindazol-6-yl)-N4-(3,4-dichlorophenyl)-5- .sup.1H
NMR (DMSO-d6): d 10.05 (s, 1H), 9.88 (s, 1H), 8.29 (d, 1H, J = 4.9
Hz), + fluoro-2,4-pyrimidinediamine 8.11 (d, 1H, J = 2.6 Hz), 7.93
(s, 1H), 7.92 (s, 1H), 7.78 (dd, 1H, J = 2.6 and 8.8 Hz), 7.64 (d,
1H, J = 8.5 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.22 (dd, 1H, J = 1.7
and 8.5 Hz), 4.19 748
N2-(1-Cyclohexylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.76 (s, 1H), 10.25 (s, 1H), 10.18 (s, 1H), +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.24 (d, 1H, J
= 4.9 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz),
7.31-7.22 (m, 3H), 6.80 (d, 1H, J = 8.5 Hz), 4.23-4.12 (m, 1H),
1.85-1.77 (m, 6H), 1.65-1.62 (m, 1H), 1.38 (s, 749
N2-(1-Cyclohexylindazol-6-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.02 (s, 1H), 9.95 (s, 1H), 8.26 (d, 1H, J = 4.3 Hz),
+ methoxyphenyl)-2,4-pyrimidinediamine 7.93 (s, 2H), 7.83 (s, 1H),
7.63 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 Hz0,
7.31-7.28 (m, 1H), 7.18 (d, 1H, J = 8.8 Hz), 7.12 (dd, 1H, J = 8.8
and 11.4 Hz), 4.11-4.00 750
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(3-methylindazol-6-yl)- .sup.1H
NMR (DMSO-d6): d 12.23 (s, 1H), 9.53 (s, 1H), 9.36 (s, 1H), + +
2,4-pyrimidinediamine 8.14 (d, 1H, J = 3.5 Hz), 8.10 (d, 1H, J =
2.7 Hz), 7.88 (s, 1H), 7.86 (dd, 1H, J = 2.7 and 8.8 Hz), 7.47 (d,
2H, J = 8.8 Hz), 7.16 (dd, 1H, J = 1.8 and 8.8 Hz), 2.36 (s, 3H).
LCMS: ret. time 751
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.62 (s, 1H), 9.63 (s, 1H), 9.44 (s, 1H),
+ + (3-methylindazol-6-yl)-2,4-pyrimidinediamine 8.13 (d, 1H, J =
41. Hz), 7.84 (s, 1H), 7.50 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J =
2.3 and 8.5 Hz), 7.31 (d, 1H, J = 2.3 Hz), 7.24 (dd, 1H, J = 1.8
and 8.8 Hz), 6.89 (d, 1H, J = 8.5 Hz), 2.41 752
N4-(3-Chloro-4-methoxyphenyl)-N2-(1,3-dimethylindazol-6-yl)-
.sup.1H NMR (DMSO-d6): d 10.49 (s, 1H), 10.43 (s, 1H), 8.33 (d, 1H,
J = 5.3 Hz), + + 5-fluoro-2,4-pyrimidinediamine 7.77 (d, 1H, J =
2.6 Hz), 7.67 (d, 1H, J = 1.2 Hz), 7.62 (d, 1H, J = 8.8 Hz), 7.55
(dd, 1H, J = 2.6 and 8.8 Hz), 7.10 (d, 1H, J = 8.8 Hz), 7.09 (d,
1H, J = 8.8 Hz), 3.83 (s, 3H), 753
N4-(3,4-Dichlorophenyl)-N2-(1,3-dimethylindazol-6-yl)-5- .sup.1H
NMR (DMSO-d6): d 9.65 (s, 1H), 9.50 (s, 1H), 8.22 (d, 1H, J = 3.5
H), + + fluoro-2,4-pyrimidinediamine 8.12 (d, 1H, J = 2.3 Hz), 7.91
(d, 1H, J = 1.8 Hz), 7.79 (dd, 1H, J = 2.3 and 8.8 Hz), 7.52 (dd,
2H, J = 2.3 and 8.8 Hz), 7.18 (dd, 1H, J = 1.8 and 8.8 Hz), 3.69
(s, 3H), 2.39 (s, 3H) 754
N2-(1,3-Dimethylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.72 (s, 1H), 10.25 (s, 2H), 8.26 (d, 1H, J = 4.9
Hz), + + + benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine
7.72 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.25 (dd, 1H, J = 2.3 and
8.5 Hz), 7.22 (app s, 1H), 7.14 (dd, 1H, J = 2.3 and 8.5 Hz), 6.87
(d, 1H, J = 8.5 Hz), 3.37 (s, 3H), 2.40 (s, 3H 755
N2-(1,3-Dimethylindazol-6-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.14 (s, 2H), 8.28 (d, 1H, J = 3.7 Hz), 7.79 (d, + +
methoxyphenyl)-2,4-pyrimidinediamine 1H, J = 1.8 Hz), 7.57 (d, 1H,
J = 8.5 Hz), 7.48 (dd, 1H, J = 2.3 and 8.5 Hz), 7.31-7.26 (m, 1H),
7.17 (dd, 1H, J = 8.8 and 11.4 Hz), 7.10 (dd, 1H, J = 1.8 and 8.8
Hz), 3.66 (s, 3H), 3.6 756
N4-(3-Chloro-4-methoxyphenyl)-N2-(1,6-dimethylindazol-5-yl)-
.sup.1H NMR (DMSO-d6): d 10.44 (s, 1H), 9.89 (s, 1H), 8.21 (d, 1H,
J = 5.6 Hz), + 5-fluoro-2,4-pyrimidinediamine 7.97 (s, 1H), 7.70
(s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.46 (d, 1H, J = 8.5 Hz), 6.91
(d, 1H, J = 8.5 Hz), 4.00 (s, 3H), 3.75 (s, 3H), 2.32 (s, 3H).
LCMS: ret. time: 9.25 min.; 757
N4-(3,4-Dichlorophenyl)-N2-(1,6-dimethylindazol-5-yl)-5- .sup.1H
NMR (DMSO-d6): d 10.34 (s, 1H), 9.70 (s, 1H), 8.24 (d, 1H, J = 4.7
Hz), + fluoro-2,4-pyrimidinediamine 7.97 (s, 1H), 7.87 (s, 1H),
7.68 (s, 1H), 7.58 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.37 (d, 1H,
J = 8.5 Hz), 4.01 (s, 3H), 2.32 (s, 3H). LCMS: ret. time: 11.58
min.; purity: 91%; 758
N2-(1,6-Dimethylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- .sup.1H
NMR (DMSO-d6): d 10.70 (s, 1H), 10.51 (s, 1H), 8.16 (d, 1H, J = 4.9
Hz), + + benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.95
(s, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.17 (d, 1H, J = 8.5 Hz), 6.69
(d, 1H, J = 8.5 Hz), 4.00 (s, 3H), 2.34 (s, 3H), 1.31 (s, 6H).
LCMS: ret. time: 8.24 min.; purity: 96%; 759
N2-(1,6-Dimethylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- .sup.1H NMR
(DMSO-d6): d 10.42 (s, 1H), 9.84 (s, 1H), 8.18 (d, 1H, J = 3.9 Hz),
+ methoxyphenyl)-2,4-pyrimidinediamine 7.96 (s, 1H), 7.74 (s, 1H),
7.57 (s, 1H), 7.45 (d, 1H, J = 8.5 Hz), 7.20 (m, 1H), 6.97 (m, 1H),
4.02 (s, 3H), 3.55 (s, 3H), 2.33 (s, 3H). LCMS: ret. time: 9.33
min.; purity: 96%; 760
N4-(3,4-Dichlorophenyl)-N2-(2-ethylindazol-6-yl)-5-fluoro-2,4-
.sup.1H NMR (DMSO-d6): d 10.25 (s, 1H), 10.06 (s, 1H), 8.36 (d, 1H,
J = 1.8 Hz), + + pyrimidinediamine 8.30 (d, 1H, J = 4.4 Hz), 8.03
(d, 1H, J = 2.3 Hz), 7.86 (s, 1H), 7.82 (dd, 1H, J = 2.6 and 8.8
Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.14 (dd,
1H, J = 1.8 and 761
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(2- .sup.1H NMR
(DMSO-d6): d 10.57 (s, 1H), 9.51 (s, 1H), 9.30 (s, 1H), + + -
ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.21 (s, 1H),
8.12 (d, 1H, J = 4.1 Hz), 8.07 (s, 1H), 7.51 (d, 1H, J = 9.1 Hz),
7.40 (d, 1H, J = 2.3 Hz), 7.27 (dd, 1H, J = 2.3 and 8.8 Hz), 7.11
(dd, 1H, J = 1.8 and 9.1 Hz), 6.89 (d, 1H, J = 762
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-n-propylindazol-5-yl)-
.sup.1H NMR (DMSO-d6): d 10.14 (s, 1H), 9.82 (s, 1H), 8.25 (d, 1H,
J = 4.4 Hz), +
+ 2,4-pyrimidinediamine 8.22 (s, 1H), 8.06 (d, 1H, J = 2.3 Hz),
7.83 (s, 1H), 7.74 (dd, 1H, J = 2.3 and 9.1 Hz), 7.57 (d, 1H, J =
9.1 Hz), 7.50 (d, 1H, J = 9.1 Hz), 7.27 (dd, 1H, J = 2.3 and 9.1
Hz), 4.34 763
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.77 (s, 1H), 10.33 (s, 1H), 10.07 (s,
1H), + + (2-n-propylindazol-5-yl)-2,4-pyrimidinediamine 8.20 (d,
1H, J = 5.3 Hz), 8.15 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H, J = 9.1
Hz), 7.23-7.18 (m, 3H), 6.86 (d, 1H, J = 9.1 Hz), 4.32 (t, 2H, J =
7.3 Hz), 1.90 (sextet, 2H, J = 7.3 Hz), 1.36 (s, 764
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.56 (s, 1H), 9.29 (s, 1H), 9.09 (s, 1H),
+ + (2-n-propylindazol-6-yl)-2,4-pyrimidinediamine 8.17 (d, 1H, J =
0.8 Hz), 8.13 (d, 1H, J = 0.8 Hz), 8.09 (d, 1H, J = 3.8 Hz), 7.48
(d, 1H, J = 9.1 Hz), 7.41 (d, 1H, J = 2.3 Hz), 7.29 (dd, 1H, J =
2.3 and 9.1 Hz), 7.12 (dd, 1H, J = 2.3 and 8 765
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-n-propylindazol-6-yl)-
.sup.1H NMR (DMSO-d6): d 9.93 (s, 1H), 9.67 (s, 1H), 8.28 (s, 1H),
8.24 (d, + + 2,4-pyrimidinediamine 1H, J = 4.1 Hz), 8.05 (d, 1H, J
= 2.3 Hz), 7.91 (s, 1H), 7.88 (dd, 1H, J = 2.6 and 8.8 Hz), 7.61
(d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.15 (d, 1H, J = 8.8
Hz), 4.28 (t, 2H, J 766
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.69 (s, 1H), 10.09 (s, 1H), 9.88 (s, 1H), + + -
(1-methylindazol-6-yl)-2,4-pyrimidinediamine DL-Camphor-1- 8.21 (d,
1H, J = 4.7 Hz), 7.91 (d, 1H, J = 0.8 Hz), 7.83 (s, 1H), 7.61 (d,
1H, sulfonic Acid Salt J = 8.5 Hz), 7.29 (dd, 1H, J = 2.3 and 8.5
Hz), 7.17 (dd, 1H, J = 2.3 and 8.5 Hz), 7.13 (d, 1H, J = 2.3 Hz),
6.85 (d, 1H, J = 8.5 Hz), 3.80 (s, 3H), 2.87 (d, 1H, AB qt, J =
14.6 Hz), 2.26-2.18 (m, 1H), 1.92 (br t, 1H, J = 4.7 Hz), 1.88-1.83
(m, 2H), 1.38 (s, 6H), 1.32-1.21 (, 2H), 1.03 (s, 3H), 0.73 (s,
3H). LCMS: ret. time: 9.53 min.; purity: 94%; MS (m/e): 434 (MH+)
767 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.70 (s, 1H), 10.22 (s, 1H), 10.00 (s,
1H), + + - (1-methylindazol-6-yl)-2,4-pyrimidinediamine
Ethanesulfonic 8.24 (d, 1H, J = 4.9 Hz), 7.92 (d, 1H, J = 0.8 Hz),
7.80 (s, 1H), 7.63 (d, Acid Salt 1H, J = 8.8 Hz), 7.28 (dd, 1H, J =
2.3 and 8.8 Hz), 7.16 (d, 1H, J = 1.8 and 8.5 Hz), 7.11 (d, 1H, J =
2.3 Hz), 6.8 768
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.69 (s, 1H), 10.17 (s, 1H), 9.92 (s,
1H), + + - (1-methylindazol-6-yl)-2,4-pyrimidinediamine p- 8.21 (d,
1H, J = 4.7 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.81 (s, 1H), 7.62 (d,
1H, Hydroxybenzenesulfonic Acid Salt J = 8.5 Hz), 7.38 (td, 2H, J =
2.6 and 8.8 Hz), J = 7.28 (dd, 1H, J = 2.3 and 8.5 Hz), 7.16 (d,
1H, J = 1.8 and 8 769
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.70 (s, 1H), 10.28 (s, 1H), 10.00 (s,
1H), + + - (1-methylindazol-6-yl)-2,4-pyrimidinediamine
Benzenesulfonic 8.22 (d, 1H, J = 4.9 Hz), 7.94 (d, 1H, J = 0.8 Hz),
7.78 (s, 1H), 7.64 (d, Acid Salt 1H, J = 8.8 Hz), 7.60-7.56 (m,
2H), 7.33-7.26 (m, 4H), 7.15 (d, 1H, J = 1.8 and 8.5 Hz), 7.10 (d,
1H, J = 2.3 Hz), 770
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H,
J = 4.9 Hz), + + - (1-methylindazol-6-yl)-2,4-pyrimidinediamine
Hydrochloric Acid 7.92 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.62 (d,
1H, J = 8.8 Hz), Salt 7.27 (dd, 1H, J = 2.3 and 8.5 Hz), 7.21 (d,
1H, J = 2.3 Hz), 7.18 (dd, 1H, J = 1.8 and 8.5 Hz), 6.86 (d, 1H, J
= 771 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(2- .sup.1H NMR
(DMSO-d6): d 10.18 (s, 1H), 9.91 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz),
+ + - methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine 7.98 (d, 1H,
J = 2.3 Hz), 7.90 (s, 1H), 7.81 (s, 1H), 7.66 (app d, 1H, J = 8.8
Hz), 7.60 (d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.37 (dd,
1H, J = 2.3 and 8.8 Hz), 4.48 (t, 772
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(2- .sup.1H NMR
(DMSO-d6): d 10.45 (s, 1H), 10.33 (s, 1H), 8.27 (d, 1H, J = 4.9
Hz), + + - methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine 7.93
(s, 1H), 7.81 (d, 1H, J = 1.5 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.65
(d, 1H, J = 8.8 Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd,
1H, J = 2.6 and 9.1 Hz), 7.10 (d, 1H, J = 773
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.78 (s, 1H), 10.35 (s, 1H), 10.19 (s,
1H), + + - [1-(2-methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine
8.21 (d, 1H, J = 4.9 Hz), 7.90 (s, 1H), 7.87 (s, 1H), 7.60 (d, 1H,
J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (dd, 1H, J =
1.8 and 8.5 Hz), 7.17 (s, 1H), 6.87 (d, 1H, J = 8.5 Hz), 774
5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1-(2- .sup.1H NMR
(DMSO-d6): d 10.19 (s, 1H), 9.93 (s, 1H), 8.20 (d, 1H, J = 4.7 Hz),
+ + - methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine 7.90 (s,
2H), 7.61 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 2.6 and 8.8 Hz),
7.37 (dd, 1H, J = 2.0 and 8.8 Hz), 7.29-7.26 (m, 1H), 7.13 (dd, 1H,
J = 8.8 and 11.1 Hz), 4.53 (t, 2H, J 775
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(2- .sup.1H NMR (DMSO-d6): d
10.08 (s, 1H), 9.96 (s, 1H), 8.26 (d, 1H, J = 4.4 Hz), + + -
methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine 8.03 (d, 1H, J =
2.3 Hz), 7.91 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.70 (dd, 1H, J =
2.3 and and 8.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8
Hz), 7.19 (dd, 1H, J = 1.8 a 776
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(2- .sup.1H NMR
(DMSO-d6): d 10.02 (br s, 2H), 8.24 (d, 1H, J = 4.7 Hz), + + -
methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine 7.95 (d, 1H, J =
0.8 Hz), 7.83 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J =
8.8 Hz), 6.59 (dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8
and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.2 777
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.71 (s, 1H), 10.18 (br s, 2H), 8.20 (d,
1H, J = 4.9 Hz), + + -
[1-(2-methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine 7.91 (d, 1H,
J = 0.8 Hz), 7.75 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.23-7.15 (m,
3H), 6.81 (d, 1H, J = 8.8 Hz), 4.24 (t, 2H, J = 5.3 Hz), 3.61 (t,
3H, J = 5.3 Hz), 3.06 (s, 3H), 778
5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1-(2- .sup.1H NMR
(DMSO-d6): d 9.92 (br s, 2H), 8.23 (d, 1H, J = 4.4 Hz), + -
methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine 7.94 (d, 1H, J =
0.8 Hz), 7.91 (s, 1H), 7.59 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J =
2.6 and 8.8 Hz), 7.34-7.30 (m, 1H), 7.21 (dd, 1H, J = 1.8 and 8.8
Hz), 7.15 (dd, 1H, J = 8.8 and 11.1 Hz), 779
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(1- .sup.1H NMR
(DMSO-d6): d 10.39 (s, 1H), 10.27 (s, 1H), 8.26 (d, 1H, J = 4.9
Hz), + methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 7.93 (s,
1H), 7.81 (d, 1H, J = 1.4 Hz), 7.74 (d, 1H, J = 2.3 Hz), 6.67 (d,
H, J = 9.1 Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd, 1H, J
= 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 780
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(1-methylethyl)indazol-
.sup.1H NMR (DMSO-d6): d 10.20 (s, 1H), 9.91 (s, 1H), 8.26 (d, 1H,
J = 4.7 Hz), + 5-yl]-2,4-pyrimidinediamine 8.02 (d, 1H, J = 2.3
Hz), 7.94 (s, 1H), 7.86 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.66 (d,
1H, J = 9.1 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 1.8
and 9.1 Hz), 4.95 (q, 1H, 781
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.76 (s, 1H), 10.32 (s, 1H), 10.11 (s,
1H), + [1-(1-methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 8.19
(d, 1H, J = 5.3 Hz), 7.90 (s, 1H), 7.89 (s, 1H), 7.62 (d, 1H, J =
8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.19 (d, 2H, J = 8.9
Hz), 6.87 (d, 1H, J = 8.8 Hz), 4.91 (q, 1H, J = 6.4 H 782
5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1-(1- .sup.1H NMR
(DMSO-d6): d 10.35 (s, 1H), 10.21 (s, 1H), 8.25 (d, 1H, J = 4.9
Hz), + methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 7.90 (s,
1H), 7.88 (s, 1H), 7.65 (d, 1H, J = 8.1 Hz), 7.43 (dd, 1H, j = 2.3
and 8.8 Hz), 7.35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.22 (m, 1H),
7.14 (dd, 1H, J = 8.8 and 11.1 Hz), 783
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(1- .sup.1H NMR
(DMSO-d6): d 10.10 (s, 2H), 8.25 (d, 1H, J = 4.7 Hz), 7.93 (s, +
methylethyl)indazol-6-yl]-2,4-pyrimidinediamine 1H), 7.86 (s, 1H),
7.78 (d, 1H, J = 2.3 Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.56 (dd, 1H, J
= 2.3 and 8.8 Hz), 7.18 (d, 1H, J = 8.8 Hz), 7.10 (d, 1H, J = 8.9
Hz), 4.45 (q, 1H, J = 6.4 Hz), 784
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(1-methylethyl)indazol-
.sup.1H NMR (DMSO-d6): d 10.06 (s, 1H), 9.93 (s, 1H), 8.30 (d, 1H,
J = 4.3 Hz), + 6-yl]-2,4-pyrimidinediamine 8.06 (d, 1H, J = 2.3
Hz), 7.93 (s, 2H), 7.76 (dd, 1H, J = 2.3 and 8.8 Hz), 7.64 (d, 1H,
J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (dd, 1H, J = 1.8 and
8.8 Hz), 4.55 (q, 1H, J = 6 785
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.76 (s, 1H), 10.14 (s, 2H), 8.24 (d, 1H,
J = 4.9 Hz), +
[1-(1-methylethyl)indazol-6-yl]-2,4-pyrimidinediamine 7.93 (s, 1H),
7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.27-7.16 (m, 3H), 6.88 (d,
1H, J = 8.8 Hz), 4.50 (q, 1H, J = 6.4 Hz), 1.37 (d, 6H, J = 6.4
Hz), 1.35 (s, 6H). LCMS: ret. t 786
(S)-N4-[2-Methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl]-5-fluoro-
.sup.1H NMR (DMSO-d6): d 10.77 (s, 1H), 10.14 (s, 1H), 9.93 (s,
1H0, + N2-[1-(1-methylethyl)indazol-6-yl]-2,4-pyrimidinediamine
8.22 (d, 1H, J = 4.7 hz), 7.93 (s, 1H), 7.92 (s, 1H), 7.60 (d, 1H,
J = 8.5 Hz), 7.27 (dd, 1H, J = 2.3 and 8.5 Hz0, 7.21-7.16 (m, 2H),
6.90 (d, 1H, J = 8.5 Hz), 4.65 (qt, 1H, J = 6.7 Hz), 4.4 787
N2-[1-(3-Acetyloxypropyl)indazol-5-yl]-N4-(3,4- 1H NMR (DMSO-d6): d
10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz), + + -
dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.97 (d, 1H, J = 2.3
Hz), 7.90 (dd, 1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz),
7.47 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41
(d, 2H, J = 6.7 Hz), 3.88 788
N2-[1-(3-Acetyloxypropyl)indazol-5-yl]-N4-(3-chloro-4- 1H NMR
(DMSO-d6): d 10.32 (s, 1H), 10.19 (s, 1H), 8.24 (d, 1H, J = 5.3
Hz), + + - methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.93 (s,
1H), 7.85 (s, 1H), 7.74 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H, J = 8.8
Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.40 (dd, 1H, J = 2.3 and
8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4. 789
N2-[1-(3-Acetyloxypropyl)indazol-5-yl]-5-fluoro-N4-(4-fluoro-3- 1H
NMR (DMSO-d6): d 10.31 (s, 1H), 10.15 (s, 1H), 8.24 (d, 1H, J = 4.7
Hz), + + - methoxyphenyl)-2,4-pyrimidinediamine 7.91 (s, 2H), 7.61
(d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 2.3 and 8.8 Hz), 7.38 (dd,
1H, J = 1.8 and 9.1 Hz), 7.27-7.25 (m, 1H), 7.15 (dd, 1H, J = 8.8
and 11.1 Hz), 4.45 (t, 2H, J 790
N2-[1-(3-Acetyloxypropyl)indazol-6-yl]-N4-(3,4- 1H NMR (DMSO-d6): d
9.96 (s, 1H), 9.83 (s, 1H), 8.27 (d, 1H, J = 4.1 Hz), + + -
dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 8.09 (d, 1H, J = 2.3
Hz), 7.94 (s, 1H), 7.92 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz),
7.63 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.23 (dd, 1H, J
= 1.8 and 8.8 Hz), 4.20 791
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.68 (s, 1H), 9.84 (s, 1H), 9.74 (s, 1H), + + -
[1-(3-hydroxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 8.18 (d,
1H, J = 4.4 Hz), 7.90 (s, 1H), 7.56 (s, 1H), 7.58 (d, 1H, J = 8.8
Hz), 7.32-7.24 (m, 3H), 6.85 (d, 1H, J = 8.8 Hz), 4.20 (t, 2H, J =
6.7 Hz), 3.29 (t, 2H, J = 6.4 Hz), 1.87 (app q, 2H 792
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6):
d 10.42 (s, 1H), 10.30 (s, 1H), 8.26 (d, 1H, J = 5.2 Hz), + + - +
methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 7.93 (s, 1H),
7.82 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.60 (d, 1H, J
= 9.1 Hz), 7.53 (dd, 1H, J = 2.3 and 9.1 Hz), 7.38 (dd, 1H, J = 1.8
and 9.1 Hz), 7.09 (d, 1H, J = 9 793
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6): d
10.36 (s, 1H), 10.13 (s, 1H), 8.30 (d, 1H, J = 5.0 Hz), + + -
methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.01 (d, 1H, J =
2.3 Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.68 (dd, 1H, J = 2.3 and 8.8
Hz), 7.61 (d, 1H, J = 9.1 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.41 (dd,
1H, J = 1.8 and 9.1 Hz), 4.4 794
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.77 (s, 1H), 10.42 (s, 1H), 10.27 (s, 1H), + + -
[1-(3-methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.23 (d,
1H, J = 4.3 Hz), 7.90 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.8
Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (app d, 2H, J = 9.1
Hz), 6.87 (d, 1H, J = 9.1 Hz), 4.39 (t, 2H, J = 6. 795
(S)-5-Fluoro-N2-[1-(3-methoxypropyl)indazol-5-yl]-N4-(2- 1H NMR
(DMSO-d6): d 10.73 (s, 1H), 10.32 (s, 1H), 10.15 (s, 1H), + + -
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 8.17 (d, 1H, J = 4.9
Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.51 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.33 (dd, 1H, J = 2.1 and 9.1 Hz), 7.16 (dd, 2H,
J = 2.3 and 9.1 Hz), 6.84 (d, 1H, J = 8.8 Hz), 4.60 (qt, 1H, 796
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6):
d 10.16 (s, 2H), 8.27 (d, 1H, J = 4.7 Hz), 7.95 (d, + + -
methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 1H, J = 0.8 Hz),
7.80 (s, 1H), 7.78 (d, 1H, J = 8.8 Hz), 7.65 (d, 1H, J = 2.3 and
9.1 Hz), 7.58 (dd, 1H, J = 2.3 and 9.1 Hz), 7.20 (dd, 1H, J = 1.8
an 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 797
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6): d
10.13 (s, 1H), 10.02 (s, 1H), 8.31 (d, 1H, J = 4.1 Hz), + + -
methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 8.06 (d, 1H, J =
2.3 Hz), 7.95 (s, 1H), 7.87 (s, 1H), 7.74 (dd, 1H, J = 2.3 and 8.8
Hz), 7.65 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.22 (d,
1H, J = 8.5 Hz), 4.17 (t, 2H, 798
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.73 (s, 1H), 9.92 (s, 2H), 8.21 (d, 1H, J = 4.7 Hz),
+ + + [1-(3-methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 7.92
(s, 1H),
7.89 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.29-7.24 (m, 3H), 6.85 (d,
1H, J = 8.5 Hz), 4.17 (t, 2H, J = 6.7 Hz), 3.14 (app qt, 2H, J =
6.4 Hz), 3.13 (s, 3H), 1.92 (app 799
(S)-5-Fluoro-N2-[1-(3-methoxypropyl)indazol-6-yl]-N4-(2- 1H NMR
(DMSO-d6): d 10.76 (s, 1H), 10.11 (s, 2H), 8.23 (d, 1H, J = 4.7
hz), + + - methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 7.94 (s,
1H), 7.86 (s, 1H), 7.62 (d, 1H, J = 8.5 Hz), pyrimidinediamine
7.28-7.19 (m, 3H), 6.88 (d, 1H, J = 8.5 Hz), 4.64 (qt, 1H, J = 6.7
Hz), 4.17 (t, 2H, J = 6.7 Hz), 3.16 (app qt, 2H, J = 6.7 Hz 800
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2-trifluoromethyl- 1H
NMR (DMSO-d6): d 10.17 (s, 1H), 8.20 (d, 1H, J = 4.9 Hz), 7.85 (s,
+ + + + 1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 1H), 7.69 (d,
1H, J = 2.3 Hz), 7.61 (d, 1H, J = 8.8 Hz), 7.59 (dd, 1H, J = 2.3
and 8.8 Hz), 7.39 (dd, 1H, J = 2.0 and 8.8 Hz), 7.04 (d, 1H, J =
9.1 Hz), 3.76 (s, 3H). 801
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR
(DMSO-d6): d 9.84 (s, 1H), 9.70 (s, 1H), 8.19 (d, 1H, J = 4.1 Hz),
+ + + + benzimidazol-5-yl)-2,4-pyrimidinediamine 8.05 (d, 1H, J =
2.3 Hz), 7.96 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz), 7.60 (d,
1H, J = 9.1 Hz), 7.47-7.43 (m, 2H). 802
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.71 (s, 1H), 10.26 (s, 1H), 10.21 (s, 1H), + + - +
(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.22
(d, 1H, J = 4.9 Hz), 7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.49
(dd, 1H, J = 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.22 (s, 1H), 6.86 (d,
1H, J = 8.8 Hz), 1.36 (s, 6H). 803
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d 10.71 (s, 1H), 10.27 (s, 1H), 10.22 (s, 1H), + + -
N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4- 8.22 (d, 1H, J =
4.9 Hz), 7.93 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), pyrimidinediamine
7.46 (dd, 1H, J = 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.21 (s, 1H), 6.89
(d, 1H, J = 8.8 Hz), 4.66 (qt, 1H, J = 6.7 Hz), 1.40 (d, 804
N2-(3-Amino-1-methylindazol-5-yl)-N4-(3-chloro-4- 1H NMR (DMSO-d6):
d 10.13 (s, 1H), 9.94 (s, 1H), 8.17 (d, 1H, J = 4.9 Hz), + +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.76 (s, 1H), 7.75
(d, 1H, J = 2.3 Hz), 7.61 (dd, 1H, J = 2.3 and 9.1 Hz), 7.44 (s,
2H), 7.05 (d, 1H, J = 9.1 Hz), 3.80 (s, 3H), 3.79 (s, 3H). 805
N2-(3-Amino-1-methylindazol-5-yl)-N4-(3,4-dichlorophenyl)-5- 1H NMR
(DMSO-d6): d 10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz),
+ fluoro-2,4-pyrimidinediamine 7.97 (d, 1H, J = 2.3 Hz), 7.90 (dd,
1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (d, 1H, J =
8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41 (d, 2H, J = 6.7
Hz), 3.88 806
N2-(3-Amino-1-methylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- 1H NMR
(DMSO-d6): d 10.75 (s, 1H), 10.46 (s, 1H), 10.40 (s, 1H), + +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J
= 4.9 Hz), 7.79 (s, 1H), 7.54 (dd, 1H, J = 2.3 and 8.8 Hz), 7.48
(d, 1H, J = 9.1 Hz), 7.28 (app br s, 1H), 7.22 (dd, 1H, J = 2.3 and
9.1 Hz), 6.54 (d, 1H, J = 8.8 Hz), 3.84 (s, 807
(S)-N2-(3-Amino-1-methylindazol-5-yl)-5-fluoro-N4-(2-methyl- 1H NMR
(DMSO-d6): d 10.76 (s, 1H), 10.38 (s, 1H), 10.28 (s, 1H), + +
3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.20 (d, 1H, J
= 5.3 Hz), 7.80 (s, 1H), 7.53 (d, 1H, J = 9.1 Hz), 7.48 (d, 1H, J =
9.1 Hz), 7.27 (s, 1H), 7.25 (s, 1H), 6.87 (d, 1H, J = 9.1 Hz), 4.63
(qt, 1H, J = 6.7 Hz), 3.83 (s, 3H), 1.3 808
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR
(DMSO-d6): d 9.53 (s, 1H), 9.40 (s, 1H), 8.14 (d, 1H, J = 3.8 Hz),
+ + - + benzimidazol-5-yl)-2,4-pyrimidinediamine 8.13 (s, 1H), 7.86
(d, 1H, J = 2.6 Hz), 7.72-7.67 (m, 2H), 7.59 (d, 1H, J = 8.8 Hz),
7.11 (d, 1H, J = 9.1 Hz), 3.83 (s, 3H), 2.72 (s, 3H). 809
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR (DMSO-d6):
d 9.93 (s, 2H), 8.28 (d, 1H, J = 4.8 Hz), 8.12 (d, + + - +
benzimidazol-5-yl)-2,4-pyrimidinediamine 1H, J = 2.6 Hz), 8.07 (s,
1H), 7.81 (dd, 1H, J = 2.3 and 9.1 Hz), 7.66 (s, 2H), 7.56 (d, 1H,
J = 8.8 Hz), 2.75 (s, 3H). 810
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.70 (s, 1H), 9.56 (s, 1H), 9.40 (s, 1H), + + - +
(2-methyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.21 (s, 1H),
8.12 (d, 1H, J = 3.8 Hz), 7.79 (dd, 1H, J = 2.3 and 9.1 Hz), 7.55
(d, 1H, J = 8.8 Hz), 7.52 (s, 1H), 7.31 (dd, 1H, J = 2.3 and 8.8
Hz), 6.88 (d, 1H, J = 8.8 Hz), 2.72 (s, 3H), 1. 811
(S)-5-Fluoro-N2-(2-methyl-3H-benzimidazol-5-yl)-N4-(2- 1H NMR
(DMSO-d6): d 10.69 (s, 1H), 9.58 (s, 1H), 9.42 (s, 1H), + + - +
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 8.23 (s, 1H), 8.12
(d, 1H, J = 3.5 Hz), 7.74 (dd, 1H, J = 2.3 and 8.8 Hz),
pyrimidinediamine 7.57 (d, 1H, J = 9.1 Hz), 7.53 (d, 1H, J = 2.3
Hz), 7.29 (dd, 1H, J = 2.3 and 8.8 Hz), 6.91 (d, 1H, J = 8.8 Hz),
4.64 812 N2-(1,3-Dimethylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-
1H NMR (DMSO-d6): d 11.06 (s, 1H), 9.53 (s, 1H), 9.44 (s, 1H), +
pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.16 (d, 1H,
J = 3.5 Hz), 7.83 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 7.45 (d, 1H, J
= 8.8 Hz), 7.30 (d, 1H, J = 8.5 Hz), 7.15 (dd, 1H, J = 2.3 and 8.8
Hz), 3.67 (s, 3H), 2.33 (s, 3H), 1.36 (s, 6H 813
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 12.21 (s, 1H), 11.02 (s, 1H), 9.30 (s, 1H), +
N2-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine 9.12 (s, 1H),
8.11 (d, 1H, J = 3.5 Hz), 7.90 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz),
7.43 (d, 1H, J = 8.5 Hz), 7.33 (d, 1H, J = 8.8 Hz), 7.19 (d, 1H, J
= 8.8 Hz), 2.34 (s, 3H), 1.36 (s, 6H). 814
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), +
N2-[1-(3-methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.12 (d,
1H, J = 3.5 Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.57 (d, 1H, J = 8.5
Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.46 (d, 1H, J = 8.8 Hz), 7.35 (d,
1H, J = 8.8 Hz), 4.37 (t, 2H, J = 6.4 Hz), 3.22 (t, 815
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR
(DMSO-d6): d 10.36 (s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = 4.9
Hz), + phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 7.85
(s, 1H), 7.79-7.75 (m, 5H), 7.67 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H,
J = 8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.32 (dd, 1H, J =
1.8 and 9.1 Hz), 7.03 (d, 1H, J = 8.8 Hz) 816
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR (DMSO-d6): d
10.24 (s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.7 Hz), -
phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 7.95 (d, 1H,
J = 2.0 Hz), 7.87 (s, 1H), 7.80 (s, 1H), 7.78-7.73 (m, 4H), 7.64
(d, 1H, J = 9.1 Hz), 7.45 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J =
1.8 and 9.1 Hz), 4.41 (t, 2H, J = 6.7 817
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.78 (s, 1H), 10.45 (s, 1H), 10.32 (s, 1H), +
[1-[3-(N-phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine
8.24 (d, 1H, J = 4.9 Hz), 7.88 (s, 1H), 7.87 (s, 1H), 7.84-7.77 (m,
4H), 7.65 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 1.8 and 9.1 Hz),
7.20 (d, 1H, J = 8.8 Hz), 6.86 (d, 1H, J = 9.1 Hz), 4.4 818
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d 10.80 (s, 1H), 10.44 (s, 1H), 10.30 (s, 1H), +
N2-[1-[3-(N-phthalimidopropyl)]indazol-5-yl]-2,4- 8.24 (d, 1H, J =
5.3 Hz), 7.89 (s, 1H), 7.87 (s, 1H), 7.82-7.77 (m, 4H),
pyrimidinediamine 7.67 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 1.8
and 9.1 Hz), 7.22 (dd, 1H, J = 1.8 and 8.8 Hz), 7.18 (s, 1H), 6.89
(d 819 N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4-(3-chloro-4-
1H NMR (DMSO-d6): d 10.22 (s, 1H), 10.05 (s, 1H), 8.21 (d, 1H, J =
4.9 Hz), + + methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.92 (s,
1H), 7.90 (m, 1H), 7.86 (s, 1H), 7.75 (d, 1H, J = 2.3 Hz), 7.64 (d,
1H, J = 9.1 Hz), 7.57 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39 (dd, 1H, J
= 1.8 and 8.8 Hz), 7.09 (d, 1H, J 820
N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4-(3,4- 1H NMR
(DMSO-d6): d 9.51 (s, 1H), 9.23 (s, 1), 8.10 (d, 1H, J = 3.8 Hz), +
dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 8.04 (d, 1H, J = 2.3
Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.74 (dd, 1H, J = 2.0 and 9.1 Hz),
7.51 (d, 1H, J = 9.1 Hz), 7.44 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J
= 1.8 and 9.1 Hz), 4.30 ( 821
N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4-(2,2-dimethyl- 1H
NMR (DMSO-d6): d 10.77 (s, 1H), 10.38 (s, 1H), 10.18 (s, 1H), +
3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.21
(d, 1H, J = 4.9 Hz), 7.90 (s, 3H), 7.61 (d, 1H, J = 8.8 Hz), 7.36
(dd, 1H, J = 2.0 and 9.1 Hz), 7.21 (d, 1H, J = 8.5 Hz), 7.18 (s,
1H), 6.89 (d, 1H, J = 8.5 Hz), 4.36 (t, 2H, J = 7.0 Hz 822
N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4-(2,2-dimethyl- 1H
NMR (DMSO-d6): d 11.05 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), + +
3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.07 (d, 1H), 3.5
Hz), 8.01 (s, 1H), 7.80 (d, 1H, J = 6.3 Hz), 7.79 (s, 1H),
pyrimidinediamine 7.52 (d, 1H, J = 8.5 Hz), 7.48-7.40 (m, 2H), 7.31
(d, 1H, J = 8.5 Hz), 4.29 (t, 2H, J = 7.0 Hz), 2.94 (qt, 2H, J =
823 N2-[1-(3-Aminopropyl)indazol-5-yl]-N4-(3-chloro-4- 1H NMR
(DMSO-d6): d 10.25 (s, 1H), 10.21 (s, 1H), 8.21 (d, 1H, J = 4.8
Hz), + methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.97 (br s,
2H), 7.88 (s, 1H), 7.84-7.78 (m, 2H), 7.70 (d, 1H, J = 2.6 Hz),
9.08 (d, 1H, J = 9.1 Hz), 7.49 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36
(dd, 1H, J = 1.8 and 8.8 Hz), 7.06 (d 824
N2-[1-(3-Aminopropyl)indazol-5-yl]-N4-(3,4-dichlorophenyl)-5- 1H
NMR (DMSO-d6): d 10.01 (s, 1H), 9.77 (s, 1H), 8.24 (d, 1H, J = 3.1
Hz), + fluoro-2,4-pyrimidinediamine 8.06 (d, 1H, J = 2.6 Hz), 7.96
(s, 1H), 7.95 (s, 1H), 7.90-7.85 (m, 2H), 7.75 (d, 1H, J = 8.5 Hz),
7.67 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.47 (dd, 1H, J
= 2.0 and 9.1 825
N2-[1-(3-Aminopropyl)indazol-5-yl]-N4-(2,2-dimethyl-3-oxo-4H- 1H
NMR (DMSO-d6): d 10.77 (s, 1H), 10.35 (s, 2H), 8.20 (d, 1H, J = 5.0
Hz), + benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.94
(br s, 2H), 7.94 (s, 1H), 7.86 (s, 1H), 7.82-7.79 (m, 1H), 7.62 (d,
1H, J = 9.1 Hz), 7.34 (dd, 1H, J = 1.8 and 9.1 Hz), 7.21 (br s,
1H), 7.15 (dd, 1H, J = 1.8 and 8.8 Hz), 826
(S)-N2-[1-(3-Aminopropyl)indazol-5-yl]-5-fluoro-N4-(2-methyl- 1H
NMR (DMSO-d6): d 10.78 (s, 1H), 10.30 (s, 2H), 8.18 (d, 1H, J = 4.9
Hz), + 3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.93
(br s, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.83-7.80 (m, 1H), 7.63 (d,
1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (br s,
1H), 7.17 (dd, 1H, J = 2.3 and 8.5 Hz), 827
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6):
d 10.39 (s, 1H), 10.03 (s, 1H), 8.20 (d, 1H, J = 5.3 Hz), + -
hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine p- 7.95 (s, 1H),
7.80 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.6 Hz), Toluenesulfonic
Acid Salt 7.64 (d, 1H, J = 8.8 Hz), 7.54 (dd, 1H, J = 2.6 and 9.1
Hz), 7.46 (d, 2H, J = 8.1 Hz), 7.38 (dd, 1H, J = 2.1 and 828
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6):
d 10.63 (s, 1H), 10.23 (s, 1H), 8.24 (d, 1H, J = 5.5 Hz), + + -
hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine Bis p- 7.97 (s,
1H), 7.76 (d, 1H, J = 1.8 Hz), 7.72 (d, 1H, J = 2.4 Hz),
Toluenesulfonic Acid Salt 7.66 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J
= 2.6 and 8.8 Hz), 7.47 (d, 4H, J = 8.1 Hz), 7.35 (dd, 1H, J = 1.8
and 829 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR
(DMSO-d6): d 10.38 (s, 1H), 10.02 (s, 1H), 8.19 (d, 1H, J = 4.7
Hz), + + + hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 7.95
(s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.65-7.58 (m, 4H),
Benzenesulfonic Acid Salt 7.38 (d, 1H, J = 9.1 Hz), 7.29 (s, 3H),
7.07 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J = 6.7 Hz), 3.82 (s, 3H),
3.37 (t, 2H, 830 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-
1H NMR (DMSO-d6): d 10.29 (s, 1H), 9.95 (s, 1H), 8.19 (d, 1H, J =
5.1 Hz), + + - hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine
Bis 7.94 (s, 1H), 7.81 (d, 1H, J = 1.8 Hz), 7.75 (d, 1H, J = 2.6
Hz), Benzenesulfonic Acid Salt 7.65-7.53 (m, 7H), 7.39 (dd, 1H, J =
2.0 and 8.8 Hz), 7.31-7.26 (m, 5H), 7.07 (d, 1H, J = 8.8 Hz), 4.42
(t, 2H, J 831 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H
NMR (DMSO-d6): d 10.36 (s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = 5.3
Hz), + + - hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine
Hydrogen 7.87 (s, 1H), 7.77 (d, 1H, J = 1.5 Hz), 7.69 (d, 1H, J =
2.1 Hz), Chloride Salt 7.57 (d, 1H, J = 9.1 Hz), 7.49 (dd, 1H, J =
2.3 and 8.8 Hz), 7.33 (dd, 1H, J = 2.0 and 9.1 Hz), 7.03 (d, 1H, J
= 832 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR
(DMSO-d6): d 10.60 (s, 1H), 10.52 (s, 1H), 8.30 (d, 1H, J = 5.6
Hz), + + - methylsulfonylamino)propyl]indazol-5-yl]-2,4- 7.95 (s,
1H), 7.81 (d, 1H, J = 1.8 Hz), 7.73 (d, 1H, J = 2.3 Hz),
pyrimidinediamine 7.69 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J = 2.3
and 8.8 Hz), 7.37 (dd, 1H, J = 2.0 and 8.8 Hz), 7.10 (br s, 1H), 7
833 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR (DMSO-d6):
d 9.53 (s, 1H), 9.25 (s, 1H), 8.11 (d, 1H, J = 3.8 Hz), + + -
methylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.04 (d, 1H, J = 2.3
Hz), 7.97 (br s, 1H), 7.83 (s, 1H), 7.73 (d, 1H, pyrimidinediamine
J = 2.3 and 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8
Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7.0 834
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.74 (s, 1H), 10.24 (s, 1H),, 9.98 (s, 1H), - + -
[1-[3-(N-methylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.21 (d, 1H,
J = 4.3 Hz), 7.93 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 1H,
J = 1.8 and 8.8 Hz), 7.17 (s, 1H), 7.09 (app t, 1H, J = 5.3 835
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d 10.80 (s, 1H), 10.42 (s, 1H), 10.25 (s, 1H), + + -
N2-[1-(3-(N-methylsulfonylamino)propyl)indazol-5-yl]-2,4- 9.98 (s,
1H), 8.22 (d, 1H, J = 4.9 Hz), 7.92 (s, 1H), 7.90 (d, 1H, J = 1.5
Hz), pyrimidinediamine 7.64 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J =
2.0 and 9.1 Hz), 7.24-7.19 (m, 3H), 7.09 (t, 1H, J = 5.3 Hz), 6.91
836 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H
NMR (DMSO-d6): d 11.11 (s, 1H), 9.25 (s, 1H), 9.24 (s, 1H), + + -
N2-[1-[3-(N-methylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.11 (d,
1H, J = 3.0 Hz), 8.07 (s, 1H), 7.85 (s, 1H), 7.58 (d, 1H, J = 8.5
Hz), pyrimidinediamine 7.54 (d, 1H, J = 9.1 Hz), 7.48 (d, 1H, J =
9.1 Hz), 7.36 (d, 1H, J = 8.5 Hz), 7.06 (t, 1H, J = 6.7 Hz), 4.39
(t, 837
N2-(3-Amino-1-methylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- 1H NMR
(DMSO-d6): d 11.17 (s, 1H), 10.22 (s, 1H), 10.13 (s, 1H), + +
5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.25 (d,
1H, J = 4.4 Hz), 7.92 (s, 1H), 7.58 (d, 1H, J = 9.1 Hz), 7.50 (d,
1H, J = 9.1 Hz), 7.34 (d, 1H, J = 8.5 Hz), 3.86 (s, 3H), 1.39 (s,
3H). 838
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.22 (s, 1H), 10.22 (s, 1H), 10.09 (s, 1H), + +
N2-[1-(3-hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.25 (d,
1H, J = 4.4 Hz), 7.90 (s, 2H), 7.57 (d, 1H, J = 9.3 Hz), 7.41-7.35
(m, 3H), 4.40 (t, 2H, J = 6.7 Hz), 3.35 (t, 2H, J = 6.4 Hz), 1.93
(app q, 2H, J = 6.7 Hz), 1.40 (s, 6H). 839
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.46 (s, 1H), 9.27 (s, 1H), + +
N2-[1-(3-methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 8.19 (d,
1H, J = 3.5 Hz), 8.01 (s, 1H), 7.87 (s, 1H), 7.65 (d, 1H, J = 8.5
Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 7.29 (d,
1H, J = 8.8 Hz), 4.19 (t, 2H, J = 6.7 Hz), 3.16 (t, 840
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR
(DMSO-d6): d 9.47 (br s, 1H), 9.28 (s, 1H), 9.17 (s, 1H), +
trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.07 (d, 1H,
J = 3.8 Hz), 8.04 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz),
pyrimidinediamine 7.64 (dd, 1H, J = 2.3 and 9.1 Hz), 7.52 (d, 1H, J
= 8.8 Hz), 7.49 (d, 1H, J = 9.1 Hz), 7.07 (d, 1H, J = 8.8 H 841
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR (DMSO-d6): d
10.48 (s, 1H), 10.28 (s, 1H), 9.55 (t, 1H, J = 5.2 Hz), +
trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.32 (d, 1H,
J = 4.9 Hz), 8.00 (d, 1H, J = 2.0 Hz), 7.98 (s, 1H),
pyrimidinediamine 7.85-7.81 (m, 1H), 7.70-7.65 (m, 2H), 7.52 (d,
1H, J = 8.8 Hz), 7.42 (dd, 1H, J = 2.0 and 9.1 Hz), 4.45 (t, 2H,
842 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H
NMR (DMSO-d6): d 10.63 (s, 1H), 9.46 (br s, 1H), 9.28 (s, 1H), +
[1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4-
9.06 (s, 1H), 8.12 (s, 1H), 8.05 (d, 1H, J = 3.8 Hz), 7.80 (s, 1H),
pyrimidinediamine 7.47 (app d, 2H, J = 9.1 Hz), 7.29 (dd, 1H, J =
2.0 and 8.8 Hz), 7.20 (d, 1H, J = 2.0 Hz), 6.89 (d, 1H, J = 8.8
Hz), 4.37 843
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d 10.74 (s, 1H), 9.88 (s, 1H), 9.68 (s, 1H), +
N2-[1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]- 9.49
(t, 1H, J = 6.7 Hz), 8.13 (d, 1H, J = 4.7 Hz), 8.01 (s, 1H), 7.87
(s, 1H), 2,4-pyrimidinediamine 7.56 (d, 1H, J = 9.1 Hz), 7.43 (d,
1H, J = 9.1 Hz), 7.26 (d, 1H, J = 8.5 Hz), 7.21 (s, 1H), 6.90 (d,
1H, J = 8.5 844
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.46 (br s, 1H), 9.23 (s, 1H), -
N2-[1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]- 9.19
(s, 1H), 8.11 (dd, 1H, J = 0.9 and 3.5 Hz), 8.07 (s, 1H), 7.86 (s,
2,4-pyrimidinediamine 1H), 7.59 (d, 1H, J = 8.5 Hz), 7.53 (d, 1H, J
= 9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 4.39
(t, 845
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.11 (s, 1H), 9.68 (s, 1H), 9.42 (s, 1H), + + +
N2-(2-methyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.20 (d,
1H, J = 3.5 Hz), 8.13 (s, 1H), 7.73 (dd, 1H, J = 1.8 and 9.1 Hz),
7.63 (d, 1H, J = 8.5 Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.39 (d, 1H, J
= 8.5 Hz), 2.73 (s, 3H), 1.42 (s, 6H). 846
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 13.56 (br s 1H), 11.07 (s, 1H), 9.43 (s, 1H), + + +
N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4- 9.20 (s, 1H), 8.16
(d, 1H, J = 3.5 Hz), 8.13 (s, 1H), 7.73 (dd, 1H, J = 1.8
pyrimidinediamine and 9.1 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.55 (d,
1H, J = 9.1 Hz), 7.36 (d, 1H, J = 8.5 Hz), 1.42 (s, 6H). 847
N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(3- 1H NMR (DMSO-d6): d 9.27
(s, 1H), 9.16 (s, 1H), 8.07 (d, 1H, J = 3.5 Hz), +
(diethylphosphonamido)propyl]indazol-5-yl]-5-fluoro-2,4- 8.03 (s,
1H), 7.82 (s, 1H), 7.79 (d, 1H, J = 2.3 Hz), 7.65 (dd, 1H, J = 2.3
pyrimidinediamine and 8.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.47 (d,
1H, J = 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.91 (dt, 1H, 848
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6):
d 10.42 (s, 1H), 10.29 (s, 1H), 8.26 (d, 1H, J = 4.9 Hz), +
pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 7.93 (s, 1H),
7.83 (s, 1H), 7.74 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.55-7.47 (m,
2H), 7.39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.35 (t,
2H, J = 7.0 Hz), 3.82 (s, 3H), 849
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6): d 9.55
(s, 1H), 9.28 (s, 1H), 8.15 (dd, 1H, J = 1.2 +
pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine and 3.7 Hz),
8.09 (d, 1H, J = 1.5 Hz), 8.00 (s, 1H), 7.87 (s, 1H), 7.79 (dd, 1H,
J = 1.8 and 9.1 Hz), 7.54-7.44 (m, 4H), 4.33 (t, 2H, J = 6.7 Hz),
3.04 (qt, 2H, J = 6.4 Hz), 1.94 (app q 850
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 1H), 9.89 (s, 1H), +
[1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.18 (d,
1H, J = 4.4 Hz), 7.93 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.5
Hz), 7.46 (t, 1H, J = 5.6 Hz), 7.37 (d, 1H, J = 9.1 Hz), 7.23 (d,
1H, J = 9.1 Hz), 7.17 (s, 1H), 6.88 (d, 1H, J = 8. 851
5-Fluoro-(S)-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- 1H NMR
(DMSO-d6): d 10.80 (s, 1H), 10.42 (s, 1H), 10.28 (s, 1H), +
[1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.22 (d,
1H, J = 4.4 Hz), 7.90 (s, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (m,
1H), 7.38 (d, 1H, J = 8.8 Hz), 7.22 (app d, 2H, J = 8.8 Hz), 6.91
(d, 1H, J = 8.8 Hz), 4.64 (qt, 1H, J = 6.7 Hz), 4 852
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- 1H
NMR (DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), +
N2-[1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.12
(d, 1H, J = 3.5 Hz), 7.84 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H, J =
8.8 Hz), 7.48-7.43 (m, 3H), 7.36 (d, 1H, J = 8.5 Hz), 4.32 (t, 2H,
J = 6.7 Hz), 3.02 (qt, 2H, J = 6.7 Hz), 1.92 (app q, 2 853
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR
(DMSO-d6): d 9.28 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J = 3.5 Hz),
+ + succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 7.82 (s,
1H), 7.78 (d, 1H, J = 2.0 Hz), 7.66 (dd, 1H, J = 2.0 and 8.5 Hz),
7.52 (d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J
= 8.5 Hz), 4.33 (t, 2H, J = 6.3 Hz), 3. 854
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3-(N- 1H NMR (DMSO-d6): d
9.55 (s, 1H), 9.28 (s, 1H), 8.16 (d, 1H, J = 3.5 Hz), + -
succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 8.08 (d, 1H,
J = 2.3 Hz), 8.01 (s, 1H), 7.88 (s, 1H), 7.80 (dd, 1H, J = 2.3 and
8.8 Hz), 7.56 (d, 1H, J = 8.8 Hz), 7.51-7.46 (m, 2H), 4.35 (t, 2H,
J = 6.7 Hz), 3.40 (t, 2H, J = 7.0 855
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.73 (s, 1H), 10.38 (s, 1H), 10.25 (s, 1H), + +
[1-[3-(N-succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine
8.18 (d, 1H, J = 3.9 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.56 (d, 1H,
J = 9.1 Hz), 7.32 (d, 1H, J = 8.8 Hz), 7.14 (d, 2H, J = 9.1 Hz),
6.84 (d, 1H, J = 8.8 Hz), 4.30 (t, 2H, J = 7.0 Hz), 3.34 (t 856
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR
(DMSO-d6): d 10.82 (s, 1H), 10.52 (s, 1H), 10.42 (s, 1H), + +
N2-[1-[3-(N-succinimidopropyl)]indazol-5-yl]-2,4- 8.24 (d, 1H, J =
4.9 Hz), 7.92 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.37 (dd, 1H, J = 1.0 and 8.8 Hz), 7.20 (d, 2H, J
= 8.8 Hz), 6.91 (d, 1H, J = 9.1 Hz), 4.65 (qt, 1H, J = 6.7 Hz 857
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.23 (s, 1H), 9.19 (s, 1H), + +
N2-[1-[3-(N-succinimidopropyl)]indazol-5-yl]-2,4- 8.12 (d, 1H, J =
3.5 Hz), 8.06 (s, 1H), 7.57 (d, 1H, J = 8.8 Hz), pyrimidinediamine
7.53-7.46 (m, 2H), 7.36 (d, 1H, J = 8.8 Hz), 4.33 (t, 2H, J = 7.0
Hz), 3.39 (t, 2H, J = 6.7 Hz), 2.54 (s, 2H), 2.48 (s, 2H), 2 858
N4-(3-Chloro-4-methoxyphenyl)-N2-[1-[3-(2,6- 1H NMR (DMSO-d6): d
10.26 (s, 1H), 10.08 (s, 1H), 8.22 (d, 1H, J = 4.3 Hz), + +
dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- 7.92 (s, 1H),
7.85 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz), 7.62 (d, 1H,
pyrimidinediamine J = 8.8 Hz), 7.57 (dd, 1H, J = 2.3 and 8.8 Hz),
7.39 (dd, 1H, J = 2.0 and 8.3 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.35
859 N4-(3,4-Dichlorophenyl)-N2-[1-[3-(2,6- 1H NMR (DMSO-d6): d
10.05 (s, 1H), 9.77 (s, 1h), 8.23 (d, 1H, J = 5.1 Hz), + +
dioxopiperidino)propyl]indazol-5-yl]-5-fluoro-2,4- 8.03 (s, 1H),
7.92 (s, 1H), 7.91 (s, 1H), 7.73 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.61 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8
Hz), 7.44 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J = 6.7 Hz), 3.67 (t, 2
860 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-[3- 1H
NMR (DMSO-d6): d 10.76 (s, 1H), 10.34 (s, 1H), 10.16 (s, 1H), + +
(2,6-dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- 8.21 (d,
1H, J = 4.3 Hz), 7.89 (s, 2H), 7.59 (d, 1H, J = 8.5 Hz),
pyrimidinediamine 7.37 (dd, 1H, J = 1.5 and 8.5 Hz), 7.21 (d, 1H, J
= 8.8 Hz), 7.19 (s, 1H), 6.88 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J =
7.0 Hz 861
(S)-N2-[1-[3-(2,6-Dioxopiperidino]propyl)indazol-5-yl]-5-fluoro- 1H
NMR (DMSO-d6): d 10.78 (s, 1H), 10.49 (s, 1H), 10.44 (s, 1H), + +
N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 8.21 (d, 1H, J
= 4.9 Hz), 7.85 (s, 1H), 7.82 (s, 1H), 7.56 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.31 (d, 1H, J = 8.8 Hz), 7.17 (s, 1H), 7.16 (d,
1H, J = 8.8 Hz), 6.86 (d, 1H, J = 8.8 Hz), 4.59 (qt, 1H, J = 862
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[1-[3- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), + +
(2,6-dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- 8.12 (d,
1H, J = 3.2 Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.2
Hz), pyrimidinediamine 7.48 (s, 2H), 7.36 (d, 1H, J = 8.2 Hz), 4.32
(t, 2H, J = 7.3 Hz), 3.66 (t, 2H, J = 7.3 Hz), 2.45 (t, 2H, J = 7.3
863 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H
NMR (DMSO-d6): d 10.33 (s, 1H), 10.23 (s, 1H), 8.32 (d, 1H, J = 4.7
Hz), + + benzimidazol-5-yl)-2,4-pyrimidinediamine Hydrogen Chloride
8.03 (d, 1H, J = 2.0 Hz), 7.90 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz),
Salt 7.69 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.45 (dd,
1H, J = 2.0 and 8.8 Hz). 864
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR
(DMSO-d6): d 10.11 (s, 1H), 9.92 (s, 1H), 8.27 (d, 1H, J = 4.4 Hz),
- + benzimidazol-5-yl)-2,4-pyrimidinediamine Ethanesulfonic Acid
8.06 (d, 1H, J = 2.0 Hz), 7.94 (s, 1H), 7.76 (d, 1H, J = 2.0 Hz),
Salt 7.67 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.41 (dd,
1H, J = 2.0 and 8.8 Hz), 2.42 (qt, 2H, J = 7.3 Hz), 1 865
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR
(DMSO-d6): d 10.25 (s, 1H), 10.04 (s, 1H), 8.29 (d, 1H, J = 4.4
Hz), - + benzimidazol-5-yl)-2,4-pyrimidinediamine Benzenesulfonic
8.03 (s, 1H), 7.91 (s, 1H), 7.73-7.26 (m, 2H), 7.58-7.43 (m, Acid
Salt 4H), 7.29-7.27 (m, 3H). 866
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR
(DMSO-d6): d 10.30 (s, 1H), 10.08 (s, 1H), 8.30 (d, 1H, J = 4.7
Hz), - + benzimidazol-5-yl)-2,4-pyrimidinediamine p-Toluenesulfonic
8.03 (d, 1H, J = 2.0 Hz), 7.90 (s, 1H), 7.71 (d, 2H, J = 8.8 Hz),
Acid Salt 7.51 (d, 1H, J = 8.8 Hz), 7.47-7.43 (m, 3H), 7.10 (d, 2H,
J = 8.8 Hz), 2.26 (s, 3H). 867
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR (DMSO-d6):
d 9.77 (s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 Hz), + +
benzimidazol-5-yl)-2,4-pyrimidinediamine Benzenesulfonic 8.14 (d,
1H, J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and Acid Salt
8.8 Hz), 7.66 (d, 2H, J = 9.1 Hz), 7.59-7.52 (m, 3H), 7.33-7.27 (m,
3H), 2.74 (s, 3H). 868
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR (DMSO-d6):
d 9.78 (s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 Hz), + +
benzimidazol-5-yl)-2,4-pyrimidinediamine p-Toluenesulfonic 8.14 (d,
1H, J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and Acid Salt
8.8 Hz), 7.66 (d, 2H, J = 9.1 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.46
(d, 2H, J = 8.2 Hz), 7.10 (d, 2H, J = 8.2 Hz), 2.7 869
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR (DMSO-d6):
d 9.93 (s, 2H), 8.28 (d, 1H, J = 3.8 Hz), 8.12 (d, + +
benzimidazol-5-yl)-2,4-pyrimidinediamine Hydrogen Chloride 1H, J =
2.3 Hz), 8.07 (s, 1H), 7.81 (dd, 1H, J = 1.8 and 8.8 Hz), Salt 7.66
(d, 2H, J = 8.8 Hz), 7.56 (d, 1H, J = 8.8 Hz), 2.75 (s, 3H). 870
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methyl-3H- 1H NMR (DMSO-d6):
d 9.75 (s, 2H), 9.72 (s, 1H), 8.24 (d, 1H, J = 3.8 Hz), + +
benzimidazol-5-yl)-2,4-pyrimidinediamine Ethanesulfonic Acid 8.14
(d, 1H, J = 2.0 Hz), 8.12 (s, 1H), 7.82 (d, 1H, J = 8.8 Hz), Salt
7.66 (d, 2H, J = 8.5 Hz), 7.53 (d, 1H, J = 8.8 Hz), 2.74 (s, 3H),
2.40 (qt, 2H, J = 7.3 Hz), 1.05 (t, 3H, J = 7.3 H 871
N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(3- 1H NMR (DMSO-d6): d 10.37
(s, 1H), 10.23 (s, 1H), 8.25 (d, 1H, J = 5.3 Hz), + +
ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.92 (s,
1H), 7.83 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.59 (d, H, J = 8.8
Hz), 7.53 (dd, 1H, J = 2.3 and 8.5 Hz), 7.38 (dd, 1H, J = 1.8 and
8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.40 872
N4-(3,4-Dichlorophenyl)-N2-[1-(3-ethoxypropyl)indazol-5-yl]-5- 1H
NMR (DMSO-d6): d 10.27 (s, 1H), 10.02 (s, 1H), 8.28 (d, 1H, J = 4.7
Hz), + fluoro-2,4-pyrimidinediamine 8.02 (d, 1H, J = 2.3 Hz), 7.95
(s, 1H), 7.87 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.60 (d, 1H, J =
8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz),
7.42 (dd, 1H, J = 2.3 and 8.8 Hz), 4.41 (t, 2H, 873
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(3- 1H NMR
(DMSO-d6): d 10.76 (s, 1H), 10.36 (s, 1H), 10.19 (s, 1H), + +
ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 8.22 (d,
1H, J = 5.3 Hz), 7.90 (s, 2H), 7.55 (d, 1H, J = 9.1 Hz), 7.37 (dd,
1H, J = 1.8 and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 7.18 (s, 1H),
6.87 (d, 1H, J = 8.8 Hz), 4.39 (t, 2H, J = 6.7 Hz 874
(S)-N2-[1-(3-Ethoxypropyl)indazol-5-yl]-5-fluoro-N4-(2-methyl- 1H
NMR (DMSO-d6): d 10.79 (s, 1H), 10.40 (s, 1H), 10.24 (s, 1H), + +
3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.22 (d,
1H, J = 5.3 Hz), 7.90 (d, 1H, J = 1.8 Hz), 7.88 (s, 1H), 7.57 (d,
1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 2H, J
= 1.8 and 8.5 Hz), 6.89 (d, 1H, J = 8.5 Hz), 4. 875
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[1-(3- 1H NMR
(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), + +
ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 8.11 (d,
1H, J = 3.5 Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.5
Hz), 7.42 (d, 2H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 4.37 (t,
2H, J = 6.7 Hz), 3.32 (qt, 2H, J = 7.0 Hz), 3.28 (t 876
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(3,4,5- 1H NMR
(DMSO-d6): d 10.32 (s, 1H), 9.63 (s, 1H), 8.19 (d, 1H, J = 4.1 Hz),
+ + trimethoxyphenyl)-2,4-pyrimidinediamine 8.06 (d, 1H, J = 8.5
Hz), 7.52 (d, 1H, J = 8.5 Hz), 6.91 (s, 2H), 3.88 (s, 3H), 3.64 (s,
6H), 3.61 (s, 3H). 877
N4-(2-Chloro-3-methoxypyrid-6-yl)-N2-(3,4-dimethoxyphenyl)- 1H NMR
(DMSO-d6): d 9.84 (s, 1H), 9.23 (s, 1H), 8.15 (d, 1H, J = 8.8 Hz),
+ 5-fluoro-2,4-pyrimidinediamine 8.14 (d, 1H, J = 3.5 Hz), 7.55 (d,
1H, J = 9.1 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.08 (d, 2H, J = 2.3
Hz), 3.88 (s, 3H), 3.65 (s, 3H). 878
N2-(3-Chloro-4-methoxyphenyl)-N4-(2-chloro-3-methoxypyrid- 1H NMR
(DMSO-d6): d 9.83 (s, 1H), 9.26 (s, 1H), 8.14 (d, 1H, J = 3.5 Hz),
- 6-yl)-5-fluoro-2,4-pyrimidinediamine 8.01 (d, 1H, J = 9.1 Hz),
7.80 (d, 1H, J = 2.6 Hz), 7.59 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J
= 2.6 and 9.1 Hz), 7.03 (d, 1H, J = 9.1 Hz), 3.88 (s, 3H), 3.78 (s,
3H). 879
N4-(2-Chloro-3-methoxypyrid-6-yl)-N2-(3,5-dimethylphenyl)-5- 1H NMR
(DMSO-d6): d 9.79 (s, 1H), 9.15 (s, 1H), 8.13 (d, 1H, J = 3.5 Hz),
+ + fluoro-2,4-pyrimidinediamine 8.08 (dd, 1H, J = 2.3 and 8.8 Hz),
7.57 (d, 1H, J = 8.8 Hz), 7.22 (s, 2H), 6.53 (s, 1H), 3.82 (s, 3H),
2.19 (s, 6H). H+). 880
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[3-(N- 1H NMR
(DMSO-d6): d 9.84 (s, 1H), 9.32 (s, 1H), 8.14 (d, 1H, J = 3.5 Hz),
+ + methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.12 (d, 1H, J =
8.8 Hz), 7.96 (qt, 1H, J = 4.7 Hz), 7.60 (d, 1H, J = 8.8 Hz),
pyrimidinediamine 7.37 (app s, 1H), 7.23 (d, 1H, J = 8.2 Hz), 7.13
(t, 1H, J = 8.2 Hz), 6.48 (dd, 1H, J = 2.3 and 8.2 Hz 881
2-Chloro-N4-(2-chloro-3-methoxypyrid-6-yl)-5-fluoro-4- 1H NMR
(DMSO-d6): d 8.33 (d, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 2.3 Hz),
pyrimidineamine 7.65 (br s, 1H), 7.38 (d, 1H, J = 8.8 Hz), 3.94 (s,
3H). 882
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(indazol-6-yl)- LCMS:
ret. time: 10.99 min.; purity: 93%; MS (m/e): 386 (MH.sup.+). +
2,4-pyrimidinediamine 883
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(2- LCMS: ret. time:
11.74 min.; purity: 97%; MS (m/e): 454 (MH.sup.+). +
trifluoromethyl-1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 884
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(2-methyl-3H- LCMS:
ret. time: 7.71 min.; purity: 93%; MS (m/e): 400 (MH.sup.+). +
benzimidazol-5-yl)-2,4-pyrimidinediamine 885
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(1- LCMS: ret. time:
12.20 min.; purity: 93%; MS (m/e): 400 (MH.sup.+). +
methylindazol-6-yl)-2,4-pyrimidinediamine 886
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(1- LCMS: ret. time:
10.79 min.; purity: 94%; MS (m/e): 400 (MH.sup.+). -
methylindazol-5-yl)-2,4-pyrimidinediamine 887
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(1-ethylindazol-
LCMS: ret. time: 12.97 min.; purity: 95%; MS (m/e): 414 (MH.sup.+).
+ 6-yl)-2,4-pyrimidinediamine 888
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-(1- LCMS: ret. time:
13.86 min.; purity: 92%; MS (m/e): 428 (MH.sup.+). +
isopropylindazol-6-yl)-2,4-pyrimidinediamine 889
N4-(2-Chloro-3-methoxypyrid-6-yl)-N2-(2,2-dimethyl-3-oxo-4H- LCMS:
ret. time: 11.84 min.; purity: 94%; MS (m/e): 445 (MH.sup.+). +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 890
N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4-(2-chloro-3- LCMS:
ret. time: 9.42 min.; purity: 95%; MS (m/e): 485 (MH.sup.+). +
methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine 891
N4-(2-Chloro-3-methoxypyrid-6-yl)-N2-[1-[3-(N- LCMS: ret. time:
10.30 min.; purity: 95%; MS (m/e): 511 (MH.sup.+). +
cyclopropanecarbonylamino)propyl]indazol-5-yl]-5-fluoro-2,4-
pyrimidinediamine 892
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[1-(3- LCMS: ret.
time: 11.73 min.; purity: 99%; MS (m/e): 527 (MH.sup.+). +
pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 893
N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[1-[3-(N- LCMS: ret.
time: 10.71 min.; purity: 97%; MS (m/e): 514 (MH.sup.+). +
isobutyrylamino)propyl]indazol-5-yl]-2,4-pyrimidinediamine 894
N4-(3,4-Dichlorophenyl)-N2-(1,2-dimethylbenzimidazol-5-yl)-5- LCMS:
ret. time: 9.44 min.; purity: 100%; MS (m/e): 418 (MH.sup.+). +
fluoro-2,4-pyrimidinediamine 895
N4-(3-Chloro-4-methoxyphenyl)-N2-(1,2- LCMS: ret. time: 7.66 min.;
purity: 96%; MS (m/e): 413 (MH.sup.+). +
dimethylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 896
N2-(1,2-Dimethylbenzimidazol-5-yl)-N4-(2,2-dimethyl-3-oxo- LCMS:
ret. time: 7.09 min.; purity: 99%; MS (m/e): 448 (MH.sup.+). + +
4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 897
(S)-N2-(1,2-Dimethylbenzimidazol-5-yl)-5-fluoro-N4-(2-methyl- LCMS:
ret. time: 6.52 min.; purity: 97%; MS (m/e): 434 (MH.sup.+). + + +
3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 898
N2-(1,2-Dimethylbenzimidazol-5-yl)-N4-(2,2-dimethyl-3-oxo- LCMS:
ret. time: 7.85 min.; purity: 91%; MS (m/e): 449 (MH.sup.+). + + +
4H-5-pyrid[1,4]oxazin-6-yl)-5-Fluoro-2,4-pyrimidinediamine 899
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)-2- LCMS:
ret. time: 8.77 min.; purity: 97%; MS (m/e): 448 (MH.sup.+). + +
methylbenzimidazol-5-yl)-2,4-pyrimidinediamine 900
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(2- LCMS: ret. time:
7.06 min.; purity: 93%; MS (m/e): 443 (MH.sup.+). +
hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4- pyrimidinediamine 901
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 6.50 min.; purity: 97%; MS (m/e): 478 (MH.sup.+). + +
[1-(2-hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4-
pyrimidinediamine 902
(S)-5-Fluoro-N2-[1-(2-hydroxyethyl)-2-methylbenzimidazol-5- LCMS:
ret. time: 5.99 min.; purity: 94%; MS (m/e): 464 (MH.sup.+). + +
yl)-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
pyrimidinediamine 903
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 6.89 min.; purity: 97%; MS (m/e): 479 (MH.sup.+). + +
N2-[1-(2-hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4-
pyrimidinediamine 904
N4-(3,4-Dichlorophenyl)-N2-(2,3-dihydro-1-methyl-2-oxo- LCMS: ret.
time: 10.32 min.; purity: 100%; MS (m/e): 420 (MH.sup.+). - -
benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 905
N4-(3-Chloro-4-methoxyphenyl)-N2-(2,3-dihydro-1-methyl-2- LCMS:
ret. time: 8.24 min.; purity: 96%; MS (m/e): 415 (MH.sup.+). + +
oxo-benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 906
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(2,3- LCMS: ret.
time: 7.53 min.; purity: 97%; MS (m/e): 450 (MH.sup.+). + +
dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5-fluoro-2,4-
pyrimidinediamine 907
(S)-N2-(2,3-Dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5- LCMS: ret.
time: 7.00 min.; purity: 98%; MS (m/e): 436 (MH.sup.+). + +
fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
pyrimidinediamine 908
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(2,3- LCMS:
ret. time: 8.19 min.; purity: 94%; MS (m/e): 451 (MH.sup.+). + +
dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5-fluoro-2,4-
pyrimidinediamine 909
5-Fluoro-N2-(2-methyl-3H-benzimidazol-5-yl)-N4-(2-methyl- LCMS:
ret. time: 7.11 min.; purity: 94%; MS (m/e): 468 (MH.sup.+). + +
1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine
910 5-Fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-
LCMS: ret. time: 10.29 min.; purity: 98%; MS (m/e): 521 (MH.sup.+).
+ + yl)-N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4-
pyrimidinediamine 911
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methyl-2- LCMS: ret. time:
14.28 min.; purity: 97%; MS (m/e): 472 (MH.sup.+). +
trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine 912
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methyl-2- LCMS: ret.
time: 11.38 min.; purity: 91%; MS (m/e): 467 (MH.sup.+). +
trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine 913
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(1- LCMS: ret.
time: 10.21 min.; purity: 94%; MS (m/e): 502 (MH.sup.+). +
methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4- pyrimidinediamine
914 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
LCMS: ret. time: 9.66 min.; purity: 93%; MS (m/e): 488 (MH.sup.+).
+ N2-(1-methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4-
pyrimidinediamine 915
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(1- LCMS:
ret. time: 11.48 min.; purity: 91%; MS (m/e): 503 (MH.sup.+). +
methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4- pyrimidinediamine
916 N4-(3,4-Dichlorophenyl)-5-fluoro-[1-(2-hydroxyethyl)-2- LCMS:
ret. time: 12.15 min.; purity: 96%; MS (m/e): 502 (MH.sup.+). +
trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 917
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-[1-(2-hydroxyethyl)-2- LCMS:
ret. time: 9.90 min.; purity: 94%; MS (m/e): 497 (MH.sup.+). +
trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 918
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-[1- LCMS:
ret. time: 9.08 min.; purity: 96%; MS (m/e): 532 (MH.sup.+). + +
(2-hydroxyethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 919
(S)-5-Fluoro-[1-(2-hydroxyethyl)-2-trifluoromethylbenzimidazol-
LCMS: ret. time: 8.67 min.; purity: 92%; MS (m/e): 518 (MH.sup.+).
+ + 5-yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
pyrimidinediamine 920
N4-(3,4-Dichlorophenyl)-5-fluoro-[1-(2-hydroxymethyl)-2- LCMS: ret.
time: 14.96 min.; purity: 97%; MS (m/e): 486 (MH.sup.+). + +
trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 921
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-[1-(2-hydroxymethyl)- LCMS:
ret. time: 12.21 min.; purity: 98%; MS (m/e): 481 (MH.sup.+). + +
2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 922
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-[1- LCMS:
ret. time: 10.93 min.; purity: 96%; MS (m/e): 516 (MH.sup.+). +
(2-hydroxymethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 923 (S)-5-Fluoro-[1-(2-hydroxymethyl)-2- LCMS:
ret. time: 10.43 min.; purity: 92%; MS (m/e): 502 (MH.sup.+). +
trifluoromethylbenzimidazol-5-yl]-N4-(2-methyl-3-oxo-2H,4H-
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 924
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-[1-
LCMS: ret. time: 12.25 min.; purity: 98%; MS (m/e): 517 (MH.sup.+).
+ (2-hydroxymethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 925
N2-(1,2-Benzisoxazol-5-yl)-N4-(3-chloro-4-methoxyphenyl)-5- LCMS:
ret. time: 9.63 min.; purity: 100%; MS (m/e): 386 (MH.sup.+). +
fluoro-2,4-pyrimidinediamine 926
N2-(1,2-Benzisoxazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- LCMS: ret.
time: 8.48 min.; purity: 100%; MS (m/e): 421 (MH.sup.+). +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 927
(S)-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro-N4-(2-methyl-3-oxo- LCMS:
ret. time: 8.11 min.; purity: 100%; MS (m/e): 407 (MH.sup.+). +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 928
N2-(1,2-Benzisoxazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H-5- LCMS: ret.
time: 9.57 min.; purity: 100%; MS (m/e): 422 (MH.sup.+). +
pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 929
racemic-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro-(2-methyl-1,1,3- LCMS:
ret. time: 9.69 min.; purity: 95%; MS (m/e): 455 (MH.sup.+). +
trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 930
N2-(1,2-Benzisoxazol-5-yl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H- LCMS:
ret. time: 10.13 min.; purity: 97%; MS (m/e): 470 (MH.sup.+). +
benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 931
racemic-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro-N4-(2-methyl-3- LCMS:
ret. time: 9.21 min.; purity: 96%; MS (m/e): 423 (MH.sup.+). +
oxo-2H,4H-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 932
N4-(3,4-Dichlorophenyl)-N2-(1-ethyl-2-methylbenzimidazol-5- LCMS:
ret. time: 10.09 min.; purity: 99%; MS (m/e): 432 (MH.sup.+). -
yl)-5-fluoro-2,4-pyrimidinediamine 933
N4-(3-Chloro-4-methoxyphenyl)-N2-(1-ethyl-2- LCMS: ret. time: 8.64
min.; purity: 92%; MS (m/e): 427 (MH.sup.+). +
methylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 934
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(1-ethyl- LCMS:
ret. time: 7.91 min.; purity: 99%; MS (m/e): 462 (MH.sup.+). +
2-methylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 935
(S)-N2-(1-Ethyl-2-methylbenzimidazol-5-yl)-5-fluoro-N4-(2- LCMS:
ret. time: 7.72 min.; purity: 95%; MS (m/e): 448 (MH.sup.+). + +
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 936
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-N2-(1- LCMS:
ret. time: 8.48 min.; purity: 96%; MS (m/e): 463 (MH.sup.+). +
ethyl-2-methylbenzimidazol-5-yl)-5-fluoro-2,4- pyrimidinediamine
937 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)-2-
LCMS: ret. time: 12.33 min.; purity: 97%; MS (m/e): 516 (MH.sup.+).
+ + trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 938
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- LCMS: ret. time:
9.85 min.; purity: 94%; MS (m/e): 511 (MH.sup.+). +
hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 939
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 9.04 min.; purity: 96%; MS (m/e): 546 (MH.sup.+). + +
[1-(3-hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 940 (S)-5-Fluoro-N2-[1-(3-hydroxypropyl)-2- LCMS:
ret. time: 8.49 min.; purity: 95%; MS (m/e): 532 (MH.sup.+). +
+
trifluoromethylbenzimidazol-5-yl]-N4-(2-methyl-3-oxo-2H,4H-
benz[1,4]oxazin-6-yl)--2,4-pyrimidinediamine 941
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 9.85 min.; purity: 93%; MS (m/e): 547 (MH.sup.+). + +
N2-[1-(3-hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-
2,4-pyrimidinediamine 942
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2-(4- LCMS: ret.
time: 9.49 min.; purity: 97%; MS (m/e): 489 (MH.sup.+). + + +
morpholino)benzimidazol-5-yl]-2,4-pyrimidinediamine 943
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2-(4- LCMS:
ret. time: 7.79 min.; purity: 93%; MS (m/e): 484 (MH.sup.+). + +
morpholino)benzimidazol-5-yl]-2,4-pyrimidinediamine 944
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 7.20 min.; purity: 99%; MS (m/e): 519 (MH.sup.+). + + +
[1-methyl-2-(4-morpholino)benzimidazol-5-yl]-2,4- pyrimidinediamine
945 (S)-5-Fluoro-N2-[1-methyl-2-(4-morpholino)benzimidazol-5- LCMS:
ret. time: 6.78 min.; purity: 90%; MS (m/e): 505 (MH.sup.+). + +
yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
pyrimidinediamine 946
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 7.86 min.; purity: 96%; MS (m/e): 520 (MH.sup.+). + +
N2-[1-methyl-2-(4-morpholino)benzimidazol-5-yl]-2,4-
pyrimidinediamine 947
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)-2- LCMS:
ret. time: 9.65 min.; purity: 95%; MS (m/e): 462 (MH.sup.+). +
methylbenzimidazol-5-yl]-2,4-pyrimidinediamine 948
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3- LCMS: ret. time:
8.28 min.; purity: 90%; MS (m/e): 457 (MH.sup.+). +
hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4- pyrimidinediamine
949 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
LCMS: ret. time: 7.70 min.; purity: 96%; MS (m/e): 492 (MH.sup.+).
+ [1-(3-hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 950
(S)-5-Fluoro-N2-[1-(3-hydroxypropyl)-2-methylbenzimidazol-5- LCMS:
ret. time: 7.22 min.; purity: 90%; MS (m/e): 478 (MH.sup.+). +
yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
pyrimidinediamine 951
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 7.97 min.; purity: 94%; MS (m/e): 493 (MH.sup.+). + +
N2-[1-(3-hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4-
pyrimidinediamine 952
N2-[1-[3-(N-Acetylamino)propyl]-2-methylbenzimidazol-5-yl]- LCMS:
ret. time: 7.89 min.; purity: 97%; MS (m/e): 533 (MH.sup.+). + +
N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-
pyrimidinediamine 953
N2-[1-[3-(N-Acetylamino)propyl]-2-methylbenzimidazol-5-yl]- LCMS:
ret. time: 8.09 min.; purity: 97%; MS (m/e): 534 (MH.sup.+). + +
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-
2,4-pyrimidinediamine 954
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2-(4- LCMS: ret.
time: 10.04 min.; purity: 96%; MS (m/e): 503 (MH.sup.+). + +
morpholinomethyl)benzimidazol-5-yl]-2,4-pyrimidinediamine 955
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2-(4- LCMS:
ret. time: 9.29 min.; purity: 93%; MS (m/e): 498 (MH.sup.+). +
morpholinomethyl)benzimidazol-5-yl]-2,4-pyrimidinediamine 956
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 8.09 min.; purity: 94%; MS (m/e): 533 (MH.sup.+). +
[1-methyl-2-(4-morpholinomethyl)benzimidazol-5-yl]-2,4-
pyrimidinediamine 957 (S)-5-Fluoro-N2-[1-methyl-2-(4- LCMS: ret.
time: 7.55 min.; purity: 98%; MS (m/e): 519 (MH.sup.+). + +
morpholinomethyl)benzimidazol-5-yl]-N4-(2-methyl-3-oxo-
2H,4H-benz[1,4]oxazin-6-yl)--2,4-pyrimidinediamine 958
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 8.34 min.; purity: 98%; MS (m/e): 534 (MH.sup.+). +
N2-[1-methyl-2-(4-morpholinomethyl)benzimidazol-5-yl]-2,4-
pyrimidinediamine 959
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[2-(4-morpholinomethyl)- LCMS:
ret. time: 9.12 min.; purity: 95%; MS (m/e): 489 (MH.sup.+). +
1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 960
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(4- LCMS: ret. time:
8.10 min.; purity: 97%; MS (m/e): 484 (MH.sup.+). +
morpholinomethyl)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 961
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 7.70 min.; purity: 93%; MS (m/e): 519 (MH.sup.+). + +
[2-(4-morpholinomethyl)-1H-benzimidazol-5-yl]-2,4-
pyrimidinediamine 962
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 7.93 min.; purity: 95%; MS (m/e): 520 (MH.sup.+). + +
N2-[2-(4-morpholinomethyl)-1H-benzimidazol-5-yl]-2,4-
pyrimidinediamine 963
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 8.01 min.; purity: 95%; MS (m/e): 569 (MH.sup.+). +
[2-methyl-1-[3-(N-methylsulfonylamino)propyl]benzimidazol-5-
yl]-2,4-pyrimidinediamine 964
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 8.36 min.; purity: 95%; MS (m/e): 570 (MH.sup.+). + +
N2-[2-methyl-1-[3-(N-
methylsulfonylamino)propyl]benzimidazol-5-yl]-2,4-
pyrimidinediamine 965
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-methyl-2- LCMS: ret. time:
10.63 min.; purity: 94%; MS (m/e): 496 (MH.sup.+). +
[(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4- pyrimidinediamine
966 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-methyl-2- LCMS:
ret. time: 9.10 min.; purity: 95%; MS (m/e): 491 (MH.sup.+). +
[(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4- pyrimidinediamine
967 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
LCMS: ret. time: 9.22 min.; purity: 91%; MS (m/e): 525 (MH.sup.+).
+ + {1-methyl-2-[(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4-
pyrimidinediamine 968 (S)-5-Fluoro-N2-{1-methyl-2- LCMS: ret. time:
8.62 min.; purity: 91%; MS (m/e): 512 (MH.sup.+). + +
[(methylsulfonyl)methyl]benzimidazol-5-yl}-N4-(2-methyl-3-
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 969
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 9.14 min.; purity: 94%; MS (m/e): 527 (MH.sup.+). + +
N2-{1-methyl-2-[(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4-
pyrimidinediamine 970
N4-(3,4-Dichlorophenyl)-N2-[2-(N,N-diethylaminomethyl)-1- LCMS:
ret. time: 9.42 min.; purity: 91%; MS (m/e): 489 (MH.sup.+). +
methylbenzimidazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 971
N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N,N- LCMS: ret. time: 7.76
min.; purity: 94%; MS (m/e): 485 (MH.sup.+). +
diethylaminomethyl)-1-methylbenzimidazol-5-yl]-5-fluoro-2,4-
pyrimidinediamine 972
N2-[2-(N,N-Diethylaminomethyl)-1-methylbenzimidazol-5-yl]- LCMS:
ret. time: 7.56 min.; purity: 94%; MS (m/e): 519 (MH.sup.+). + +
N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-
pyrimidinediamine 973
(S)-N2-[2-(N,N-Diethylaminomethyl)-1-methylbenzimidazol-5- LCMS:
ret. time: 7.21 min.; purity: 97%; MS (m/e): 505 (MH.sup.+). + +
yl]-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
2,4-pyrimidinediamine 974
N2-[2-(N,N-Diethylaminomethyl)-1-methylbenzimidazol-5-yl]- LCMS:
ret. time: 7.51 min.; purity: 97%; MS (m/e): 520 (MH.sup.+). + +
N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-
2,4-pyrimidinediamine 975
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[2-(4-morpholino)-1H- LCMS:
ret. time: 8.89 min.; purity: 90%; MS (m/e): 475 (MH.sup.+). + +
benzimidazol-5-yl]-2,4-pyrimidinediamine 976
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 7.76 min.; purity: 96%; MS (m/e): 505 (MH.sup.+). + +
[2-(4-morpholino)-1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 977
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 8.05 min.; purity: 926%; MS (m/e): 506 (MH.sup.+). + +
N2-[2-(4-morpholino)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine
978 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(4-morpholino)-
LCMS: ret. time: 8.03 min.; purity: 92%; MS (m/e): 470 (MH.sup.+).
+ 1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 979
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2-(4-methyl-1- LCMS:
ret. time: 8.12 min.; purity: 98%; MS (m/e): 502 (MH.sup.+).
piperazino)-1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 980
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2-(4- LCMS:
ret. time: 7.34 min.; purity: 96%; MS (m/e): 497 (MH.sup.+).
methyl-1-piperazino)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine
981 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
LCMS: ret. time: 6.99 min.; purity: 97%; MS (m/e): 532 (MH.sup.+).
[1-methyl-2-(4-methyl-1-piperazino)-1H-benzimidazol-5-yl]-2,4-
pyrimidinediamine 982
(S)-5-Fluoro-N2-[1-methyl-2-(4-methyl-1-piperazino)-1H- LCMS: ret.
time: 6.62 min.; purity: 97%; MS (m/e): 518 (MH.sup.+).
benzimidazol-5-yl]-N4-(2-methyl-3-oxo-2H,4H-
benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 983
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 7.05 min.; purity: 96%; MS (m/e): 533 (MH.sup.+).
N2-[1-methyl-2-(4-methyl-1-piperazino)-1H-benzimidazol-5-yl]-
2,4-pyrimidinediamine 984
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.22 (1H, s), 9.79 (1H, s), 9.62 (1H, s),
+ + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.27
(1H, d, J = 3.9 Hz), 8.08 (1H, d, J = 4.5 Hz), 7.68-7.64 (3H, m),
pyrimidinediamine Benzensulfonic Acid Salt 7.47 (1H, d, J = 8.7
Hz), 7.42-7.31 (5H, m), 7.22 (1H, t, J = 8.1 Hz), 6.63 (1H, dd, J =
8.1 Hz, J = 2.4 Hz), 4.47 (2H, 985
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.23 (1H, s), 9.91 (1H, s), 9.70 (1H, s),
+ + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.29
(1H, d, J = 3.9 Hz), 8.06 (1H, m), 7.65-7.61 (1H, m), 7.55 (1H, d,
J = 8.1 Hz), pyrimidinediamine p-Toluenesulfonic Acid Salt 7.48
(1H, d, J = 8.1 Hz), 7.33-7.18 (5H, m), 6.66 (1H, d, J = 7.5 Hz),
4.48 (2H, s), 2.75 (3H, d, J = 3.6 986
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.18 (1H, s), 9.54 (2H, broad s), 8.26
(1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s),
8.05 (1H, broad s), 7.70-7.66 (1H, m), 7.47 (1H, d, J = 8.4 Hz),
pyrimidinediamine Hydrogen Chloride Salt 7.40 (1H, s), 7.34 (1H, d,
J = 9 Hz), 7.20 (1H, t, J = 7.9 Hz), 6.61 (1H, d, J = 7.5 Hz), 4.47
(2H, s), 2.75 (3H, d, J 987
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.18 (1H, s), 9.50 (2H, broad s), 8.25
(1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- d, J
= 3.3 Hz), 8.06 (1H, m), 7.74-7.67 (1H, m), 7.47 (1H, d, J = 8.4
Hz), pyrimidinediamine Bis-Hydrogen Chloride Salt 7.41 (1H, s),
7.37 (1H, d, J = 8.1 Hz), 7.20 (1H, t, J = 7.9 Hz), 6.59 (1H, d, J
= 8.1 Hz), 4.47 (2H, s), 2.74 ( 988
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.19 (1H, s), 9.58 (1H, broad s), 9.52
(1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s),
8.25 (1H, d, J = 3.6 Hz), 8.06 (1H, m), 7.70-7.66 (1H, m), 7.47
(1H, pyrimidinediamine Nitric Acid Salt d, J = 8.7 Hz), 7.40 (1H,
s), 7.34 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.61 (1H,
d, J = 7.5 Hz), 4.47 ( 989
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.21 (1H, s), 9.64 (1H, broad s), 9.54
(1H, s), + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-
8.26 (1H, d, J = 3.6 Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz),
pyrimidinediamine Bis-Nitric Acid Salt 7.47 (1H, d, J = 8.7 Hz),
7.39 (1H, s), 7.34 (1H, d, J = 7.8 Hz), 7.21 (1H, t, J = 8.2 Hz),
6.62 (1H, d, J = 8.4 Hz), 4 990
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.24 (1H, s), 9.79 (1H, broad s), 9.63
(1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s),
8.27 (1H, d, J = 3.9 Hz), 8.07 (1H, m), 7.64 (1H, d, J = 8.4 Hz),
pyrimidinediamine Methanesulfonic Acid Salt 7.48 (1H, d, J = 8.4
Hz), 7.36 (1H, s), 7.32 (1H, d, J = 7.5 Hz), 7.22 (1H, t, J = 7.9
Hz), 6.64 (1H, d, J = 8.7 Hz), 991
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.25 (1H, s), 9.72 (1H, brad s), 9.59
(1H, s), + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-
8.27 (1H, d, J = 3.6 Hz), 8.07 (1H, m), 7.65 (1H, d, J = 8.4 Hz),
pyrimidinediamine (1S)-(+)-Camphorsulfonic Acid Salt 7.47 (1H, d, J
= 8.7 Hz), 7.37 (1H, s), 7.33 (1H, d, J = 8.7 Hz), 7.21 (1H, t, J =
8.1 Hz), 6.62 (1H, dd, J = 8.1 Hz, J 992
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.21 (1H, s), 9.63 (1H, brad s), 9.54
(1H, s), + + -
N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.26 (1H, d,
J = 3.6 Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz),
pyrimidinediamine (+)-Camphorsulfonic Acid Salt 7.47 (1H, d, J =
8.7 Hz), 7.39 (1H, s), 7.34 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J =
8.1 Hz), 6.61 (1H, dd, J = 8.1 Hz, J 993
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO-d6): d 10.78 (1H, s), 10.11 (1H, broad s), 9.89
(1H, + + + (1-methylindazol-6-yl)-2,4-pyrimidinediamine p- broad
s), 8.29 (1H, d, J = 4.8 Hz), 8.01 (1H, s), 7.95 (1H, s), 7.70 (1H,
Toluenesulfonic Acid Salt d, J = 8.7 Hz), 7.55 (2H, d, J = 8.1 Hz),
7.40 (1H, d, J = 8.4 Hz), 7.29-7.18 (4H, m), 6.95 (1H, d, J = 8.7
Hz), 994 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-
.sup.1H NMR (DMSO-d6): d 10.73 (1H, s), 9.65 (1H, s), 9.41 (1H, s),
+ + + + oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine
8.20 (1H, d, J = 4.2 Hz), 7.71 (1H, s), 7.54 (2H, d, J = 8.1 Hz),
7.43 (1H, s), p-Toluenesulfonic Acid Salt 7.35 (1H, dd, J = 8.4 Hz,
J = 2.4 Hz), 7.23-7.17 (3H, m), 7.00 (1H, d, J = 8.4 Hz), 3.76 (3H,
s), 2.38 (3H, s) 995
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 9.19 (1H, d, J = 1.5 Hz), 9.05 (1H, s), 8.64 (1H, + +
+ ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine s), 8.10 (1H,
d, J = 3.9 Hz), 7.62 (1H, d, J = 2.7 Hz), 7.36 (1H, d, J = 1.8 Hz),
7.31 (1H, m), 7.27 (1H, d, J = 2.7 Hz), 6.87 (1H, d, J = 8.4 Hz),
4.31 (4H, s), 2.22 (3H, s); LCMS: purity: 996
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3- .sup.1H
NMR (DMSO-d6): d 11.16 (1H, s), 9.27 (1H, s), 9.15 (1H, s), + + -
oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.67
(1H, s), 8.19 (1H, d, J = 3.6 Hz), 7.64 (2H, m), 7.42 (1H, d, J =
8.4 Hz),
7.29 (1H, d, J = 2.7 Hz), 2.22 (3H, s), 1.53 (6H, s); LCMS: purity:
97.69%; MS (m/e): 444 (M+). 997
N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 11.16 (1H, s), 9.23 (1H, s), 9.11 (1H, s), + + - +
4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.19
(1H, d, J = 3.6 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.4
Hz), 7.33 (2H, s), 3.68 (3H, s), 2.23 (6H, s), 1.53 (6H, s); LCMS:
purity: 99%; MS (m/e): 439 (MH+). 998
N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(3,4- .sup.1H NMR (DMSO-d6): d
10.06 (1H, s), 9.85 (1H, s), 8.25 (1H, d, J = 4.8 Hz), + + -
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.33 (1H, d, J
= 2.4 Hz), 7.24 (2H, s), 7.20 (1H, d, J = 2.7 Hz), 6.91 (1H, d, J =
8.4 Hz), 4.32 (4H, s), 3.71 (3H, s), 2.25 (6H, s); LCMS: purity:
96.69%; MS (m/e): 397 (MH+). 999
N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(3,4- .sup.1H NMR
(DMSO-d6): d 9.88 (2H, broad s), 8.26 (1H, d, J = 4.2 Hz), + + +
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.64 (1H, s),
7.41 (1H, s), 7.30-7.28 (1H, m), 7.25-7.20 (1H, m), 6.92 (1H, d, J
= 10.2 Hz), 4.32 (4H, s), 3.79 (3H, s), 2.29 (3H, s); LCMS: purity:
94.81%; MS (m/e): 417 (MH+). 1000
N4-(3,4-Dihydro-2,2-dimethyl-4H-benz[1,4]oxazin-6-yl)-5- .sup.1H
NMR (DMSO-d6): d 9.15 (1H, s), 9.08 (1H, s), 8.09 (1H, d, J = 3.6
Hz), + fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-
8.04 (1H, d, J = 4.5 Hz), 7.45-7.42 (2H, m), 7.17 (1H, t, J = 8.4
Hz), 2,4-pyrimidinediamine 7.01 (1H, d, J = 2.4 Hz), 6.95 (1H, d, J
= 8.4 Hz), 6.65 (1H, d, J = 8.7 Hz), 6.53 (1H, d, J = 9.3 Hz), 5.88
1001 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(3,4-dihydro-2,2-
.sup.1H NMR (DMSO-d6): d 9.59 (1H, broad s), 8.17 (1H, d, J = 4.2
Hz), + dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.65 (1H,
s), 7.46 (1H, s), 6.94-6.86 (2H, m), 6.68 (1H, d, J = 8.7 Hz),
pyrimidinediamine 3.77 (3H, s), 3.08 (2H, s), 2.27 (3H, s), 1.34
(6H, s); purity: 94.5%; MS (m/e): 444 (M). 1002
N4-(3,4-Dihydro-2,2-dimethyl-4H-benz[1,4]oxazin-6-yl)-N2- .sup.1H
NMR (DMSO-d6): d 9.06 (2H, s), 8.09 (1H, d, J = 3.6 Hz), +
(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.03 (1H, dd,
J = 6.9 Hz, J = 1.8 Hz), 6.95 (1H, dd, J = 8.1 Hz, J = 2.7 Hz),
6.63 (1H, d, J = 8.7 Hz), 6.11 (1H, s), 5.82 (1H, s), 3.71 (6H, s),
3.07 (2H, s), 1.34 (6H, s); purity 95.9%; MS ( 1003
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.17 (1H, s), 9.27 (1H, s), 9.24 (1H, s),
+ + N2-(3-isopropylphenyl)-2,4-pyrimidinediamine 8.21 (1H, d, J =
3.6 Hz), 7.67 (1H, m), 7.61 (1H, d, J = 9 Hz), 7.52 (1H, s), 7.44
(1H, d, J = 8.7 Hz), 7.19 (1H, t, J = 7.65 Hz), 6.85 (1H, d, J =
7.8 Hz), 2.82 (1H, m), 1.53 (6H, s), 1.25 1004
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 11.23 (1H, s), 10.12 (1H, s), 9.39 (1H,
s), + - N2-(2-methylphenyl)-2,4-pyrimidinediamine 8.27 (1H, d, J =
4.8 Hz), 7.52 (1H, d, J = 6.9 Hz), 7.43 (1H, d, J = 8.7 Hz),
7.34-7.16 (4H, m), 2.30 (3H, s), 1.50 (6H, s); purity 97.9%; MS
(m/e): 395 (MH+). 1005
2-Chloro-5-fluoro-N4-methyl-N4-(3-oxo-2,2,4-trimethyl-5- 1H NMR
(DMSO-d6): d 8.43 (1H, d, J = 5.1 Hz), 7.57 (1H, d, J = 8.4 Hz), +
- pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine 7.15 (1H, dd, J = 8.1
Hz, J = 0.9 Hz), 3.59 (3H, s), 3.30 (3H, s), 1.55 (6H, s); purity
97.2%; MS (m/e): 352 (MH+). 1006
2-Chloro-5-fluoro-N4-(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin- 1H
NMR (DMSO-d6): d 10.35 (1H, s), 8.47 (1H, d, J = 3.3 Hz), - -
6-yl)-4-pyrimidineamine 7.62 (1H, d, J = 8.7 Hz), 7.58 (1H, d, J =
8.4 Hz), 3.45 (3H, s), 1.55 (6H, s); purity 96%; MS (m/e): 338
(MH+). 1007
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.14 (1H, s), 9.24 (1H, s), 9.19 (1H, s), + + - +
N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 8.21 (1H, d, J =
3.3 Hz), 7.76 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.12
(2H, s), 3.75 (6H, s), 3.69 (3H, s), 1.52 (6H, s); purity 96%; MS
(m/e): 471 (MH+) 1008
N2-(3-Chloro-4-ethoxy-5-methylphenyl)-N4-(2,2-dimethyl-3- .sup.1H
NMR (DMSO-d6): d 10.67 (1H, s), 9.40 (1H, s), 9.20 (1H, s), + + + +
oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.16
(1H, d, J = 3.9 Hz), 7.74 (1H, d, J = 3 Hz), 7.45 (1H, d, J = 2.7
Hz), 7.36 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.25 (1H, d, J = 2.4
Hz), 6.98 (1H, d, J = 8.7 Hz), 3.94 (2H, q, J = 7.2 Hz 1009
N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(3-oxo- 1H NMR
(DMSO-d6): d 9.62 (1H, s), 9.41 (1H, s), 8.27 (1H, s), + + -
2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.80
(1H, s), 7.73 (1H, d, J = 8.7 Hz), 7.48 (1H, d, J = 8.7 Hz), 7.43
(1H, s), 3.78 (3H, d, J = 2.4 Hz), 2.92 (3H, s), 1.55 (6H, d, J =
2.4 Hz); purity 97%; MS (m/e): 473 (MH+). 1010
N2-(3-Chloro-4-ethoxy-5-methylphenyl)-N4-(2,2-dimethyl-3- 1H NMR
(DMSO-d6): d 11.18 (1H, s), 9.41 (1H, s), 9.38 (1H, s), + -
oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.23
(1H, d, J = 3.6 Hz), 7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.4
Hz), 7.46 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 2.1 Hz), 3.95 (2H,
q, J = 7.2 Hz), 2.27 (3H, s), 1.53 (6H, s), 1.42 ( 1011
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.74 (1H, s), 9.56 (1H, s), 9.49 (1H, s), + + - +
[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.21-8.19 (2H, m),
7.89 (2H, d, J = 9 Hz), 7.84 (2H, d, J = 9 Hz), 7.37 (1H, d, J =
0.6 Hz), 7.33 (1H, dd, J = 8.1 Hz, J = 2.4 Hz), 7.26 (1H, d, J =
2.7 Hz), 7.02 (1H, d, J = 8.7 Hz), 1.53 ( 1012
5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H
NMR (DMSO-d6): d 9.76 (1H, s), 9.74 (1H, s), 8.41 (1H, s), + + -
5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 8.32 (1H, d, J = 3.6
Hz), 8.25 (1H, s), 7.89-7.83 (2H, m), 7.64 (1H, d, J = 7.8 Hz),
7.48 (1H, d, J = 7.8 Hz), 7.44 (1H, s), 7.36 (1H, d, J = 7.2 Hz),
3.42 (3H, s), 1.54 (6H, s); purity 96%. 1013
5-Fluoro-N2-[4-(oxazol-2-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H
NMR (DMSO-d6): d 9.76 (1H, s), 9.73 (1H, s), 8.31 (1H, d, J = 3.6
Hz), + - 5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 8.21 (1H,
d, J = 0.9 Hz), 7.92 (2H, d, J = 9.3 Hz), 7.88 (2H, d, J = 9.6 Hz),
7.76 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J
= 0.9 Hz), 3.44 (3H, s), 1.57 (6H, 1014
N2-[3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl]- 1H NMR
(DMSO-d6): d 10.69 (1H, s), 9.43 (1H, s), 9.27 (1H, s), + + +
N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.17
(1H, d, J = 3.6 Hz), 7.76 (1H, d, J = 2.7 Hz), 7.46 (1H, d, J = 2.4
Hz), pyrimidinediamine 7.36 (1H, dd, J = 9 Hz, J = 2.7 Hz), 7.24
(1H, d, J = 2.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 4.58 (2H, s), 4.28
(2H, 1015
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR
(DMSO-d6): d 9.58 (1H, s), 9.42 (1H, s), 8.25 (1H, d, J = 3.3 Hz),
+ + - N4-[3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl]-2,4- 8.06
(1H, broad s), 7.88 (1H, d, J = 8.4 Hz), 7.49 (2H, m),
pyrimidinediamine 7.36 (1H, d, J = 7.5 Hz), 7.20 (1H, t, J = 8.1
Hz), 6.56 (1H, dd, J = 8.4 Hz, J = 2.4 Hz), 4.46 (2H, s), 3.44 (3H,
s), 1016
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.67 (1H, s), 9.53 (1H, s), 9.38 (1H, s), + + - +
[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.47 (1H, s), 8.20
(1H, d, J = 3.6 Hz), 8.04 (1H, s), 7.78 (1H, m), 7.58 (1H, s), 7.41
(1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.35 (2H, d, J = 4.8 Hz), 7.29
(1H, d, J = 2.4 Hz), 6.89 (1H, d, J = 1017
5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H
NMR (DMSO-d6): d 9.65 (1H, s), 9.57 (1H, s), 8.47 (1H, s), + + -
5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 8.29 (1H, d, J = 3.6
Hz), 8.12 (1H, s), 8.84 (1H, d, J = 8.1 Hz), 7.74 (1H, m), 7.62
(1H, s), 7.43-7.32 (3H, m), 3.42 (3H, s), 1.54 (6H, s); purity
96.4%; MS (m/e): 462 (MH+). 1018
N2-[3-Chloro-4-cyclopentyloxy-5-methylphenyl]-N4-(2,2- 1H NMR
(DMSO-d6): d 10.68 (1H, s), 9.41 (1H, s), 9.20 (1H, s), + + -
dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.16 (1H, d,
J = 3.6 Hz), 7.73 (1H, d, J = 2.7 Hz), 7.45 (1H, d, J = 2.4 Hz),
pyrimidinediamine 7.36 (1H, dd, J = 9 Hz, J = 2.7 Hz), 7.24 (1H, d,
J = 2.4 Hz), 6.98 (1H, d, J = 8.7 Hz), 4.65 (1H, m), 2.23 (3H, 1019
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 10.72 (1H, s), 9.65 (1H, s), 8.71 (1H, s), + + -
methyl-N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.27 (1H,
t, J = 1.2 Hz), 8.09 (1H, dd, J = 5.4 Hz, J = 0.9 Hz), 7.82 (1H,
dd, J = 8.1 Hz, J = 0.9 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.48-7.43
(2H, m), 7.05-6.97 (2H, m), 6.87 (1H, d, J = 2.1 H 1020
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.75 (1H, s), 9.56 (1H, s), 9.49 (1H, s), + + -
[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.43 (1H, s), 8.20
(1H, d, J = 3.9 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7
Hz), 7.53 (1H, s), 7.33-7.28 (2H, m), 7.02 (1H, d, J = 8.4 Hz),
1.52 (6H, s); purity 97.4%; MS (m/e): 1021
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 10.72 (1H, s), 9.72 (1H, s), 8.20 (1H, d, J = 0.9 Hz),
+ + + methyl-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.11
(1H, d, J = 5.7 Hz), 7.89 (4H, s), 7.38 (1H, d, J = 0.9 Hz),
7.07-6.97 (2H, m), 6.87 (1H, d, J = 2.7 Hz), 3.54 (3H, s), 1.52
(6H, s); purity 97.1%; MS (m/e): 461 (MH+). 1022
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 10.70 (1H, s), 9.38 (1H, s), 8.05 (2H, d, J = 5.4 Hz),
+ + - methyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 7.55
(1H, m), 7.37 (1H, d, J = 8.4 Hz), 7.20 (1H, t, J = 7.8 Hz),
2,4-pyrimidinediamine 7.03 (1H, d, J = 8.4 Hz), 6.97 (1H, dd, J =
8.4 Hz, J = 2.1 Hz), 6.85 (1H, d, J = 2.1 Hz), 6.57 (1H, dd, J =
7.8 1023
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 10.71 (1H, s), 9.55 (1H, s), 8.50 (1H, s), + + -
methyl-N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.37 (1H,
s), 8.08 (1H, d, J = 5.7 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.66 (1H,
s), 7.43-7.34 (2H, m), 7.05-6.97 (2H, m), 6.87 (1H, d, J = 2.4 Hz),
3.55 (3H, s), 1.51 (6H, s); purity 95.6%; MS 1024
5-Fluoro-N4-methyl-N2-[4-(oxazol-2-yl)phenyl]-N4-(3-oxo- 1H NMR
(DMSO-d6): d 9.71 (1H, s), 8.20 (1H, d, J = 0.9 Hz), + +
2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.10
(1H, d, J = 6 Hz), 7.90 (4H, s), 7.38 (1H, d, J = 0.6 Hz), 7.27
(1H, s), 7.09 (2H, s), 3.59 (3H, s), 3.34 (3H, s), 1.52 (6H, s);
purity 97.4%; MS (m/e): 475 (MH+). 1025
5-Fluoro-N4-methyl-N2-[3-(oxazol-2-yl)phenyl]-N4-(3-oxo- 1H NMR
(DMSO-d6): d 9.65 (1H, s), 8.72 (1H, d, J = 1.8 Hz), + +
2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.27
(1H, d, J = 0.6 Hz), 8.08 (1H, d, J = 6 Hz), 7.83-7.79 (1H, m),
7.60 (1H, d, J = 7.2 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J
= 0.9 Hz), 7.28 (1H, s), 7.07 (2H, s), 3.62 (3H, s), 3.35 1026
5-Fluoro-N4-methyl-N2-[4-(oxazol-5-yl)phenyl]-N4-(2,2,4- 1H NMR
(DMSO-d6): d 9.60 (1H, s), 8.44 (1H, s), 8.07 (1H, d, J = 6 Hz), +
- trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.88
(2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.57 (1H, s), 7.27
(1H, s), 7.08 (2H, s), 3.58 (3H, s), 3.34 (3H, s), 1.52 (6H, s);
purity 98.61%; MS (m/e): 475 (MH+). 1027
N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-N4-(2,2- 1H NMR
(DMSO-d6): d 11.18 (1H, s), 9.38 (1H, s), 9.35 (1H, s), + -
dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.22 (1H,
d, J = 3.6 Hz), 7.74 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.7 Hz),
pyrimidinediamine 7.46 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.7
Hz), 4.67 (1H, m), 2.26 (3H, s), 2.00-1.60 (8H, m), 1.53 (6H, s)
1028 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
1H NMR (DMSO-d6): d 11.18 (1H, s), 9.60 (1H, s), 9.37 (1H, s), + +
- N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.38 (1H, s),
8.27 (2H, m), 7.93 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.7 Hz),
7.60 (1H, d, J = 8.1 Hz), 7.44-7.34 (3H, m), 1.53 (6H, s); purity
95%; MS (m/e): 448 (MH+). 1029
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.17 (1H, s), 9.45 (1H, s), 9.31 (1H, s), + + -
N2-[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 8.54 (2H, dd, J =
9.9 Hz, J = 0.9 Hz), 8.24 (1H, d, J = 3.6 Hz), 8.10 (1H, s),
7.78-7.72 (2H, m), 7.42-7.29 (3H, m), 1.52 (6H, s); purity 96.4%;
MS (m/e): 448 (MH+). 1030
5-Fluoro-N4-methyl-N2-[3-(oxazol-4-yl)phenyl]-N4-(3-oxo- 1H NMR
(DMSO-d6): d 9.47 (1H, s), 8.59 (1H, s), 8.51 (1H, s), + +
2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.41
(1H, s), 8.05 (1H, d, J = 5.4 Hz), 7.66 (1H, d, J = 7.5 Hz),
7.41-7.32 (2H, m), 7.27 (1H, s), 7.07 (2H, s), 3.60 (3H, s), 3.35
(3H, s), 1.51 (6H, s); purity 97.4%; MS (m/e): 475 (MH+). 1031
N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-methyl-N4-(3- 1H NMR
(DMSO-d6): d 9.11 (1H, s), 8.00 (1H, J = 5.7 Hz), 7.42 (2H, + -
oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- s), 7.24 (1H, s),
7.05 (2H, s), 3.68 (3H, s), 3.55 (3H, s), 3.33 (3H, s),
pyrimidinediamine 2.25 (6H, s), 1.51 (6H, s); purity 97.84%; MS
(m/e): 466(M). 1032
N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 9.49 (1H, s), 8.07 (1H, dd, J = 6 Hz, J = 1.5 Hz), - -
methyl-N4-(3-oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- 7.81
(1H, d, J = 2.7 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.27 (1H, s),
pyrimidinediamine 7.07 (2H, s), 4.69 (1H, m), 3.61 (3H, s), 3.33
(3H, s), 2.29 (3H, s), 2.0-1.6 (8H, m), 1.51 (6H, s); purity
96.15%; 1033
N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-(3-oxo-2,2,4- 1H NMR
(DMSO-d6): d 9.49 (1H, d, J = 0.9 Hz), 9.15 (1H, s), + + +
trimethyl-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.21 (1H, d,
J = 3.6 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 8.4 Hz),
7.35 (2H, s), 3.69 (3H, s), 3.43 (3H, s), 2.23 (6H, s), 1.54 (6H,
s); purity 98.82%; MS (m/e): 453 (M). 1034
N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-5-fluoro-N4- 1H NMR
(DMSO-d6): d 9.63 (1H, s), 9.40 (1H, s), 8.26 (1H, d, J = 3.6 Hz),
+ - (3-oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- 7.78 (1H, d,
J = 2.4 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz),
pyrimidinediamine 7.41 (1H, d, J = 2.4 Hz), 4.68 (1H, m), 3.41 (3H,
s), 2.26 (3H, s), 1.95-1.60 (8H, m), 1.54 (6H, s); 1035
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.23 (1H, s), 9.70 (1H, s), 9.53 (1H, s), -
N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.27 (1H, d, J =
3.6 Hz), 8.20 (1H, d, J = 0.9 Hz), 7.90 (2H, d, J = 9.3 Hz),
8.86 (2H, d, J = 9.5 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J
= 8.4 Hz), 7.37 (1H, J = 0.9 Hz), 1.56 (6H, s 1036
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.65 (1H, s), 9.41 (1H, d, J = 1.2 Hz), + + +
[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 9.32 (1H, s), 8.50
(1H, d, J = 0.6 Hz), 8.47 (1H, s), 8.17 (1H, d, J = 3.9 Hz), 8.08
(1H, s), 7.78 (1H, d, J = 8.7 Hz), 7.43 (1H, dd, J = 8.7 Hz, J =
2.4 Hz), 7.39-7.27 (3H, m), 6.88 (1H, d, J 1037
N2-[3-Chloro-5-methyl-4-(N- 1H NMR (DMSO-d6): d 11.19 (1H, s), 9.43
(2H, s), 8.24 (1H, d, J = 7.8 Hz), + -
methylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl- 8.18 (1H,
d, J = 4.5 Hz), 7.78 (1H, d, J = 2.4 Hz), 7.60 (1H, d,
3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- J = 8.4 Hz), 7.47
(1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 2.4 Hz), pyrimidinediamine
4.32 (2H, s), 2.79 (3H, d, J = 4.8 Hz), 2.29 (3H 1038
N2-(3,5-Dimethyl-4-ethoxycarbonylmethyleneoxyphenyl)-N4- 1H NMR
(DMSO-d6): d 11.18 (1H, s), 9.26 (1H, s), 9.16 (1H, s), + -
(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.19
(1H, d, J = 3.3 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4
Hz), pyrimidinediamine 7.33 (2H, s), 4.49 (2H, s), 4.28 (2H, q, J =
7.2 Hz), 2.23 (6H, s), 1.52 (6H, s), 1.33 (3H, t, J = 7.2 Hz); pur
1039 N2-(3-Chloro-4-isopropoxy-5-methylphenyl)-N4-(2,2-dimethyl- 1H
NMR (DMSO-d6): d 10.72 (1H, s), 9.68 (1H, s), 9.44 (1H, s), + +
3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.20
(1H, d, J = 3.6 Hz), 7.70 (1H, d, J = 2.1 Hz), 7.42 (1H, d, J = 2.4
Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.24 (1H, d, J = 2.4
Hz), 6.98 (1H, d, J = 8.4 Hz), 4.36 (1H, quint, J = 1040
N2-(3-Chloro-4-isopropoxy-5-methylphenyl)-N4-(2,2-dimethyl- 1H NMR
(DMSO-d6): d 11.17 (1H, s), 9.37 (1H, s), 9.35 (1H, s), - +
3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.22 (1H, d, J =
3.0 Hz), 7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.7 Hz),
pyrimidinediamine 7.45 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 2.7
Hz), 4.36 (1H, quint, J = 6.0 Hz), 2.25 (3H, s), 1.52 (6H, s), 1.
1041 N2-[3,5-Dimethyl-4-(N- 1H NMR (DMSO-d6): d 11.18 (1H, s), 9.28
(1H, s), 9.18 (1H, s), + + +
methylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl- 8.19 (2H,
d, J = 3.6 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.7 Hz),
3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.34 (2H, s), 4.22
(2H, s), 2.79 (3H, d, J = 4.5 Hz), 2.23 (6H, s), pyrimidinediamine
1.52 (6H, s); purity 98%; MS (m/e): 496 (MH 1042
N2-(3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl)- 1H NMR
(DMSO-d6): d 11.19 (1H, s), 9.42 (2H, s), 8.23 (1H, d, J = 3.6 Hz),
- - N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
7.76 (1H, d, J = 2.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.47 (1H, d,
2,4-pyrimidinediamine J = 8.4 Hz), 7.42 (1H, d, J = 2.1 Hz), 4.60
(2H, s), 4.27 (2H, q, J = 7.2 Hz), 2.29 (3H, s), 1.52 (6H, s), 1.33
( 1043 N2-[3-Chloro-4-[N-(2,3- 1H NMR (DMSO-d6): d 11.17 (1H, s),
9.42 (1H, s), 9.40 (1H, s), + + -
dihydroxypropyl)amino]carbonylmethyleneoxy-5- 8.23 (1H, d, J = 3.6
Hz), 7.98 (1H, t, J = 5.7 Hz), 7.78 (1H, d, J = 2.7 Hz),
methylphenyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6- 7.61
(1H, d, J = 8.7 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.34 (1H, d, J = 1.8
Hz), yl)-5-fluoro-2,4-pyrimidinediamine 4.94 (1H, broad s), 4.67
(1H, broa 1044 N2-[3,5-Dimethyl-4-(N- 1H NMR (DMSO-d6): d 11.18
(1H, s), 9.27 (1H, s), 9.17 (1H, s), - - -
cyclopentylamino)carbonylmethyleneoxyphenyl]-N4-(2,2- 8.19 (1H, d,
J = 3.6 Hz), 8.03 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 8.7 Hz),
dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.45 (1H,
d, J = 8.7 Hz), 7.34 (2H, s), 4.23 (1H, m), 4.21 (2H, s),
pyrimidinediamine 2.23 (6H, s), 1.91 (2H, m), 1.76 (2H, m), 1. 1045
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 12.12 (1H, s), 9.95 (1H, s), 9.58 (1H, s), + + -
[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.26 (1H, d, J =
3.6 Hz), 8.06 (1H, d, J = 4.2 Hz), 7.65 (1H, d, J = 2.1 Hz),
pyrimidinediamine Hydrogen Chloride Salt 7.61 (1H, d, J = 2.4 Hz),
7.41 (1H, s), 7.35 (1H, d, J = 8.7 Hz), 7.30 (1H, d, J = 9.0 Hz),
7.21 (1H, t, J = 7.8 1046
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 12.05 (1H, s), 9.81 (1H, s), 9.38 (1H, s), + + -
[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.24 (1H, d, J =
3.6 Hz), 8.04 (1H, d, J = 4.2 Hz), 7.66 (1H, dd, J = 10.5 Hz,
pyrimidinediamine Methanesulfonic Acid Salt J = 1.5 Hz), 7.51 (1H,
d, J = 1.8 Hz), 7.43 (1H, s), 7.36-7.29 (2H, m), 7.19 (1H, t, J =
7.8 Hz), 6.59 (1H, d, 1047
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.74 (1H, s), 10.11 (1H, s), 9.82 (1H, s), - + -
(indazol-6-yl)-2,4-pyrimidinediamine Methanesulfonic Acid Salt 8.26
(1H, d, J = 4.5 Hz), 8.05 (1H, s), 7.88 (1H, s), 7.71 (1H, d, J =
8.4 Hz), 7.45 (1H, dd, J = 9.0 Hz, J = 2.7 Hz), 7.31 (1H, dd, J =
8.7 Hz, J = 1.5 Hz), 7.24 (1H, d, J = 2.4 Hz), 6.97 1048
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.73 (1H, s), 9.282 (1H, s), 9.60 (1H, s), + + -
(indazol-6-yl)-2,4-pyrimidinediamine Hydrogen Chloride Salt 8.24
(1H, d, J = 4.2 Hz), 8.02 (2H, s), 7.67 (1H, d, J = 8.4 Hz), 7.47
(1H, d, J = 8.7 Hz), 7.36-7.33 (2H, m), 6.98 (1H, d, J = 8.7 Hz),
1.49 (6H, s); purity 99.3%; MS (m/e): 420 (MH+). 1049
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(1- 1H NMR
(DMSO-d6): d 11.21 (1H, s), 9.56 (1H, s), 9.40 (1H, s), + + -
ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.29 (1H, d, J =
3.6 Hz), 8.11 (1H, s), 7.96 (1H, s), 7.71 (1H, d, J = 7.2 Hz), 7.64
(1H, d, J = 9.0 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J =
8.7 Hz, J = 1.5 Hz), 4.25 (2H, q, J = 7. 1050
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(1- 1H NMR
(DMSO-d6): d 11.22 (1H, s), 9.56 (1H, s), 9.41 (1H, s), + + -
isopropylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.29 (1H, d,
J = 3.3 Hz), 8.15 (1H, s), 7.96 (1H, s), 7.70 (1H, d, J = 8.4 Hz),
7.63 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.7 Hz), 7.35 (1H, dd, J
= 8.7 Hz, J = 1.2 Hz), 4.63 (1H, quint, J 1051
2-Chloro-N4-(3,4-dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin- 1H NMR
(DMSO-d6): d 9.84 (1H, s), 8.35 (1H, d, J = 3.3 Hz), - -
6-yl)-5-fluoro-4-pyrimidineamine 7.09 (1H, d, J = 8.1 Hz), 7.06
(1H, d, J = 8.1 Hz), 6.79 (1H, s), 3.23 (2H, s), 1.36 (6H, s);
purity 96.73%; MS (m/e): 310 (MH+). 1052
N4-(3,4-Dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 9.50 (1H, s), 8.94 (1H, s), 8.21 (1H, d, J = 3.6 Hz),
+ + + fluoro-N2-(1-methylindazol-6-yl)-2,4-pyrimidinediamine 8.17
(1H, s), 7.93 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J =
1.5 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.72
(1H, s), 3.92 (3H, s), 3.24 (2H, d, J = 2. 1053
N4-(3,4-Dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR
(DMSO-d6): d 9.29 (1H, s), 8.83 (1H, s), 8.15 (1H, d, J = 3.6 Hz),
+ + - fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 8.03
(1H, m), 7.47 (1H, t, J = 2.1 Hz), 7.40 (1H, d, J = 7.5 Hz),
2,4-pyrimidinediamine 7.34 (1H, d, J = 6.9 Hz), 7.20 (1H, t, J =
8.4 Hz), 7.02 (1H, d, J = 8.1 Hz), 6.67 (1H, s), 6.56 (1H, dd, J =
7.8 1054 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-(2,2- 1H
NMR (DMSO-d6): d 11.19 (1H, s), 9.70 (1H, s), 9.52 (1H, s), + + -
dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.28 (1H,
d, J = 2.4 Hz), 8.21 (1H, d, J = 5.1 Hz), 7.97 (1H, s),
pyrimidinediamine 7.62-7.57 (2H, m), 7.50 (1H, d, J = 9.0 Hz), 7.34
(1H, d, J = 8.4 Hz), 2.81 (3H, d, J = 3.6 Hz), 1.53 (6H, s); purity
99.5% 1055
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,4- 1H NMR
(DMSO-d6): d 11.12 (1H, s), 9.25 (1H, s), 9.12 (1H, s), + + -
ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 8.17 (1H, d, J
= 3.3 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.35
(1H, d, J = 2.4 Hz), 7.10 (1H, dd, J = 9.0 Hz, J = 2.4 Hz), 6.76
(1H, d, J = 9.0 Hz), 4.26 (4H, m), 1.53 (6H, 1056
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.23 (1H, s), 9.88 (1H, s), 9.28 (1H, s), + + -
N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine Hydrogen 8.33 (1H,
d, J = 3.6 Hz), 8.02 (1H, s), 7.98 (1H, s), 7.66 (2H, t, J = 8.4
Hz). Chloride Salt 7.45 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4
Hz, J = 1.5 Hz), 3.93 (3H, s), 1.53 (6H, s); purity 100%; MS 1057
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.23 (1H, s), 9.81 (2H, s), 8.32 (1H, d, J = 3.9 Hz),
+ + - N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine p- 8.02 (1H,
s), 7.98 (1H, s), 7.67 (2H, t, J = 8.7 Hz), 7.55 (2H, d,
Toluenesulfonic Acid Salt J = 7.8 Hz), 7.44 (1H, d, J = 8.4 Hz),
7.31 (1H, dd, J = 8.4 Hz, J = 0.9 Hz), 7.19 (2H, d, J = 8.4 Hz),
3.94 (3 1058
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR
(DMSO-d6): d 11.22 (1H, s), 9.76 (1H, s), 9.72 (1H, s), + + -
N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine 8.31 (1H, d, J =
3.3 Hz), 8.04 (1H, s), 7.97 (1H, s), 7.67 (2H, d, J = 8.4 Hz),
Methanesulfonic Acid Salt 7.45 (1H, d, J = 8.1 Hz), 3.32 (1H, d, J
= 8.4 Hz), 3.93 (3H, s), 2.41 (3H, s), 1.53 (6H, s); purity 99%; MS
1059 N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-(3-oxo- 1H NMR
(DMSO-d6): d 2.13 (s, 6H), 3.58 (s, 3H), 4.62 (s, 2H), 7.22 (s, +
2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H), 7.33 (d,
J = 9.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 3.6 Hz,
1H), 9.01 (s, 1H), 9.15 (s, 1H), 11.13 (s, 1H); 19F NMR (282 MHz,
DMSO-d6): d - 163.82; LCMS: ret. time: 10.29 min.; purity: 97.75%;
MS (m/e): 411.18 (MH+) 1060
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (CDCl3): d 1.45 (s, 6H), 2.13 (s, 3H), 6.78 (m, 3H),
6.90 (d, + (3-hydroxy-2-methylphenyl)-2,4-pyrimidinediamine J = 7.5
Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.74 (d, J = 5.1
Hz, 1H), 7.91 (s, 1H), 9.09 (s, 1H), 10.86 (s, 1H); 19F NMR (282
MHz, CDCl3): d - 162.90; LCMS: ret. time: 8.06 min 1061
5-Fluoro-N2-(3-methoxy-2-methylphenyl)-N4-(3-oxo-2H,4H-5- .sup.1H
NMR (DMSO-d6): d 1.99 (s, 3H), 3.79 (s, 3H), 4.60 (s, 2H), 6.54 (d,
+ pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 7.8 Hz, 1H),
6.78 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 2.4 and 8.1 Hz, 1H), 7.12
(t, J = 8.4 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 3.9 Hz,
1H), 8.73 (s, 1H), 9.23 (s, 1H), 11.08 1062
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (CDCl3): d 1.49 (s, 6H), 2.12 (s, 3H), 3.95 (s, 3H),
6.71 (dd, + (3-methoxy-2-methylphenyl)-2,4-pyrimidinediamine J =
2.1 and 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.8 Hz,
1H), 6.98 (d, J = 8.4 Hz, 1H), 7.26 (m, 3H), 7.66 (d, J = 4.2 Hz,
1H), 7.93 (s, 1H), 11.04 (s, 1H); 19F NMR (282 MHz, 1063
5-Fluoro-N2-(3-hydroxy-2-methylphenyl)-N4-(3-oxo-2H,4H-5- .sup.1H
NMR (CDCl3): d 2.02 (s, 3H), 4.48 (s, 2H), 6.72 (m, 2H), 6.82 (m, +
pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 6.96 (t, J = 8.1
Hz, 1H), 7.25 (m, 1H), 7.79 (d, J = 4.8 Hz, 1H); LCMS: ret. time:
7.10 min.; purity: 77.55%; MS (m/e): 383.14 (MH+). 1064
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (CDCl3): d 1.41 (s, 6H), 2.04 (s, 3H), 6.61 (t, J = 4.5
Hz, 1H), + N2-(3-hydroxy-2-methylphenyl)-2,4-pyrimidinediamine 6.94
(m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 3.9 Hz, 1H); 19F
NMR (282 MHz, CDCl3): d - 165.40; LCMS: ret. time: 7.83 min.;
purity: 99.01%; MS (m/e): 411.19 (MH+). 1065
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (CDCl3): d 1.57 (s, 6H), 2.19 (s, 3H), 3.88 (s, 3H),
6.79 (dd, + N2-(3-methoxy-2-methylphenyl)-2,4-pyrimidinediamine J =
2.1 and 7.2 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.17 (m, 2H), 7.70
(d, J = 8.7 Hz, 1H), 7.85 (d, J = 3.6 Hz, 1H); 19F NMR (282 MHz,
CDCl3): d - 161.49; LCMS: ret. time: 10.92 min.; purit 1066
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (CDCl3): d 1.49 (s, 6H), 2.26 (s, 3H), 3.80 (s, 3H),
4.84 (s, + [3-methoxycarbonylmethyleneoxy-2-methylphenyl]-2,4- 2H),
6.69 (dd, J = 2.4 and 8.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.86
(d, pyrimidinediamine J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H),
7.19 (t, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.46 (s, 1H), 7.72 (s, 1H),
7.79 1067
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (CDCl3): d 1.50 (s, 6H), 2.25 (s, 3H), 2.93 (d, J = 4.8
Hz, 3H), + [2-methyl-3-(N-methylamino)carbonylmethyleneoxyphenyl]-
4.57 (s, 2H), 6.82 (m, 4H), 6.97 (t, J = 8.1 Hz, 1H), 7.19 (m, 2H),
2,4-pyrimidinediamine 7.40 (s, 1H), 7.54 (s, 1H), 7.81 (d, J = 4.2
Hz, 1H); LCMS: ret. time: 8.08 min.; purity: 99.78%; MS (m/e):
481.21 (MH 1068 5-Fluoro-N2-[2-methyl-3-(N- .sup.1H NMR (DMSO-d6):
d 2.08 (s, 3H), 2.66 (d, J = 4.5 Hz, 3H), 4.46 (s, +
methylamino)carbonylmethyleneoxyphenyl]-N4-(3-oxo-2H,4H- 2H), 4.58
(s, 2H), 6.65 (dd, J = 1.8 and 7.2 Hz, 1H), 7.04 (m, 2H),
5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.15 (d, J = 8.7 Hz,
1H), 7.47 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 4.2 Hz, 1H), 8.01 (d, J
= 3.6 Hz, 1H), 8.54 (s, 1H), 8.96 ( 1069
N2-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H- .sup.1H
NMR (DMSO-d6): d 2.09 (s, 6H), 4.62 (s, 2H), 7.05 (s, 2H), 7.28 (d,
+ 5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 8.4 Hz, 1H),
7.55 (d, J = 8.1 Hz, 1H), 7.89 (br, 1H), 8.07 (d, J = 3.6 Hz, 1H),
9.03 (s, 1H), 9.36 (s, 1H), 11.15 (s, 1H); 19F NMR (282 MHz,
DMSO-d6): d - 163.98; LCMS: ret. time: 7.9 1070
N2-[3-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4-(3- .sup.1H
NMR (CDCl3): d 1.14 (t, J = 7.2 Hz, 3H), 3.00 (t, J = 5.1 Hz, 4H),
+ oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 3.46 (t,
J = 5.1 Hz, 4H), 4.00 (q, J = 7.2 Hz, 2H), 4.47 (s, 2H), 6.55 (dd,
J = 1.8 and 8.4 Hz, 1H), 6.90 (dd, J = 1.2 and 7.8 Hz, 1H), 6.98
(t, J = 2.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.08 1071
N2-[3-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-(3-oxo-2H,4H-5-
.sup.1H NMR (CDCl3): d 2.01 (s, 3H), 3.02 (t, J = 5.1 Hz, 2H), 3.08
(t, J = 5.1 Hz, + pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H),
3.50 (t, J = 5.1 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 4.50 (s, 2H),
6.66 (dd, J = 2.4 and 8.4 Hz, 1H), 6.87 (t, J = 2.4 Hz, 1H), 6.92
(ddd, J = 0.9, 2.1 and 7.8 Hz, 1H), 6.98 (d, J 1072
N2-[4-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4-(3- .sup.1H
NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.1 Hz,
4H), + oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine
3.49 (t, J = 5.1 Hz, 4H), 4.05 (q, J = 7.2 Hz, 2H), 4.63 (s, 2H),
6.83 (d, J = 9.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.47 (d, J =
9.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 3.6 Hz, 1
1073 5-Fluoro-N2-(3-morpholinophenyl)-N4-(3-oxo-2H,4H-5- .sup.1H
NMR (DMSO-d6): d 2.98 (t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz,
4H), + pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 4.62 (s, 2H),
6.50 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 7.17 (d, J =
7.2 Hz, 1H), 7.18 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.58 (d, J =
8.7 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.09 (s 1074
5-Fluoro-N2-[3-(4-methylpiperazino)phenyl]-N4-(3-oxo-2H,4H- .sup.1H
NMR (DMSO-d6): d 2.85 (s, 3H), 2.90 (m, 2H), 3.23 (m, 4H), +
5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 3.67 (m, 2H), 4.63
(s, 2H), 6.57 (dd, J = 2.1 and 8.4 Hz, 1H), 7.08 (t, J = 8.1 Hz,
1H), 7.20 (s, 1H), 7.28 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.59 (d,
J = 8.4 Hz, 1H), 8.11 (d, J = 3.3 Hz, 1H), 9.1 1075
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[3-(4-
.sup.1H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.42 (s, 6H),
3.00 (t, + ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 4H), 3.45
(t, J = 4.8 Hz, 4H), 4.04 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 9.3 Hz,
pyrimidinediamine 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.20
(d, J = 6.6 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz
1076 N2-[3-(4-Acetylpiperazino)phenyl]-N4-(2,2-dimethyl-3-oxo-4H-
.sup.1H NMR (CDCl3): d 1.46 (s, 6H), 2.06 (s, 3H), 3.08 (t, J = 5.1
Hz, 2H), + 5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine
3.13 (t, J = 5.1 Hz, 2H), 3.54 (t, J = 5.1 Hz, 2H), 3.65 (t, J =
5.1 Hz, 2H), 6.67 (dd, J = 2.4 and 8.4 Hz, 1H), 6.94 (t, J = 2.1
Hz, 1H), 7.01 (ddd, J = 0.9, 1.8 and 7.8 Hz, 1H), 7.05 (d, J 1077
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-N2-[4-(4-
.sup.1H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 1.43 (s, 6H),
3.03 (t, + ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 4H), 3.50
(t, 4H), 4.05 (q, J = 7.2 Hz, 2H), 6.88 (d, J = 9.3 Hz, 2H),
pyrimidinediamine 7.38 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 9.9 Hz,
2H), 7.51 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 3.9 Hz, 1H), 9.24 (s,
1H), 9.44 1078
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 1.42 (s, 6H), 3.00 (t, J = 4.8 Hz, 4H),
3.69 (t, J = 4.8 Hz, +
N2-(3-morpholinophenyl)-2,4-pyrimidinediamine 4H), 6.51 (dd, J =
7.5 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.17 (d, J =
8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H),
8.12 (d, J = 3.6 Hz, 1H), 9.17 ( 1079
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (DMSO-d6): d 1.39 (s, 6H), 2.08 (s, 3H), 2.65 (d, J =
4.8 Hz, + N2-[2-methyl-3-(N- 3H), 4.45 (s, 2H), 6.64 (dd, J = 2.7
and 6.6 Hz, 1H), 7.04 (m, 2H),
methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.15 (d, J = 8.4 Hz,
1H), 7.48 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 3.9 Hz, 1H),
pyrimidinediamine 8.01 (d, J = 3.6 Hz, 1H), 8.56 (s, 1H), 8.98 (
1080 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-5-fluoro-
.sup.1H NMR (CDCl3): d 1.42 (s, 6H), 2.77 (s, 3H), 3.20 (m, 4H),
3.30 (m, + N2-[3-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine
4H), 6.61 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 2.4 Hz, 1H), 7.04 (d, J
= 8.4 Hz, 1H), 7.13 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.81 (d, J =
4.2 Hz, 1H); 19F NMR (282 MHz, CDCl3): d - 162.81; LCMS 1081
(S)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (DMSO-d6): d 1.45 (d, J = 6.6 Hz, 3H), 3.77 (s, 3H), 4.73 (q, +
+ oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 6.6
Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.48
(m, 2H), 7.80 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.21
(s, 1H), 9.26 (s, 1H), 11.09 (s, 1H); 19F NMR (282 M 1082
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-5-pyrid[1,4]oxazin-6- .sup.1H
NMR (DMSO-d6): d 1.45 (d, J = 6.9 Hz, 3H), 3.59 (s, 3H), 3.65 (s, +
+ yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 6H), 4.72
(q, J = 6.6 Hz, 1H), 7.02 (s, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.65
(d, J = 8.4 Hz, 1H), 8.11 (d, J = 3.3 Hz, 1H), 9.10 (s, 1H), 9.17
(s, 1H), 11.07 (s, 1H); 19F NMR (282 MHz, DMSO-d6 1083
N2,N4-Bis(3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- .sup.1H
NMR (DMSO-d6): d 4.46 (s, 2H), 4.52 (s, 2H), 6.76 (d, J = 9.3 Hz, +
+ + pyrimidinediamine 1H), 6.86 (d, J = 8.7 Hz, 1H), 7.18 (m, 2H),
7.23 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 2.4 and 8.7 Hz, 1H), 8.00
(d, J = 3.6 Hz, 1H), 8.94 (s, 1H), 9.29 (s, 1H), 10.58 (s, 1H),
10.63 (s, 1H); 1 1084
(S)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo- .sup.1H
NMR (DMSO-d6): d 1.44 (d, J = 6.9 Hz, 3H), 2.17 (s, 6H), 4.72 (q, -
+ 2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 6.9 Hz,
1H), 6.52 (s, 1H), 7.22 (s, 2H), 7.35 (d, J = 8.7 Hz, 1H), 7.89 (d,
J = 8.4 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.09 (s, 1H), 9.16 (s,
1H), 11.08 (s, 1H); 19F NMR (282 MHz, DMSO-d6 1085
N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4-
.sup.1H NMR (CDCl3): d 1.82 (m, 2H), 2.03 (m, 2H), 2.15 (s, 3H),
2.46 (m, + - pyrimidinediamine 2H), 3.20 (m, 4H), 3.63 (t, J = 5.1
Hz, 2H), 3.78 (t, J = 5.1 Hz, 2H), 4.58 (m, J = 8.1 Hz, 1H), 5.26
(d, J = 6.6 Hz, 1H), 6.58 (dd, J = 1.8 and 8.1 Hz, 1H), 7.01 (dd, J
= 1.5 and 7.8 Hz, 1H), 1086
N2-(5-tert-Butylpyrazol-3-yl)-5-fluoro-N4-(3-oxo-2H,4H-5- .sup.1H
NMR (DMSO-d6): d 1.29 (s, 9H), 4.64 (s, 2H), 5.59 (s, 1H), 7.10 (d,
+ - pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.47 (d, J =
6.6 Hz, 1H), 8.24 (d, 1H), 10.02 (s, 1H), 10.40 (s, 1H); 19F NMR
(282 MHz, DMSO-d6): d -162.59; LCMS: ret. time: 10.51 min.; purity:
78.44%; MS (m/e): 399.24 (MH+). 1087
N4-Cyclobutyl-N2-(3,5-dimethylphenyl)-5-fluoro-2,4- 1H NMR (CDCl3):
d 1.78-1.87 (m, 2H), 1.96-2.03 (m, 2H), 2.32 (s, + + -
pyrimidinediamine 6H), 2.44-2.53 (m, 2H), 4.56 (m, J = 7.8 Hz, 1H),
5.26 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 7.23 (s, 2H), 7.34 (br, NH,
1H), 7.72 (d, J = 2.7 Hz, 1H); 19F NMR (282 MHz, CDCl3): d -
168.35; LCMS: 1088
N4-Cyclobutyl-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4- 1H NMR
(CDCl3): d 1.71-1.86 (m, 2H), 1.93-2.06 (m, 2H), + + -
pyrimidinediamine 2.43-2.53 (m, 2H), 3.81 (s, 6H), 4.60 (m, J = 7.8
Hz, 1H), 5.31 (d, 1H), 6.16 (t, J = 2.1 Hz, 1H), 6.84 (d, J = 2.1
Hz, 2H), 7.57 (br, NH, 1H), 7.72 (d, J = 3.6 Hz, 1H); 19F NMR (282
MHz, CDCl3): d - 167 1089 N4-Cyclobutyl-5-fluoro-N2-(3-methoxy-5-
1H NMR (CDCl3): d 1.75-2.04 (m, 4H), 2.43-2.53 (m, 2H), 3.85 (s, +
+ - trifluoromethylphenyl)-2,4-pyrimidinediamine 3H), 4.58 (m, J =
7.8 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 6.76 (s, 1H), 7.18 (t, J =
2.1 Hz, 1H), 7.52 (br, NH, 1H), 7.76 (s, 2H); 19F NMR (282 MHz,
CDCl3): d - 167.20, -63.67; LCMS: ret. time: 1090
N4-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N2-(3- LCMS: ret. time:
11.58 min.; purity: 90.45%; MS (m/e): 412.33 (MH+). + + -
morpholinophenyl)-2,4-pyrimidinediamine 1091
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(5-tert-butyl-1H-pyrazol- 1H
NMR (CDCl3): d 1.20 (s, 9H), 2.04 (s, 3H), 3.06 (t, J = 5.4 Hz,
2H), + + - 3-yl)-5-fluoro-2,4-pyrimidinediamine 3.11 (t, J = 5.1
Hz, 2H), 3.53 (t, J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 6.10
(s, 1H), 6.57 (m, 1H), 6.96 (s, 1H), 7.13 (m, 2H), 7.82 (d, J = 3.9
Hz, 1H); LCMS: ret. time: 8.84 min.; 1092
(S)-N2-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N4-(2-methyl-3- 1H
NMR (DMSO-d6): d 1.30 (s, 9H), 1.47 (d, J = 6.6 Hz, 3H), 4.74 (q, +
+ - oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J =
6.3 Hz, 1H), 5.60 (s, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.49 (d, J =
8.4 Hz, 1H), 8.23 (d, J = 3.9 Hz, 1H), 10.02 (s, 1H), 10.39 (s,
1H); 19F NMR (282 MHz, DMSO-d6): d - 162.62; LCMS: ret. t 1093
N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-[3-(N-2- 1H NMR
(DMSO-d6): d 2.16 (s, 6H), 3.61 (s, 4H), 3.64 (s, 3H), + + - +
imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 6.98 (d, J = 11
Hz, 1H), 7.00 (s, 1H), 7.23 (s, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.75
(d, J = 6.6 Hz, 1H), 8.19 (d, J = 4.5 Hz, 1H), 8.29 (s, 2H), 9.57
(s, 1H), 9.89 (s, 1H), 10.82 (s, 1H); 19F NMR ( 1094
5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-[3-(N-2- 1H NMR
(DMSO-d6): d 3.63 (s, 4H), 3.79 (s, 3H), 6.96 (d, J = 9.3 Hz, + -
imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 1H), 7.04 (t, J
= 9.3 Hz, 1H), 7.28 (m, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.63 (dd, J
= 2.1, 13.8 Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.80 (s, 1H), 8.18
(d, J = 4.2 Hz, 1H), 8.27 (s, 1H), 9.56 (s, 1095
N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[3-(N-2-imidazolin-2- 1H NMR
(DMSO-d6): d 2.20 (s, 6H), 3.60 (s, 4H), 6.92 (s, 1H), + -
yl)aminophenyl]-2,4-pyrimidinediamine 6.98 (m, 1H), 7.22 (s, 1H),
7.35 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H),
8.21 (d, J = 4.2 Hz, 1H), 8.26 (s, 2H), 9.60 (s, 1H), 9.86 (s, 1H),
10.80 (s, 1H); 19F NMR (282 MHz, D 1096
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[3-(N-2-imidazolin-2- 1H NMR
(DMSO-d6): d 3.62 (s, 4H), 3.66 (s, 6H), 6.13 (t, J = 2.1 Hz, + - -
yl)aminophenyl]-2,4-pyrimidinediamine 1H), 6.92 (d, J = 2.1 Hz,
1H), 6.95 (dd, J = 1.5, 8.4 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.71
(d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 8.20 (d, J = 3.9 Hz, 1H), 8.26
(s, 2H), 9.61 (s, 1H), 9.81 (s, 1097
5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2-(3- 1H NMR
(DMSO-d6): d 3.01 (t, J = 4.5 Hz, 4H), 3.60 (s, 4H), 3.70 (t, J =
4.5 Hz, - - morpholinophenyl)-2,4-pyrimidinediamine 4H), 6.51 (dd,
J = 2.1, 8.4 Hz, 1H), 6.90 (dd, J = 1.5, 7.8 Hz, 1H), 7.05 (t, J =
8.1 Hz, 1H), 7.29 (m, 3H), 7.64 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H),
8.12 (d, J = 3.6 Hz, 1H), 9.20 ( 1098
N2-[3-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4-[3-(N- 1H NMR
(DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 3.02 (t, J = 5.4 Hz, 4H), -
- 2-imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 3.47 (t, J =
5.4 Hz, 4H), 3.60 (s, 4H), 4.05 (q, J = 7.2 Hz, 2H), 6.53 (dd, J =
1.5, 8.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.1 Hz,
1H), 7.30 (m, 3H), 7.66 (d, J = 8.7 Hz, 1H), 7 1099
5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2-[4-(4- 1H NMR
(DMSO-d6): d 3.30 (m, 4H), 3.62 (s, 4H), 6.84 (d, J = 9.0 Hz, - -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 6.91 (d, J =
8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H),
7.73 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.09 (d, J = 3.3 Hz, 1H),
8.27 (s, 1H), 9.06 (s, 1H), 9.44 (s, 1H); 1 1100
5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2-[4-(4- 1H NMR
(DMSO-d6): d 3.00 (t, J = 5.1 Hz, 4H), 3.50 (t, J = 4.5 Hz, 4H), -
- methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine 3.61 (s,
7H), 6.84 (d, J = 9.0 Hz, 2H), 6.91 (dd, J = 1.5, 7.5 Hz, 1H), 7.34
(t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.1 Hz,
1H), 7.94 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9 1101
N4-(5-tert-Butyl-1H-pyrazol-3-yl)-N2-[3-(4- 1H NMR (CDCl3): d 1.28
(t, J = 7.2 Hz, 3H), 1.31 (s, 9H), 3.13 (t, J = 5.1 Hz, + -
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 4H), 3.60 (t, J =
5.4 Hz, 4H), 4.15 (q, J = 7.2 Hz, 2H), 6.35 (s, pyrimidinediamine
1H), 6.61 (m, 1H), 7.03 (s, 1H), 7.18 (m, 2H), 7.73 (br, 1H), 7.90
(d, J = 3.3 Hz, 1H), 8.20 (br, 1H); 19F NMR (282 1102
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(5-tert-butyl-1H-pyrazol-
LCMS: ret. time: 8.02 min.; purity: 94.49%; MS (m/e): 453.29 (MH+).
+ + - 3-yl)-5-fluoro-2,4-pyrimidinediamine 1103
N4-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N2-[4-(4- LCMS: ret.
time: 10.38 min.; purity: 97.48%; MS (m/e): 469.35 (MH+). + + -
methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine 1104
N4-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N2-[4-(4- 1H NMR
(DMSO-d6): d 1.26 (s, 9H), 2.61 (m, 7H), 3.00 (m, 4H), + + -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 6.30 (br, 1H), 6.86
(d, J = 8.4 Hz, 2H), 7.48 (d, J = 9.3 Hz, 2H), 7.97 (s, 1H); 19F
NMR (282 MHz, DMSO-d6): d - 165.34; LCMS: ret. time: 6.04 min.;
purity: 90.75%; MS (m/e): 425 (MH+). 1105
N2-[4-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-[3-(N-2- 1H NMR
(DMSO-d6): d 2.04 (s, 3H), 2.97 (t, J = 4.8 Hz, 2H), 3.04 (t, J =
4.8 Hz, - - imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 2H),
3.57 (m, 4H), 3.61 (s, 4H), 6.84 (d, J = 9.0 Hz, 2H), 6.90 (d, J =
9.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H),
7.69 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 8.08 1106
N2-[3-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-[3-(N-2- LCMS: ret.
time: 7.31 min.; purity: 84.11%; MS (m/e): 490.34 (MH+). - -
imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 1107
N4-Cyclobutyl-N2-[2-(ethoxycarbonyl)indol-7-yl]-5-fluoro-2,4- 1H
NMR (CDCl3): d 1.42 (t, J = 7.2 Hz, 3H), 1.63-2.06 (m, 4H), + +
pyrimidinediamine 2.27-2.36 (m, 2H), 4.41 (q, J = 7.2 Hz, 2H), 5.17
(d, J = 6.0 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.14 (d, 1H), 7.22
(m, 2H), 7.28 (br, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 3.6
Hz, 1H), 10.68 1108
N4-Cyclobutyl-5-fluoro-N2-(3-morpholinophenyl)-2,4- 1H NMR (CDCl3):
d 1.73-2.05 (m, 4H), 2.40-2.50 (m, 2H), 3.20 (t, J = 4.8 Hz, + + -
pyrimidinediamine 4H), 3.88 (t, J = 4.8 Hz, 4H), 4.60 (m, J = 7.8
Hz, 1H), 5.14 (d, J = 6.3 Hz, 1H), 6.57 (dd, J = 2.4, 8.1 Hz, 1H),
6.97 (dd, J = 1.8, 7.5 Hz, 1H), 7.06 (br, NH, 1H), 7.19 (t, J = 8.1
Hz 1109 N4-Cyclobutyl-N2-[3-(4-ethoxycarbonylpiperazino)pheny]-5-
1H NMR (CDCl3): d 1.29 (t, J = 6.9 Hz, 3H), 1.71-2.02 (m, 4H), + -
fluoro-2,4-pyrimidinediamine 2.41-2.51 (m, 2H), 3.18 (t, J = 5.1
Hz, 4H), 3.64 (t, J = 5.1 Hz, 4H), 4.17 (q, J = 6.9 Hz, 2H), 4.59
(m, J = 8.1 Hz, 1H), 5.16 (d, J = 7.8 Hz, 1H), 6.58 (dd, J = 2.4,
8.1 Hz, 1H), 6.97 (dd, J = 1.8, 1110
N4-Cyclobutyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H
NMR (CDCl3): d 1.65-1.74 (m, 2H), 1.85-1.95 (m, 2H), + -
pyrimidinediamine 2.19-2.33 (m, 2H), 2.71 (s, 3H), 3.15 (t, 4H),
3.32 (t, J = 4.8 Hz, 4H), 4.36 (m, J = 8.1 Hz, 1H), 6.80 (d, J =
9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 7.55 (d, J = 4.2 Hz, 1H);
19F NMR (282 MHz, CDCl3): d 1111
N4-Cyclobutyl-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR
(CDCl3): d 1.31 (t, 3H), 1.50-2.04 (m, 4H), 2.41-2.50 (m, 2H), + -
fluoro-2,4-pyrimidinediamine 3.08 (t, J = 4.8 Hz, 4H), 3.64 (t, J =
5.1 Hz, 4H), 4.17 (q, 2H), 4.52 (m, J = 7.8 Hz, 1H), 5.18 (d, J =
6.6 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 7.07 (br, 1H), 7.45 (d, J =
9.0 Hz, 2H), 7.70 ( 1112
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(3-cyclopropyl-1H- LCMS: ret.
time: 9.04 min.; purity: 87.21%; MS (m/e): 437.32 (MH+). + + +
pyrazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 1113
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[4-(4- 1H NMR
(CDCl3): d 0.54-0.64 (m, 2H), 0.76-0.86 (m, 2H), 1.74 (m, + + -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1H), 2.42 (s, 3H),
2.76 (br, 4H), 3.17 (t, J = 4.8 Hz, 4H), 5.90 (br, 1H), 6.82 (d, J
= 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 3.6 Hz, 1H);
19F NMR (282 MHz, CDCl3): d - 167.69; LCM 1114
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-(3- LCMS: ret. time:
8.57 min.; purity: 88.76%; MS (m/e): 396.24 (MH+). + + -
morpholinophenyl)-2,4-pyrimidinediamine 1115
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-N2-[3-(4- 1H NMR (DMSO-d6): d
0.67 (m, 2H), 0.88 (m, 2H), 1.19 (t, J = 7.1 Hz, + +
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3H), 1.85 (m, 1H),
3.06 (m, 4H), 3.48 (m, 4H), 4.05 (q, J = 7.1 Hz, 2H),
pyrimidinediamine 6.52 (d, J = 8.1 Hz, 1H), 7.07 (m, 1H), 7.20 (m,
2H); LCMS: ret. time: 11.80 min.; purity: 79.43%; MS (m/e): 467.30
1116 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-N2-[4-(4- 1H NMR (DMSO-d6):
d 0.62 (m, 2H), 0.90 (m, 2H), 1.20 (t, J = 7.2 Hz, + +
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3H), 1.84 (m, J =
3.9 Hz, 1H), 3.08 (br, 4H), 3.44 (br, 4H), 4.05 (q, J = 6.9 Hz,
pyrimidinediamine 2H), 6.12 (br, 1H), 6.93 (d, J = 8.7 Hz, 2H),
7.40 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 4.2 Hz, 1H), 9.37 (br, 1H
1117 2-Chloro-5-fluoro-N4-(3,4-dihydro-2H,4H-5-pyrid[1,4]oxazin-6-
1H NMR (DMSO-d6): d 3.40 (t, J = 4.5 Hz, 2H), 4.10 (t, J = 4.5 Hz,
2H), - - yl)-4-pyrimidineamine 6.92 (d, J = 8.4 Hz, 1H), 7.04 (d, J
= 8.1 Hz, 1H), 8.27 (d, J = 3.6 Hz, 1H), 9.80 (br, 1H); 19F NMR
(282 MHz, DMSO-d6): d - 152.34; LCMS: ret. time: 9.69 min.; purity:
93.93%; MS (m/e): 2 1118
N4-(1-tert-Butoxycarbonylazetidin-3-yl)-5-fluoro-N2-(4- 1H NMR
(CDCl3): d 1.45 (s, 9H), 3.18 (t, J = 4.8 Hz, 4H), 3.89 (m, 4H), +
+ morpholinophenyl)-2,4-pyrimidinediamine 3.96 (m, 2H), 4.28 (m,
2H), 4.69 (m, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz,
2H), 7.66 (d, J = 3.6 Hz, 1H); 19F NMR (282 MHz, CDCl3): d -
163.92; LCMS: ret. time: 9.28 min.; p 1119
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(1-tert- 1H NMR (CDCl3): d
1.46 (s, 9H), 2.16 (s, 3H), 3.15 (p, J = 5.1 Hz, 4H), + -
butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine 3.64
(t, J = 5.1 Hz, 2H), 3.78 (t, J = 5.1 Hz, 2H), 3.91 (dd, J = 5.4,
9.9 Hz, 2H), 4.30 (dd, J = 7.8, 9.6 Hz, 2H), 4.70 (m, 1H), 6.91 (d,
J = 9.3 Hz, 2H), 7.38 (d, J = 9.3 Hz, 2H), 7.72 (d, 1120
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(1-tert- 1H NMR (CDCl3): d
1.45 (s, 9H), 2.16 (s, 3H), 3.21 (m, 4H), 3.64 (m, - -
butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine 2H),
3.78 (m, 2H), 3.99 (dd, J = 4.8, 9.0 Hz, 2H), 4.30 (dd, J = 7.8,
9.3 Hz, 2H), 4.74 (m, 1H), 6.75 (d, J = 5.1 Hz, 1H), 6.90 (d, J =
8.7 Hz, 1H), 7.19 (m, 1H), 7.26 (m, 1H), 7.69 (d, J = 4 1121
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-(4- LCMS: ret. time:
7.80 min.; purity: 96.17%; MS (m/e): 396.22 (MH+). + + -
morpholinophenyl)-2,4-pyrimidinediamine 1122
N4-(1-tert-Butoxycarbonylazetidin-3-yl)-N2-[4-(4- LCMS: ret. time:
10.44 min.; purity: 82.19%; MS (m/e): 516.26 (MH+). + -
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- pyrimidinediamine
1123 N4-(Azetidin-3-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4- LCMS:
ret. time: 2.12 min.; purity: 88.18%; MS (m/e): 345.21 (MH+). - +
pyrimidinediamine 1124
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(azetidin-3-yl)-5-fluoro-
LCMS: ret. time: 2.33 min.; purity: 92.29%; MS (m/e): 386.25 (MH+).
- - 2,4-pyrimidinediamine 1125
N4-(Azetidin-3-yl)-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]- LCMS:
ret. time: 7.44 min.; purity: 85.69%; MS (m/e): 416 (MH+). - -
5-fluoro-2,4-pyrimidinediamine 1126
N4-(Azetidin-3-yl)-5-fluoro-N2-(3-morpholinophenyl)-2,4- LCMS: ret.
time: 2.85 min.; purity: 100%; MS (m/e): 345.24 (MH+). - +
pyrimidinediamine 1127
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(azetidin-3-yl)-5-fluoro-
LCMS: ret. time: 3.10 min.; purity: 88.30%; MS (m/e): 386.28 (MH+).
+ - 2,4-pyrimidinediamine 1128
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(4- 1H
NMR (DMSO-d6): d 3.00 (t, J = 4.8 Hz, 4H), 3.38 (t, 2H), 3.72 (t, J
= 4.8 Hz, + - morpholinophenyl)-2,4-pyrimidinediamine 4H), 4.08 (t,
J = 4.2 Hz, 2H), 6.50 (br, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.93 (d,
J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 9.3 Hz,
2H), 7.99 (d, J = 3.6 Hz, 1H), 8.65 ( 1129
N4-(1-tert-Butoxycarbonylazetidin-3-yl)-N2-[3-(4- LCMS: ret. time:
11.35 min.; purity: 86.05%; MS (m/e): 516.32 (MH+). -
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- pyrimidinediamine
1130 N4-(Azetidin-3-yl)-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-
LCMS: ret. time: 8.39 min.; purity: 96.94%; MS (m/e): 416 (MH+). -
5-fluoro-2,4-pyrimidinediamine 1131
N4-(Azetidin-3-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-
LCMS: ret. time: 1.20 min.; purity: 96.44%; MS (m/e): 358.24 (MH+).
- 2,4-pyrimidinediamine 1132
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 3.38 (t, 2H), 4.08 (t, J = 4.5 Hz, 2H), 6.52 (br,
+ (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1H), 6.78 (d, J = 8.1
Hz, 1H), 7.27 (m, 3H), 7.50 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 8.01
(s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 8.38 (s, 1H), 8.82 (s, 1H), 9.35
(s, 1H); 19F NMR (282 MHz, DMSO 1133
2-Chloro-N4-cyclobutyl-5-fluoro-N4-methyl-4-pyrimidineamine 1H NMR
(CDCl3): d 1.68-1.76 (m, 2H), 2.17-2.25 (m, 4H), 3.14 (d, J = 3.0
Hz, - 3H), 4.79 (m, J = 8.4 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H); 19F
NMR (282 MHz, CDCl3): d - 150.50; LCMS: ret. time: 13.83 min.;
purity: 96.47%; MS (m/e): 216.10 (MH+). 1134
N2-[4-(4-Acetylpiperazino)phenyl]-N4-(3,4-dihydro-2H,4H-5- 1H NMR
(DMSO-d6): d 2.03 (s, 3H), 2.97 (t, J = 5.1 Hz, 2H), 3.03 (t, J =
5.1 Hz, + + pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine
2H), 3.39 (t, 2H), 3.56 (t, 4H), 4.08 (t, J = 4.2 Hz, 2H), 6.51 (s,
1H), 6.84 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.19 (d, J
= 8.1 Hz, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.99 1135
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-N2-[4-(4- 1H NMR
(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.4 Hz, 4H), +
+ ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3.39 (t, 2H), 3.49
(t, 4H), 4.04 (q, J = 7.2 Hz, 2H), 4.08 (t, J = 4.8 Hz,
pyrimidinediamine 2H), 6.51 (s, 1H), 6.84 (d, J = 9.3 Hz, 2H), 6.93
(d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 9.0 Hz
1136 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-
1H NMR (DMSO-d6): d 2.99 (t, J = 5.1 Hz, 4H), 3.39 (t, 2H), 3.69
(t, J = 4.8 Hz, + + morpholinophenyl)-2,4-pyrimidinediamine 4H),
4.08 (t, J = 4.2 Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H),
7.04 (t, J = 8.1 Hz, 1H), 7.19 (m, 3H), 8.04 (d, J = 3.6 Hz, 1H),
8.74 (s, 1H), 9.02 (s, 1H); 19F NMR (282 MH 1137
N2-[3-(4-Acetylpiperazino)phenyl]-N4-(3,4-dihydro-2H,4H-5- 1H NMR
(DMSO-d6): d 2.03 (s, 3H), 2.98 (t, J = 4.8 Hz, 2H), 3.05 (t, J =
4.8 Hz, + + pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine
2H), 3.39 (t, 2H), 3.53 (t, J = 5.4 Hz, 4H), 4.08 (t, 2H), 6.50 (m,
2H), 6.91 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.21 (m,
3H), 8.04 (d, J = 3.6 Hz, 1H), 8.75 (s, 1H), 9 1138
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-N2-[3-(4- 1H NMR
(DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 3.01 (t, J = 4.8 Hz, 4H), +
+ ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3.41 (t, 2H), 3.46
(t, J = 4.8 Hz, 4H), 4.08 (t, 2H), 6.50 (m, 2H), 6.91 (d,
pyrimidinediamine J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.19
(d, J = 8.1 Hz, 2H), 7.25 (t, 1H), 8.04 (d, J = 3.6 Hz, 1H), 8.73
1139 N4-Cyclobutyl-5-fluoro-N4-methyl-N2-(4-morpholinophenyl)- 1H
NMR (DMSO-d6): d 1.56-1.69 (m, 2H), 2.07-2.27 (m, 4H), 3.07 (t, + -
2,4-pyrimidinediamine J = 4.5 Hz, 4H), 3.12 (d, J = 3.0 Hz, 3H),
3.73 (t, J = 4.5 Hz, 4H), 4.76 (m, J = 8.4 Hz, 1H), 6.92 (d, J =
9.0 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H),
9.36 (br, 1H); 19F NMR 1140
N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-N4- 1H NMR
(DMSO-d6): d 1.59-1.69 (m, 2H), 2.03 (s, 3H), 2.10-2.27 (m, + -
methyl-2,4-pyrimidinediamine 4H), 3.03 (t, J = 4.5 Hz, 2H), 3.11
(d, J = 3.0 Hz, 5H), 3.56 (t, 4H), 4.76 (m, J = 7.5 Hz, 1H), 6.93
(d, J = 9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 7.96 (d, J = 7.2 Hz,
1H), 9.26 (br, 1H); LCMS 1141
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4- 1H
NMR (DMSO-d6): d 2.23 (s, 3H), 3.03 (t, 4H), 3.29 (m 4H), 3.38 (t,
+ + - (4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 4.08
(t, J = 4.5 Hz, 2H), 6.50 (br, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.92
(d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 9.0 Hz,
2H), 7.98 (d, J = 3.6 Hz, 1H), 8.64 (br, 1H), 1142
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 2.20 (s, 3H), 2.41 (t, 4H), 3.03 (t, 4H), 3.38 (t,
+ + - (4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 4.08
(t, J = 4.8 Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 7.8 Hz, 1H), 7.02
(t, J = 7.8 Hz, 1H), 7.20 (m, 3H), 8.03 (d, J = 3.6 Hz, 1H), 8.72
(s, 1H), 8.99 (s, 1H); 19F NMR (282 MHz, DMSO- 1143
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 3.53 (t, J = 4.2 Hz, 2H), 4.16 (t, J = 4.2 Hz,
2H), + + - (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.84 (d, J =
8.7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.35 (s, 1H), 7.40 (t, J =
7.8 Hz, 1H), 7.56 (dt, J = 1.2, 8.1 Hz, 1H), 7.89 (d, J = 8.4 Hz,
1H), 8.18 (s, 1H), 8.32 (d, J = 3.3 Hz, 1H), 8 1144
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[3-(oxazol-2- 1H NMR
(DMSO-d6): d 0.61-0.66 (m, 2H), 0.86 (m, 2H), 1.81 (m, 1H), + + - +
yl)phenyl]-2,4-pyrimidinediamine 6.41 (br, 1H), 7.35 (m, 2H), 7.52
(d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 8.04 (s, 1H), 8.19 (m, 2H), 9.34
(s, 1H), 9.60 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d -163.42; LCMS:
ret. time: 9.50 mi 1145
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 3.49 (t, 2H), 3.61 (s, 3H), 3.69 (s, 6H), 4.14 (t, + +
- + (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine J = 4.5 Hz, 2H),
6.94 (d, J = 7.8 Hz, 1H), 7.07 (s, 2H), 7.14 (d, 1H), 8.20 (d, J =
3.6 Hz, 1H), 9.75 (s, 1H); LCMS: ret. time: 8.80 min.; purity:
100%; MS (m/e): 429.45 (MH+). 1146
N2-(3-Chloro-4-methoxyphenyl)-N4-(3,4-dihydro-2H,4H-5- 1H NMR
(DMSO-d6): d 3.39 (s, 2H), 3.78 (s, 3H), 4.08 (t, J = 3.9 Hz, + -
pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 2H), 6.54
(br, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.13
(d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.4, 9.0 Hz, 1H), 7.84 (d, J =
2.4 Hz, 1H), 8.04 (d, J = 3.3 Hz, 1H), 8.80 (s, 1H 1147
N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[4-(4- 1H NMR (DMSO-d6): d
1.56-1.68 (m, 2H), 2.10-2.26 (m, 4H), 2.21 (s, + + - +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 3H), 2.44 (t, 4H),
3.02 (t, J = 4.8 Hz, 4H), 3.05 (d, J = 2.7 Hz, 3H), 4.74 (m, J =
7.8 Hz, 1H), 6.82 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H),
7.88 (d, J = 6.6 Hz, 1H), 8.79 (br, 1H); 19F 1148
N4-Cyclobutyl-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR
(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.56-1.69 (m, 2H), + + -
fluoro-N4-methyl-2,4-pyrimidinediamine 2.07-2.27 (m, 4H), 3.06 (t,
J = 4.8 Hz, 4H), 3.11 (d, J = 3.0 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J
= 7.2 Hz, 2H), 4.76 (m, J = 8.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H),
7.43 (d, J = 8.7 Hz, 2H), 7.97 (d, 1149
N4-Cyclobutyl-5-fluoro-N4-methyl-N2-(3-morpholinophenyl)- 1H NMR
(DMSO-d6): d 1.57-1.70 (m, 2H), 2.13-2.24 (m, 4H), 3.07 (t, + -
2,4-pyrimidinediamine J = 4.8 Hz, 4H), 3.11 (d, J = 3.3 Hz, 3H),
3.73 (t, J = 4.5 Hz, 4H), 4.78 (m, J = 8.7 Hz, 1H), 6.57 (m, 1H),
7.08 (m, 2H), 7.24 (m, 1H), 7.98 (d, J = 6.9 Hz, 1H), 9.19 (br,
1H); LCMS: ret. time 1150
N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-N4- 1H NMR
(CDCl3): d 1.66-1.78 (m, 2H), 2.15 (s, 3H), 2.22 (m, 4H), + -
methyl-2,4-pyrimidinediamine 3.17 (d, J = 2.7 Hz, 3H), 3.22 (m,
4H), 3.62 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 4.85 (m, J
= 8.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.1 Hz, 1H), 7.04 (d, J = 8.4 Hz,
1H), 7.19 (t, J = 8.1 Hz, 1151
N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[3-(4- 1H NMR (CDCl3): d
1.63-1.77 (m, 2H), 2.21 (m, 4H), 2.45 (s, 3H), + + -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 2.72 (t, J = 4.8 Hz,
4H), 3.13 (d, J = 3.9 Hz, 3H), 3.32 (t, J = 4.8 Hz, 4H), 4.84 (m, J
= 8.7 Hz, 1H), 6.56 (dd, J = 2.4, 8.1 Hz, 1H), 6.82 (br, 1H), 7.00
(d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1152
N4-Cyclobutyl-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR
(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.60-1.70 (m, 2H), + -
fluoro-N4-methyl-2,4-pyrimidinediamine 2.13-2.28 (m, 4H), 3.08 (t,
J = 5.1 Hz, 4H), 3.12 (d, J = 3.3 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J
= 7.2 Hz, 2H), 4.79 (m, J = 9.0 Hz, 1H), 6.59 (d, J = 6.9 Hz, 1H),
7.09 (m, 2H), 7.27 (s, 1H), 7.99 1153
N2-(2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4- 1H NMR
(DMSO-d6): d 1.69-1.78 (m, 2H), 2.28 (m, 4H), 3.36 (d, J = 3.3 Hz,
- - cyclobutyl-5-fluoro-N4-methyl-2,4-pyrimidinediamine 3H), 3.90
(s, 3H), 4.94 (m, 1H), 5.30 (s, 2H), 7.12 (s, 1H), 7.35-7.48 (m,
6H), 9.04 (d, J = 9.0 Hz, 1H); LCMS: ret. time: 11.25 min.; purity:
98.01%; MS (m/e): 435.22 (M-16). 1154
N2-(4-Benzamidophenyl)-N4-cyclobutyl-5-fluoro-2,4- 1H NMR
(DMSO-d6): d 1.62-1.74 (m, 2H), 2.02-2.15 (m, 2H), + -
pyrimidinediamine 2.23-2.31 (m, 2H), 4.50 (m, J = 8.1 Hz, 1H),
7.46-7.68 (m, 8H), 7.84 (d, J = 3.6 Hz, 1H), 7.92 (td, J = 1.2, 6.6
Hz, 2H), 8.99 (s, 1H), 10.07 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d
-167.01; LCMS: ret 1155
N4-Cyclopentyl-5-fluoro-N2-(4-morpholinophenyl)-2,4- 1H NMR
(DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.94 (m, 2H), + -
pyrimidinediamine 2.98 (t, J = 4.8 Hz, 4H), 3.70 (t, J = 4.8 Hz,
4H), 4.30 (q, J = 6.9 Hz, 1H),
6.80 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 7.55 (d, J =
9.3 Hz, 2H), 7.76 (d, J = 3.6 Hz, 1H), 8.74 (br, 1H); 19F 1156
N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclopentyl-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), + -
pyrimidinediamine 2.02 (s, 3H), 2.94 (t, J = 4.8 Hz, 2H), 3.01 (t,
J = 5.1 Hz, 2H), 3.54 (t, 4H), 4.30 (q, J = 6.9 Hz, 1H), 6.83 (d, J
= 8.7 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H),
7.76 (d, J = 3.9 1157
N4-Cyclopentyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]- 1H NMR
(DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), + -
2,4-pyrimidinediamine 2.21 (s, 3H), 2.44 (t, 4H), 3.01 (t, 4H),
4.30 (q, J = 6.3 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 7.22 (d, J =
6.3 Hz, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.0 Hz, 1H),
8.72 (br, 1H); 19F NMR (28 1158
N4-Cyclopentyl-5-fluoro-N2-(3-morpholinophenyl)-2,4- 1H NMR
(DMSO-d6): d 1.52 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), + -
pyrimidinediamine 3.03 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.8 Hz,
4H), 4.36 (m, 1H), 6.45 (d, J = 9.6 Hz, 1H), 7.02 (t, J = 7.8 Hz,
1H), 7.13 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.42 (s,
1H), 7.80 (d, J = 3.6 1159
N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclopentyl-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 1.53 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), + -
pyrimidinediamine 2.03 (s, 3H), 3.02 (t, J = 5.1 Hz, 2H), 3.08 (t,
J = 4.8 Hz, 2H), 3.55 (t, 4H), 4.36 (q, J = 6.6 Hz, 1H), 6.47 (d, J
= 7.8 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H),
7.30 (d, J = 7.2 1160
N4-Cyclopentyl-5-fluoro-N2-[3-(4-methylpiperazino)phenyl]- LCMS:
ret. time: 6.49 min.; purity: 79.17%; MS (m/e): 371.23 (MH+). + -
2,4-pyrimidinediamine 1161
N4-Cyclopentyl-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5- LCMS:
ret. time: 10.76 min.; purity: 77.07%; MS (m/e): 429.50 (MH+). + -
fluoro-2,4-pyrimidinediamine 1162
N4-Cyclohexyl-5-fluoro-N2-(4-morpholinophenyl)-2,4- 1H NMR
(DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.64 (d, 1H), + -
pyrimidinediamine 1.75 (m, 2H), 1.90 (m, 2H), 2.98 (t, J = 4.8 Hz,
4H), 3.71 (t, J = 4.8 Hz, 4H), 3.86 (m, 1H), 6.80 (d, J = 9.3 Hz,
2H), 7.14 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.76 (d, J
= 3.9 Hz, 1H), 8 1163
N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclohexyl-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), + -
pyrimidinediamine 1.90 (m, 2H), 2.02 (s, 3H), 2.94 (t, J = 4.8 Hz,
2H), 3.01 (t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.86 (m, 1H), 6.82 (d,
J = 9.0 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.7 Hz,
2H), 7.76 (d, J = 1164
N4-Cyclohexyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H
NMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), + - +
pyrimidinediamine 1.90 (m, 2H), 2.21 (s, 3H), 2.46 (t, J = 4.8 Hz,
4H), 3.01 (t, J = 4.8 Hz, 4H), 3.85 (m, 1H), 6.79 (d, J = 9.0 Hz,
2H), 7.12 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.76 (d, J
= 3.9 Hz, 1H), 8 1165
N4-Cyclohexyl-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR
(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.31 (m, 5H), 1.64 (d, + +
fluoro-2,4-pyrimidinediamine 1H), 1.76 (m, 2H), 1.90 (m, 2H), 2.97
(t, J = 4.8 Hz, 4H), 3.48 (t, 4H), 3.86 (m, 1H), 4.04 (q, J = 7.2
Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 6.9 Hz, 1H), 7.55
(d, J = 9.3 Hz, 2H), 7 1166
N4-Cyclohexyl-5-fluoro-N2-(3-morpholinophenyl)-2,4- 1H NMR
(DMSO-d6): d 1.27 (m, 5H), 1.63 (d, 1H), 1.76 (m, 2H), + -
pyrimidinediamine 1.87 (m, 2H), 3.04 (t, J = 4.8 Hz, 4H), 3.72 (t,
J = 4.8 Hz, 4H), 3.90 (m, 1H), 6.46 (dd, J = 2.1, 7.8 Hz, 1H), 7.03
(t, J = 8.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.24 (m, 2H), 7.80
(d, J = 3.9 Hz, 1167
N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclohexyl-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 1.31 (m, 5H), 1.61 (m, 1H), 1.76 (m, 2H), + -
pyrimidinediamine 1.87 (m, 2H), 2.03 (s, 3H), 3.04 (t, 2H), 3.09
(t, 2H), 3.56 (t, 4H), 3.90 (m, 1H), 6.48 (d, J = 9.0 Hz, 1H), 7.04
(t, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.25 (m, 2H), 7.80
(d, J = 3.6 Hz, 1168
N4-Cyclohexyl-5-fluoro-N2-[3-(4-methylpiperazino)phenyl]-2,4- 1H
NMR (DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.63 (d, 1H), + -
pyrimidinediamine 1.76 (m, 2H), 1.86 (m, 2H), 2.26 (s, 3H), 3.09
(t, 4H), 3.32 (t, 4H), 3.88 (m, 1H), 6.45 (d, J = 6.9 Hz, 1H), 7.01
(t, J = 8.1 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.24 (m, 2H), 7.80
(d, J = 3.9 Hz, 1169
N4-Cyclohexyl-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR
(DMSO-d6): d 1.19 (t, J = 6.9 Hz, 3H), 1.31 (m, 5H), 1.62 (d, + -
fluoro-2,4-pyrimidinediamine 1H), 1.76 (m, 2H), 1.87 (m, 2H), 3.05
(t, J = 4.8 Hz, 4H), 3.49 (t, 4H), 3.90 (m, 1H), 4.05 (q, J = 7.2
Hz, 2H), 6.48 (d, J = 4.5 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.16
(d, J = 6.6 Hz, 1H), 7 1170
N2-(4-Benzamidophenyl)-N4-cyclopentyl-5-fluoro-2,4- 1H NMR
(DMSO-d6): d 1.57 (m, 4H), 1.72 (m, 2H), 1.96 (m, 2H), + -
pyrimidinediamine 4.32 (q, J = 7.5 Hz, 1H), 7.29 (d, J = 6.3 Hz,
1H), 7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 9.6
Hz, 2H), 8.97 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d
-166.85; LCMS: 1171
N2-(2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4- 1H NMR
(DMSO-d6): d 1.60 (m, 4H), 1.74 (m, 2H), 1.96 (m, 2H), + -
cyclopentyl-5-fluoro-2,4-pyrimidinediamine 3.85 (s, 3H), 4.43 (q, J
= 6.9 Hz, 1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31-7.50 (m, 6H), 8.53
(d, J = 7.2 Hz, 1H), 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282 MHz,
DMSO-d6): d -155.92; LCMS: ret. time: 1172
N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclopentyl-5- 1H NMR
(DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), + -
fluoro-2,4-pyrimidinediamine 3.09 (s, 3H), 3.31 (s, 3H), 4.32 (q, J
= 7.2 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H),
7.77 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.14 (s, 1H);
19F NMR (282 MHz, DMSO-d6) 1173
N4-Cyclopentyl-5-fluoro-N2-[3-(N-2-imidazolin-2- 1H NMR (DMSO-d6):
d 1.55 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), - -
yl)aminophenyl]-2,4-pyrimidinediamine 3.62 (s, 4H), 4.31 (q, J =
6.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H),
7.40 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.84 (s, 2H),
8.22 (s, 1H), 9.23 (s, 1H), 10.54 (br, 1 1174
N2-(4-Benzamidophenyl)-N4-cyclohexyl-5-fluoro-2,4- 1H NMR
(DMSO-d6): d 1.33 (m, 5H), 1.65 (d, 1H), 1.78 (m, 2H), - + - +
pyrimidinediamine 1.92 (m, 2H), 3.88 (m, 1H), 7.22 (d, J = 8.1 Hz,
1H), 7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 6.6
Hz, 2H), 8.99 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d
-166.98; LC 1175 N2-(2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4-
1H NMR (DMSO-d6): d 1.36 (m, 5H), 1.65 (d, 1H), 1.79 (m, 2H), + -
cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1.88 (m, 2H), 3.85 (s,
3H), 4.05 (m, 1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31-7.50 (m, 6H),
8.44 (d, J = 7.5 Hz, 1H), 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282
MHz, DMSO-d6): d -156.00; LCMS: ret. tim 1176
N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclohexyl-5- 1H NMR
(DMSO-d6): d 1.32 (m, 5H), 1.64 (d, 1H), 1.74 (m, 2H), + -
fluoro-2,4-pyrimidinediamine 1.90 (m, 2H), 3.09 (s, 3H), 3.32 (s,
3H), 3.88 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.5 Hz,
1H), 7.75 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.15 (s,
1H); 19F NMR (282 MHz, DMSO- 1177
N4-Cyclohexyl-5-fluoro-N2-[3-(N-2-imidazolin-2- LCMS: ret. time:
6.42 min.; purity: 86.49%; MS (m/e): 370.47 (MH+). - -
yl)aminophenyl]-2,4-pyrimidinediamine 1178
N2,N4-Bis[3-(oxazol-2-yl)phenyl]-5-fluoro-2,4- 1H NMR (DMSO-d6): d
7.22 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 9.3 Hz, - -
pyrimidinediamine 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.46 (d, J = 7.5
Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.08
(d, J = 7.5 Hz, 1H), 8.11 (d, 2H), 8.18 (d, J = 3.6 Hz, 1H), 8.24
(t, J = 1.8 Hz, 1 1179
N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[3-(oxazol-2-yl)phenyl]- 1H NMR
(DMSO-d6): d 1.53-1.71 (m, 2H), 2.11-2.32 (m, 4H), 3.16 (d, + -
2,4-pyrimidinediamine J = 3.6 Hz, 3H), 4.89 (m, J = 8.4 Hz, 1H),
7.36 (d, J = 0.9 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.57 (m, 2H),
8.06 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 0.9 Hz, 1H), 8.57 (t, J =
1.8 Hz, 1H), 9.68 (s, 1180
(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-(4- 1H NMR (DMSO-d6):
d 1.83 (m, 1H), 2.16 (m, 1H), 2.40 (dd, J = 5.1, + -
morpholinophenyl)-2,4-pyrimidinediamine 9.3 Hz, 1H), 2.58 (m, 2H),
2.89 (dd, J = 7.2, 9.3 Hz, 1H), 2.99 (t, J = 4.8 Hz, 4H), 3.58 (d,
J = 1.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 4.41 (m, 1H), 6.78 (d, J
= 9.0 Hz, 2H), 7.22 (m, 1H), 7.2 1181
(S)-N2-[4-(4-Acetylpiperazino)phenyl]-N4-(1-benzylpyrrolidin- 1H
NMR (DMSO-d6): d 1.81-1.87 (m, 1H), 2.03 (s, 3H), 2.14-2.23 (m, + -
3-yl)-5-fluoro-2,4-pyrimidinediamine 1H), 2.40 (dd, J = 5.7, 9.6
Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.3 Hz, 1H), 2.95 (t, J =
5.1 Hz, 2H), 3.02 (t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.58 (s, 2H),
4.41 (m, 1H), 6.81 (d, J = 9.0 1182
(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[4-(4- LCMS: ret.
time: 1.17 min.; purity: 95.41%; MS (m/e): 462.15 (MH+). - -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1183
(S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[4-(4- 1H NMR (DMSO-d6): d 1.19
(t, J = 7.2 Hz, 3H), 1.83 (m, 1H), 2.17 (m, + -
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 1H), 2.40 (dd, J =
5.1, 9.0 Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.0 Hz,
pyrimidinediamine 1H), 2.98 (t, J = 5.1 Hz, 4H), 3.49 (t, J = 5.1
Hz, 4H), 3.58 (d, J = 1.8 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 4.44 (
1184 (S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-(3- LCMS: ret.
time: 6.81 min.; purity: 100%; MS (m/e): 449 (MH+). + -
morpholinophenyl)-2,4-pyrimidinediamine 1185
(S)-N2-[3-(4-Acetylpiperazino)phenyl]-N4-(benzylpyrrolidin-3- 1H
NMR (DMSO-d6): d 1.82-1.88 (m, 1H), 2.02 (s, 3H), 2.16-2.26 (m, + -
yl)-5-fluoro-2,4-pyrimidinediamine 1H), 2.37 (dd, J = 5.7, 9.0 Hz,
1H), 2.56 (m, 2H), 2.92 (dd, J = 6.9, 9.0 Hz, 1H), 3.03 (t, J = 5.1
Hz, 2H), 3.10 (t, J = 5.1 Hz, 2H), 3.56 (m, 4H), 3.58 (s, 2H), 4.53
(m, 1H), 6.47 (d, J = 8.4 1186
(S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[3-(4- LCMS: ret.
time: 2.79 min.; purity: 97.87%; MS (m/e): 462 (MH+). + -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1187
(S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[3-(4- 1H NMR (DMSO-d6): d 1.18
(t, J = 7.2 Hz, 3H), 1.82 (m, J = 6.5 Hz, + -
ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 1H), 2.19 (m, 1H),
2.37 (dd, J = 5.7, 9.0 Hz, 1H), 2.56 (m, 2H), pyrimidinediamine
2.91 (dd, J = 7.2, 9.0 Hz, 1H), 3.06 (t, J = 5.1 Hz, 4H), 3.51 (t,
J = 5.1 Hz, 4H), 3.58 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 4.55 (
1188 N4-Cyclobutyl-5-fluoro-N2-[3-chloro-4-(4- 1H NMR (DMSO-d6): d
1.61-1.73 (m, 2H), 2.01-2.14 (m, 2H), +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 2.25-2.33 (m, 2H),
2.29 (s, 3H), 2.55 (m, 4H), 2.91 (t, 4H), 4.47 (m, J = 8.1 Hz, 1H),
7.03 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz, 1H), 7.69 (d,
J = 7.2 Hz, 1H), 7.84 (d, J = 3.6 Hz, 1H), 8.07 1189
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 2.28 (s, 6H), 2.86 (d, J = 4.8 Hz, 3H), 2.92 (m, +
+ (4-methylpiperazino)phenyl]-2,4-pyrimidinediamine Bis p- 2H),
3.13 (q, J = 10.8 Hz, 2H), 3.49 (m, 4H), 3.74 (d, J = 13.2 Hz, 2H),
Toluenesulfonic Acid Salt 4.15 (t, J = 4.2 Hz, 2H), 6.66 (d, J =
7.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 4H),
7.17 (m, 4H), 7. 1190
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H
NMR (DMSO-d6): d 2.81 (d, J = 4.5 Hz, 3H), 3.08 (m, 4H), 3.48 (d, +
+ (4-methylpiperazino)phenyl]-2,4-pyrimidinediamine Bis J = 11.7
Hz, 2H), 3.55 (t, 2H), 3.72 (d, J = 11.7 Hz, 2H), 4.18 (t, J = 4.2
Hz, Hydrogen Chloride Salt 2H), 6.65 (d, J = 9.0 Hz, 1H), 6.74 (d,
J = 8.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz,
1H), 7.41 1191
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclohexyl-5- 1H NMR
(DMSO-d6): d 1.14 (m, 1H), 1.33 (m, 4H), 1.63 (d, 1H), + +
fluoro-2,4-pyrimidinediamine 1.74 (m, 2H), 1.90 (m, 2H), 2.21 (s,
3H), 2.45 (m, 4H), 2.88 (t, 4H), 3.89 (m, 1H), 7.01 (d, J = 8.7 Hz,
1H), 7.24 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.81
(d, J = 3.9 Hz, 1H), 8.0 1192
N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4- 1H
NMR (DMSO-d6): d 1.65-1.76 (m, 2H), 2.04 (s, 3H), 2.08-2.26 (m, +
pyrimidinediamine Bis Hydrogen Chloride Salt 4H), 3.10 (t, 2H),
3.17 (t, 2H), 3.58 (t, 4H), 4.43 (m, J = 7.8 Hz, 1H), 7.02 (d, J =
8.1 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 5.1 Hz, 1H),
9.10 (br, 1H), 10.02 (br, 1H); 19F NMR (2 1193
N4-Cyclohexyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H
NMR (DMSO-d6): d 1.24 (m, 4H), 1.37 (q, 1H), 1.62 (d, 1H), +
pyrimidinediamine Bis p-Toluenesulfonic Acid Salt 1.76 (d, 2H),
1.85 (d, 2H), 2.28 (s, 6H), 2.86 (d, J = 3.9 Hz, 3H), 2.92 (d, 2H),
3.15 (m, 2H), 3.52 (d, 2H), 3.80 (d, 3H), 7.00 (d, J = 9.3 Hz, 2H),
7.09 (d, J = 7.8 Hz, 4H), 7.36 (d, J = 9.3 Hz, 1194
N4-Cyclohexyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H
NMR (DMSO-d6): d 1.33 (m, 5H), 1.61 (d, 1H), 1.77 (d, 2H), +
pyrimidinediamine Bis Hydrogen Chloride Salt 1.87 (d, 2H), 2.79 (d,
J = 4.8 Hz, 3H), 3.09 (m, 4H), 3.47 (d, 2H), 3.78 (d, 2H), 3.83 (m,
1H), 7.01 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 8.10 (d, J
= 5.4 Hz, 1H), 9.08 (d, J = 8.1 Hz, 1H) 1195
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclopentyl-5- 1H NMR
(DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.98 (m, 2H), +
fluoro-2,4-pyrimidinediamine 2.31 (s, 3H), 2.57 (m, 4H), 2.91 (t,
4H), 4.30 (q, J = 6.9 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 7.36 (d, J
= 6.9 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz, 1H), 7.82 (d, J = 3.9 Hz,
1H), 8.07 (d, J = 2.4 Hz, 1196
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-(3-cyclopropyl- 1H
NMR (DMSO-d6): d 0.69 (m, 2H), 0.91 (m, 2H), 1.87 (m, 1H), +
1H-pyrazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 2.22 (s, 3H), 2.46
(m, 4H), 2.90 (t, 4H), 6.31 (br, 1H), 7.04 (d, J = 9.0 Hz, 1H),
7.51 (br, 1H), 7.79 (s, 1H), 8.02 (s, 1H), 9.14 (br, 1H), 9.52 (br,
1H), 12.07 (br, 1H); 19F NMR (282 MHz, DMSO 1197
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-(3,4-dihydro- 1H NMR
(DMSO-d6): d 2.21 (s, 3H), 2.45 (t, 4H), 2.88 (t, 4H), 3.39 (m, + +
2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 2H),
4.09 (t, J = 4.2 Hz, 2H), 6.53 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H),
7.01 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.46 (dd, J =
2.7, 8.7 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 8.04 (d, 1198
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclobutyl-5- 1H NMR
(DMSO-d6): d 1.67-1.76 (m, 2H), 2.11-2.18 (m, 2H), +
fluoro-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt 2.25-2.31
(m, 2H), 2.82 (d, J = 4.5 Hz, 3H), 3.02-3.20 (m, 4H), 3.35 (m, 2H),
3.48 (m, 2H), 4.44 (m, J = 7.5 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H),
7.40 (dd, J = 2.4, 8.7 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 1199
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclohexyl-5- 1H NMR
(DMSO-d6): d 1.17 (m, 1H), 1.36 (m, 4H), 1.63 (d, 1H), + +
fluoro-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt 1.78 (m,
2H), 1.86 (m, 2H), 2.83 (d, J = 4.8 Hz, 3H), 3.00-3.20 (m, 4H),
3.34 (m, 2H), 3.48 (m, 2H), 3.87 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H),
7.36 (dd, J = 2.4, 9.0 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H) 1200
N4-Cyclopentyl-5-fluoro-N2-[3-methyl-4-(4- LCMS: ret. time: 9.70
min.; purity: 89.34%; MS (m/e): 385 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1201
N4-Cyclohexyl-5-fluoro-N2-[3-methyl-4-(4- LCMS: ret. time: 11.34
min.; purity: 94.34%; MS (m/e): 399.24 (MH+). + +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1202
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[3-methyl-4-(4-
LCMS: ret. time: 10.35 min.; purity: 96.72%; MS (m/e): 423 (MH+). +
+ methylpiperazino)phenyl]-2,4-pyrimidinediamine 1203
N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3-
LCMS: ret. time: 10.77 min.; purity: 93.79%; MS (m/e): 451 (MH+). +
+ methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 1204
5-Fluoro-N4-isopropyl-N2-[4-(4-methylpiperazino)phenyl]-2,4- LCMS:
ret. time: 3.64 min.; purity: 95.29%; MS (m/e): 345 (MH+). +
pyrimidinediamine 1205
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-N4- LCMS: ret.
time: 5.14 min.; purity: 92.47%; MS (m/e): 379 (MH+). +
isopropyl-2,4-pyrimidinediamine 1206
5-Fluoro-N4-isopropyl-N2-[3-methyl-4-(4- LCMS: ret. time: 1.99
min.; purity: 93.17%; MS (m/e): 359 (MH+). + -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1207
N4-Cyclobutyl-5-fluoro-N2-[4-(4-methylpiperazino)-3- LCMS: ret.
time: 15.09 min.; purity: 94.19%; MS (m/e): 425 (MH+). +
trifluoromethylphenyl]-2,4-pyrimidinediamine 1208
N4-Cyclopentyl-5-fluoro-N2-[4-(4-methylpiperazino)-3- LCMS: ret.
time: 15.32 min.; purity: 92.83%; MS (m/e): 439.30 (MH+). +
trifluoromethylphenyl]-2,4-pyrimidinediamine 1209
N4-Cyclohexyl-5-fluoro-N2-[4-(4-methylpiperazino)-3- LCMS: ret.
time: 15.74 min.; purity: 95.26%; MS (m/e): 453 (MH+). +
trifluoromethylphenyl]-2,4-pyrimidinediamine 1210
5-Fluoro-N4-isopropyl-N2-[4-(4-methylpiperazino)-3- LCMS: ret.
time: 7.29 min.; purity: 88.24%; MS (m/e): 413.05 (MH+). +
trifluoromethylphenyl]-2,4-pyrimidinediamine 1211
N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[(4- LCMS: ret.
time: 8.27 min.; purity: 94.19%; MS (m/e): 477 (MH+). +
methylpiperazino)-3-trifluoromethylphenyl]-2,4- pyrimidinediamine
1212 2-chloro-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-4-
LCMS: ret. time: 9.57 min.; purity: 90.78%; MS (m/e): 301.19 (MH+).
- pyrimidineamine 1213
2-chloro-N4-(1-ethoxycarbonylpiperidin-4-yl)-5-fluoro-4- LCMS: ret.
time: 10.29 min.; purity: 94%; MS (m/e): 303.04 (MH+). -
pyrimidineamine 1214
5-Fluoro-N4-isopropyl-N2-[3-(4-methylpiperazino)phenyl]-2,4- LCMS:
ret. time: 4.63 min.; purity: 97.16%; MS (m/e): 345.41 (MH+). -
pyrimidinediamine 1215
N4-tert-Butyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- LCMS:
ret. time: 2.80 min.; purity: 97.03%; MS (m/e): 359 (MH+). -
pyrimidinediamine 1216
N4-tert-Butyl-5-fluoro-N2-[3-(4-methylpiperazino)phenyl]-2,4- LCMS:
ret. time: 7.81 min.; purity: 94.56%; MS (m/e): 359.23 (MH+). -
pyrimidinediamine 1217
N4-tert-Butyl-N2-[3-chloro-4-(4-methylpiperazino)phenyl]-5- LCMS:
ret. time: 10.53 min.; purity: 93.25%; MS (m/e): 393 (MH+). +
fluoro-2,4-pyrimidinediamine 1218
N4-tert-Butyl-5-fluoro-N2-[3-methyl-4-(4- LCMS: ret. time: 4.35
min.; purity: 87.23%; MS (m/e): 373.26 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1219
5-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(1,2,2,6,6- LCMS:
ret. time: 1.30 min.; purity: 95.14%; MS (m/e): 456.63 (MH+). -
pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1220
N4-Cyclobutyl-5-fluoro-N2-[3-methyl-4-(4- LCMS: ret. time: 9.16
min.; purity: 93.00%; MS (m/e): 371.26 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1221
5-Fluoro-N2-[3-(4-methylpiperazino)phenyl]-N4-(1,2,2,6,6- LCMS:
ret. time: 1.40, 1.71 min.; purity: 95%; MS (m/e): 456.30 (MH+). -
pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1222
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-N4- LCMS: ret.
time: 1.44, 1.74 min.; purity: 97%; MS (m/e): 490.11 (MH+). -
(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1223
5-Fluoro-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-N4- LCMS: ret.
time: 1.46, 2.03 min.; purity: 100%; MS (m/e): +
(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 470.29
(MH+). 1224
5-Fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-N2-[3- LCMS: ret.
time: 1.46, 2.70 min.; purity: 97%; MS (m/e): 524.23 (MH+). -
trifluoromethyl-4-(4-methylpiperazino)phenyl]-2,4-
pyrimidinediamine 1225
N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4-(4- LCMS: ret.
time: 6.13 min.; purity: 95.45%; MS (m/e): 458 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1226
N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3-(4- LCMS: ret.
time: 9.94 min.; purity: 97%; MS (m/e): 458.27 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1227
N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-(1- LCMS: ret. time:
14.71 min.; purity: 98.79%; MS (m/e): 492 (MH+). +
ethoxycarbonylpiperidin-4-yl)-5-fluoro-2,4-pyrimidinediamine 1228
N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3-methyl-4- LCMS:
ret. time: 9.26 min.; purity: 97.16%; MS (m/e): 472 (MH+). +
(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 1229
N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4-(4- LCMS: ret.
time: 15.48 min.; purity: 97.96%; MS (m/e): 526 (MH+). +
methylpiperazino)-3-trifluoromethylphenyl]-2,4- pyrimidinediamine
1230
N4-Cyclobutyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4-
LCMS: ret. time: 5.52 min.; purity: 94.98%; MS (m/e): 372 (MH+). +
pyrimidinediamine 1231
N4-Cyclopentyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro- LCMS:
ret. time: 6.27 min.; purity: 90.61%; MS (m/e): 386.36 (MH+). +
2,4-pyrimidinediamine 1232
N4-Cyclohexyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro- LCMS:
ret. time: 6.83 min.; purity: 97.62%; MS (m/e): 400 (MH+). +
2,4-pyrimidinediamine 1233
N4-tert-Butyl-5-fluoro-N2-[4-(4-methylpiperazino)-3- LCMS: ret.
time: 15.37 min.; purity: 96.00%; MS (m/e): 427 (MH+). +
trifluoromethylphenyl]-2,4-pyrimidinediamine 1234
N2-[2-(4-Ethylpiperazino)pyrid-5-yl]-5-fluoro-N4-isopropyl-2,4-
LCMS: ret. time: 1.44, 1.80 min.; purity: 96%; MS (m/e): 360.28
(MH+). + pyrimidinediamine 1235
N4-Cyclobutyl-5-fluoro-N2-[3-hydroxymethyl-4-(4- LCMS: ret. time:
1.82 min.; purity: 90%; MS (m/e): 387.14 (MH+). -
methylpiperazino)phenyl]-2,4-pyrimidinediamine 1236
N4-tert-Butyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4-
LCMS: ret. time: 4.27 min.; purity: 100%; MS (m/e): 374.18 (MH+). -
pyrimidinediamine 1237
N2-[2-(4-Ethylpiperazino)pyrid-5-yl]-5-fluoro-N4-(1,2,2,6,6- LCMS:
ret. time: 1.27 min.; purity: 99.58%; MS (m/e): 471.73 (MH+). -
pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1238
N4-(1-Ethoxycarbonylpiperidin-4-yl)-N2-[2-(4- LCMS: ret. time: 7.03
min.; purity: 94.74%; MS (m/e): 473 (MH+). -
ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4-pyrimidinediamine 1239
N4-Cyclobutyl-5-fluoro-N2-[2-(4-methylpiperazino)-3- LCMS: ret.
time: 9.65 min.; purity: 97.08%; MS (m/e): 372.11 (MH+). -
methylpyrid-5-yl]-2,4-pyrimidinediamine 1240
N4-Cyclopentyl-5-fluoro-N2-[2-(4-methylpiperazino)-3- LCMS: ret.
time: 10.50 min.; purity: 91.36%; MS (m/e): 385.85 (MH+). +
methylpyrid-5-yl]-2,4-pyrimidinediamine 1241
N4-Cyclohexyl-5-fluoro-N2-[2-(4-methylpiperazino)-3- LCMS: ret.
time: 9.22 min.; purity: 93.96%; MS (m/e): 400.11 (MH+). +
methylpyrid-5-yl]-2,4-pyrimidinediamine 1242
5-Fluoro-N4-isopropyl-N2-[2-(4-methylpiperazino)-3- LCMS: ret.
time: 4.21 min.; purity: 91.67%; MS (m/e): 360.15 (MH+). +
methylpyrid-5-yl]-2,4-pyrimidinediamine 1243
N4-Cyclobutyl-5-fluoro-N2-[3-hydroxymethyl-4-(4- LCMS: ret. time:
1.43, 1.85 min.; purity: 94%; MS (m/e): 387.05 (MH+). +
methylpiperazino)phenyl]-2,4-pyrimidinediamine Bishydrogen chloride
salt 1244
5-Fluoro-N2-[2-(4-methylpiperazino)-3-methylpyrid-5-yl]-N4- LCMS:
ret. time: 7.05 min.; purity: 95.56%; MS (m/e): 471.26 (MH+). -
(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1245
N4-Cyclobutyl-5-fluoro-N2-[2-(4-methylpiperazino)-4- LCMS: ret.
time: 9.37 min.; purity: 92.45%; MS (m/e): 371.99 (MH+). -
methylpyrid-5-yl]-2,4-pyrimidinediamine 1246
N4-Cyclopentyl-5-fluoro-N2-[2-(4-methylpiperazino)-4- LCMS: ret.
time: 10.12 min.; purity: 95.69%; MS (m/e): 386.09 (MH+). -
methylpyrid-5-yl]-2,4-pyrimidinediamine 1247
N4-Cyclohexyl-5-fluoro-N2-[2-(4-methylpiperazino)-4- LCMS: ret.
time: 10.35 min.; purity: 92.30%; MS (m/e): 400.13 (MH+). +
methylpyrid-5-yl]-2,4-pyrimidinediamine 1248
5-Fluoro-N4-isopropyl-N2-[2-(4-methylpiperazino)-4- LCMS: ret.
time: 6.77 min.; purity: 84.20%; MS (m/e): 359.97 (MH+). -
methylpyrid-5-yl]-2,4-pyrimidinediamine 1249
5-Fluoro-N2-[2-(4-methylpiperazino)-4-methylpyrid-5-yl]-N4- LCMS:
ret. time: 1.48, 2.77 min.; purity: 98%; MS (m/e): 471.22 (MH+). -
(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1250
5-Fluoro-N4-(1-hydroxymethylcyclopent-1-yl)-N2-[3-methyl-4- LCMS:
ret. time: 11.16 min.; purity: 99.47%; MS (m/e): 415.57 (MH+). +
(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 1251
N4-(5-Amino-1,2,4-triazol-3-yl)-5-fluoro-N2-[3-(N- LCMS: purity:
93.2%; MS (m/e): 374.52 (MH+, 100). +
methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 1252
N4-(3-Amino-1,2,4-triazol-5-yl)-N2-(3,5-dimethylphenyl)-5- .sup.1H
NMR (DMSO): d 8.71 (d, 1H, J = 4.5 Hz), 7.75 (s, 1H), 7.53 (s, 2H),
- fluoro-2,4-pyrimidinediamine 7.21 (s, 1H), 6.61-6.74 (m, 2H),
5.83 (bs, 2H), 2.43 (s, 6H); LCMS: purity: 88.8%; MS (m/e): 315.24
(MH+, 100). 1253 N4-(5-Amino-1,2,4-triazol-3-yl)-N2-(3-chloro-4-
LCMS: purity: 92.8%; MS (m/e): 351.09 (MH+, 100). -
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1254
N4-(5-Amino-1,2,4-triazol-3-yl)-N2-(3,4-dichlorophenyl)-5- LCMS:
purity: 93.2%; MS (m/e): 355.23 (MH+, 100). -
fluoro-2,4-pyrimidinediamine 1255
N4-(5-Amino-1,2,4-triazol-3-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-
LCMS: purity: 94.3%; MS (m/e): 327.14 (MH+, 100). + +
pyrimidinediamine 1256
N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-N2-(3,5- .sup.1H NMR
(DMSO): d 10.09 (bs, 1H), 9.12 (bs, 1H), 8.13 (d, 1H, J = 5.1 Hz),
+ dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.17 (s, 2H),
6.74-6.87 (m, 5H), 4.29-4.50 (m, 2H), 3.98 (dd, 1H, 6.3, 11.4 Hz),
3.59-3.80 (m, 2H), 2.23 (s, 6H); LCMS: purity: 97.8%; MS (m/e):
379.14 (M-, 100). 1257
N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-5-fluoro-N2-[3- LCMS:
purity: 97.4%; MS (m/e): 438.13 (M-, 100). +
(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine
1258 N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-N2-(3,5- .sup.1H
NMR (DMSO): d 10.13 (s, 1H), 9.05 (bs, 1H), 8.19 (d, 1H, J = 4.8
Hz), + dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 6.79-6.86
(m, 6H), 6.24 (m, 1H), 4.29-4.49 (m, 2H), 4.00 (dd, 1H, 6.9, 11.4
Hz), 3.62-3.79 (m, 8H); LCMS: purity: 96.7%; MS (m/e): 411.10 (M-,
100). 1259 N2-(3-Chloro-4-methoxyphenyl)-N4-[(2,3-dihydro-1,4-
.sup.1H NMR (DMSO): d 10.22 (s, 1H), 9.11 (bs, 1H), 8.12 (d, 1H, J
= 5.1 Hz), +
benzodioxan-2-yl)methyl]-5-fluoro-2,4-pyrimidinediamine 7.70 (d,
1H, J = 2.4 Hz), 7.35 (dd, 1H, J = 2.7, 9.0 Hz), 7.08 (d, 1H, J =
9.0 Hz), 6.78-6.87 (m, 4H), 4.28-4.49 (m, 2H), 3.99 (dd, 1H, 6.9,
11.7 Hz), 3.59-3.84 (m, 5H); LCMS: purity 1260
N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-5-fluoro-N2- LCMS:
purity: 95.0%; MS (m/e): 391.10 (M-, 100). +
(indazol-6-yl)-2,4-pyrimidinediamine 1261
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(4- LCMS: purity: 100%; MS
(m/e): 405.09 (M-, 100). -
methoxycarbonylphenyl)-2,4-pyrimidinediamine 1262
N2-[4-(N-Carboxymethyleneamino)carbonylphenyl]-N4-(3,4- LCMS:
purity: 100%; MS (m/e): 450.11 (M-) -
dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 1263
(S)-5-Fluoro-N2-(4-methoxycarbonylphenyl)-N4-(2-methyl-3- .sup.1H
NMR (DMSO): d 10.74 (s, 1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J = 4.2
Hz), 7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J =
6.6 Hz), 3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LCMS: purity:
96.8%; MS (m/e): 422.12 (M-, 100). 1264
(S)-N2-[4-(N-Carboxymethyleneamino)carbonylphenyl]-5- .sup.1H NMR
(DMSO): d 10.75 (s, 1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, -
fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J =
4.5 Hz), 7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q,
pyrimidinediamine 1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d,
3H, J = 6.9 Hz); LCMS: purity: 91.2%; MS (m/e): 465.21 (M-, 100).
1265 (R)-N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-(2-methyl-3-oxo-
LCMS: purity: 95.5%; MS (m/e): 407.17 (M-, 100). +
2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1266
(R)-5-Fluoro-N2-(4-methoxycarbonylphenyl)-N4-(2-methyl-3- .sup.1H
NMR (DMSO): d 10.74 (s, 1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J = 4.2
Hz),
7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J = 6.6
Hz), 3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LCMS: purity: 98.5%;
MS (m/e): 422.17 (M-, 100). 1267
(R)-N2-[4-(N-Carboxymethyleneamino)carbonylphenyl]-5- .sup.1H NMR
(DMSO): d 10.75 (s, 1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, -
fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J =
4.5 Hz), 7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q,
pyrimidinediamine 1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d,
3H, J = 6.9 Hz); LCMS: purity: 87.5%; MS (m/e): 465.21 (M-, 100).
1268 N2,N4-Bis[4-(N-tert-butoxycarbonylamino)methylenephenyl]-5-
LCMS: purity: 100%; MS (m/e): 537.34 (M-, 100). +
fluoro-2,4-pyrimidinediamine 1269
N2,N4-Bis(4-aminomethylenephenyl)-5-fluoro-2,4- 1H NMR (DMSO): d
9.25 (bs, 1H), 9.09 (bs, 1H), 8.05 (d, 1H, J = 2.4 Hz), + + + +
pyrimidinediamine 7.69 (d, 2H, J = 8.7 Hz), 7.56 (d, 2H, J = 8.7
Hz), 7.04-7.40 (m, 4H), 3.67 (s, 3H), 3.61 (s, 3H), 3.35 (bs, 4H);
LCMS: purity: 95.5%; MS (m/e): 337.18 (M-, 100) 1270
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-(N- .sup.1H NMR (DMSO): d
10.21 (s, 2H), 8.33 (m, 1H), 8.33 (d, 1H, J = 4.5 Hz), +
methoxycarbonylmethyleneamino)carbonylphenyl]-2,4- 8.10 (d, 1H, J =
2.4 Hz), 7.59-7.83 (m, 6H), 3.99 (m, 2H), 3.65 (s,
pyrimidinediamine 3H); LCMS: purity: 100%; MS (m/e): 462.11 (M-,
100). 1271 (S)-5-Fluoro-N2-[4-(N- .sup.1H NMR (DMSO): d 10.77 (s,
1H), 9.93 (bs, 1H), 8.77 (m, 1H), 8.20 (d, + -
methoxycarbonylmethyleneamino)carbonylphenyl]-N4-(2- 1H, J = 4.5
Hz), 7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q,
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 6.6 Hz), 3.97
(m, 2H), 3.64 (s, 3H), 1.44 (d, 3H, J = 6.6 Hz); pyrimidinediamine
LCMS: purity: 96.7%; MS (m/e): 481.16 (MH+, 1272
(R)-5-Fluoro-N2-[4-(N- .sup.1H NMR (DMSO): d 10.77 (s, 1H), 9.93
(bs, 1H), 8.77 (m, 1H), 8.20 (d, + -
methoxycarbonylmethyleneamino)carbonylphenyl]-N4-(2- 1H, J = 4.5
Hz), 7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q,
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 6.6 Hz), 3.97
(m, 2H), 3.64 (s, 3H), 1.44 (d, 3H, J = 6.6 Hz); pyrimidinediamine
LCMS: purity: 100%; MS (m/e): 481.39 (MH+, 1273
N2,N4-Bis[3-(N-tert-butoxycarbonylamino)methylenephenyl]-5- .sup.1H
NMR (DMSO): d 9.43 (s, 1H), 9.22 (s, 1H), 9.08 (d, 1H, J = 3.6 Hz),
+ fluoro-2,4-pyrimidinediamine 7.24-7.72 (m, 7H), 7.15 (t, 1H, J =
7.8 Hz), 6.94 (d, 1H, J = 7.5 Hz), 6.78 (d, 1H, J = 7.5 Hz), 4.08
(m, 4H), 1.39 (s, 18H); LCMS: purity: 95.8%; MS (m/e): 537.16 (M-,
100). 1274 N2,N4-Bis(3-aminomethylenephenyl)-5-fluoro-2,4- .sup.1H
NMR (DMSO): d 9.24 (s, 1H), 8.35 (s, 1H), 8.01-8.07 (m, 2H), + +
pyrimidinediamine 6.73-7.71 (m, 7H), 3.69 (s, 2H), 3.61 (s, 2H);
LCMS: purity: 100%; MS (m/e): 337.21 (M-, 100). 1275
N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(3,4- LCMS:
purity: 93.5%; MS (m/e): 476.19 (M-, 100). + +
dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 1276
(S)-N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-5- .sup.1H
NMR (DMSO): d 10.61 (s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.03 (d, +
+ fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J
= 3.9 Hz), 7.22-7.54 (m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92 (d,
pyrimidinediamine 1H, J = 7.5 Hz), 4.64 (q, 1H, J = 6.6 Hz), 4.01
(m, 2H), 1.44 (d, 3H, J = 6.6 Hz), 1.39 (s, 9H); LCMS: purity: 95.1
1277 (R)-N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-5-
.sup.1H NMR (DMSO): d 10.61 (s, 1H), 9.30 (s, 1H), 9.04 (s, 1H),
8.03 (d, + + fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)
1H, J = 3.9 Hz), 7.22-7.54 (m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92
(d, 1H, J = 7.5 Hz), 4.64 (q, 1H, J = 6.6 Hz), 4.01 (m, 2H), 1.44
(d, 3H, J = 6.6 Hz), 1.39 (s, 9H); LCMS: purity: 92.2 1278
N2-(3-Aminomethylenephenyl)-N4-(3,4-dichlorophenyl)-5- .sup.1H NMR
(DMSO): d 9.60 (bs, 1H), 9.31 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz), +
+ fluoro-2,4-pyrimidinediamine 8.12 (d, 1H, J = 2.7 Hz), 6.81-7.88
(m, 6H), 3.70 (s, 2H); LCMS: purity: 96.4%; MS (m/e): 376.11 (M-,
100). 1279 (S)-N2-(3-Aminomethylenephenyl)-5-fluoro-N4-(2-methyl-3-
.sup.1H NMR (DMSO): d 9.30 (s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), + +
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 6.76-7.60 (m,
8H), 4.63 (q, 1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9
Hz); LCMS: purity: 100%; MS (m/e): 393.20 (M-, 100). 1280
(R)-N2-(3-Aminomethylenephenyl)-5-fluoro-N4-(2-methyl-3- .sup.1H
NMR (DMSO): d 9.30 (s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), + +
oxo-2H,4H-benz[1,4]oxazin-6-yl-2,4-pyrimidinediamine 6.76-7.60 (m,
8H), 4.63 (q, 1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9
Hz); LCMS: purity: 98.5%; MS (m/e): 393.20 (M-, 100). 1281
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO): d 10.69 (s, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J
= 4.5 Hz), + + - [3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine
8.12-8.17 (m, 2H), 7.73 (d, 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 7.5
Hz), 7.21-7.39 (m, m, 4H), 6.76 (d, 1H, J = 8.4 Hz), 1.38 (s, 6H);
LCMS: purity: 100%; MS (m/e): 445.14 (M-, 100). 1282
(S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
.sup.1H NMR (DMSO): d 10.69 (s, 1H), 9.98 (bs, 2H), 8.22 (d, 1H, J
= 2.4 Hz), + + - N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine
8.16 (m, 1H), 7.21-7.75 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q,
1H, J = 6.9 Hz), 1.42 (d, 3H, J = 6.9 Hz); LCMS: purity: 97.3%; MS
(m/e): 431.15 (M-, 100). 1283
(R)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-
.sup.1H NMR (DMSO): d 10.69 (s, 1H), 9.98 (bs, 2H), 8.22 (d, 1H, J
= 2.4 Hz), + + - N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine
8.16 (m, 1H), 7.21-7.75 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q,
1H, J = 6.9 Hz), 1.42 (d, 3H, J = 6.9 Hz); LCMS: purity: 94.9%; MS
(m/e): 431.15 (M-, 100). 1284
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO): d 12.05 (s, 1H), 10.05 (s, 1H), 9.95 (s, 1H), +
+ - [3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.27 (m, 1H),
8.25 (d, 1H, J = 4.5 Hz), 8.14 (s, 1H), 7.32-7.75 (m, 6H), 7.13 (d,
1H, J = 9.0 Hz); LCMS: purity: 98.0%; MS (m/e): 453.12 (M-, 100).
1285 N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-
LCMS: purity: 87.8%; MS (m/e): 417.18 (M-, 100). + + -
[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1286
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
.sup.1H NMR (DMSO): d 10.71 (s, 1H), 9.91 (bs, 1H), 8.73 (m, 1H),
1.19 (d, + + - +
[4-(N-methoxycarbonylmethyleneamino)carbonylphenyl]-2,4- 1H, J =
4.5 Hz), 7.19-7.74 (m, 6H), 6.94 (d, 1H, J = 8.4 Hz), 3.97 (m,
pyrimidinediamine 2H), 3.64 (s, 3H), 1.38 (s, 6H); LCMS: purity:
97.5%; MS (m/e): 493.22 (M-, 100). 1287
N4-(4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1- LCMS: purity:
89.3%; MS (m/e): 517.26 (M-, 100). + -
benzopyran-6-yl)-5-fluoro-N2-[3-(oxazol-5-yl)phenyl]-2,4-
pyrimidinediamine 1288
N4-(4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1- LCMS: purity:
96.6%; MS (m/e): 516.90 (M-, 100). + + +
benzopyran-6-yl)-5-fluoro-N2-[4-(oxazol-5-yl)phenyl]-2,4-
pyrimidinediamine 1289
N4-(4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1- LCMS: purity:
87.2%; MS (m/e): 517.54 (M-, 100). + +
benzopyran-6-yl)-5-fluoro-N2-[4-(oxazol-2-yl)phenyl]-2,4-
pyrimidinediamine 1290
5-Fluoro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)- LCMS:
purity: 100%; MS (m/e): 518.16 (M-, 100). + + -
N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1291
5-Fluoro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)- .sup.1H
NMR (DMSO): d 10.40 (s, 1H), 10.25 (s, 1H), 8.26 (d, 1H, J = 4.8
Hz), + + - N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.15
(s, 1H), 7.65-7.83 (m, 4H), 7.50 (d, 1H, J = 2.7 Hz), 7.40 (dd, 1H,
J 2.7, 8.4 Hz), 7.32 (s, 1H), 6.81 (d, 1H, J = 8.7 Hz), 4.59 (t,
1H, J = 5.1 Hz), 4.20-4.24 (m, 2H), 1.70-2.1 1292
(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- 1H NMR
(DMSO-d6): d 9.25 (s, 1H), 9.19 (s, 1H), 8.35 (s, 1H), + + -
fluoro-N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.05 (d, J
= 3.6 Hz, 1H), 7.99 (m, 1H), 7.20-7.63 (m, 5H), 6.62 (d, J = 8.7
Hz, 1H), 3.86-4.20 (m, 3H), 1.75-2.0 (m, 2H); LCMS: purity: 91.8%;
MS (m/e): 419.3 (MH+). 1293
(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS:
purity: 98.0%; MS (m/e): 419.2 (MH+). +
fluoro-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1294
(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS:
purity: 93.5%; MS (m/e): 419.3 (MH+). +
fluoro-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1295
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.73 (s, 1H), 9.97 (s, 1H), 9.87 (s, 1H), + + -
[4-[N-(N- 8.53 (m, 1H), 8.19 (d, J = 4.2 Hz, 1H), 7.66-7.83 (m,
5H), 7.24-7.27 (m, 2H),
methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 6.94 (d, J
= 8.4 Hz, 1H), 3.78 (d, J = 5.7 Hz, 2H), 2.58 (d, J = 4.5 Hz,
pyrimidinediamine 3H), 1.41 (s, 6H); purity 98.2%; MS (m 1296
(S)-5-Fluoro-N2-[4-[N-(N- 1H NMR (DMSO-d6): d 10.85 (s, 1H), 10.21
(s, 1H), 9.98 (s, 1H), + + -
methylamino)carbonylmethylene]aminocarbonylphenyl]-N4-(2- 8.58 (m,
1H), 8.22 (d, J = 4.5 Hz, 1H), 7.68-7.79 (m, 6H), 7.43 (m, 1H),
methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 7.23 (m, 1H), 6.95
(d, J = 9.0 Hz, 1H), 4.65 (q, J = 6.3 Hz, 1H), 3.79 (m,
pyrimidinediamine 2H), 2.58 (d, J = 4.5 Hz, 3H), 1.43 (d, J = 1297
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 12.11 (s, 1H), 9.87 (s, 1H), 9.81 (s, 1H), + -
[4-[N-(N- 8.53 (m, 1H), 8.20 (d, J = 3.9 Hz, 1H), 7.67-7.78 (m,
6H), 7.54 (dd, J = 2.4,
methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 8.7 Hz,
1H), 7.29 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H), 2.58 (d,
pyrimidinediamine J = 4.2 Hz, 1H); LCMS: purity: 97.8%; MS 1298
(R,S)-N4-[4-(N-tert-Butoxycarbonyl)amino-3,4-dihydro-2H-1- LCMS:
purity 97%; MS (m/e): 566.4 (MH+). + -
benzopyran-6-yl]-5-fluoro-N2-[4-[N-(N-
methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4-
pyrimidinediamine 1299
(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS:
purity: 93.5%; MS (m/e): 466.3 (MH+). + + - + fluoro-N2-[4-[N-(N-
methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4-
pyrimidinediamine 1300
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N-(N- 1H NMR (DMSO-d6): d
9.84 (s, 1H), 9.81 (s, 1H), 8.54 (m, 1H), + + -
methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 8.24 (d, J
= 3.9 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.68-7.81 (m, 6H),
pyrimidinediamine 7.56 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz,
2H), 2.58 (d, J = 3.9 Hz, 3H); LCMS: purity: 100%; MS (m/e): 463.2
(MH+). 1301 N4-(3,4-Dichlorophenyl)-5-fluoro-N4-methyl-N2-[4-[N-(N-
1H NMR (DMSO-d6): d 9.75 (s, 1H), 8.50 (m, 1H), 8.12 (d, J = 4.8
Hz, + + - methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4-
1H), 7.63-7.79 (m, 7H), 7.34 (dd, J = 2.4, 9.6 Hz, 1H), 3.78 (d, J
= 4.8 Hz, pyrimidinediamine 2H), 3.09 (s, 3H), 2.58 (d, J = 4.5 Hz,
3H); LCMS: purity: 94.1%; MS (m/e): 477.2 (MH+). 1302
N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 10.71 (s, 1H), 9.93 (bs, 2H), 8.32 (m, 1H), + + +
[4-[N-(2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 8.19 (d, J
= 4.8 Hz, 1H), 7.61-7.69 (m, 4H), 7.22-7.25 (m, 2H), 6.94 (d,
pyrimidinediamine J = 6.93 Hz, 1H), 3.60 (s, 3H), 3.44 (q, J = 6.9
Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 1.41 (s, 6H); LCMS: purity:
97.5%; 1303 (S)-5-Fluoro-N2-[4-[N-(2- 1H NMR (DMSO-d6): d 10.83 (s,
1H), 10.32 (s, 1H), 10.13 (s, 1H), + + -
methoxycarbonylethyl)aminocarbonyl]phenyl]-N4-(2-methyl-3- 8.39 (m,
1H), 8.25 (d, J = 4.8 Hz, 1H), 7.62-7.72 (m, 4H), 7.35 (s, 1H),
oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.21 (dd, J =
2.4, 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.66 (q, J = 6.9 Hz,
1H), 3.59 (s, 3H), 3.43 (m, 2H), 2.57 1304
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR
(DMSO-d6): d 12.15 (s, 1H), 9.85 (m, 2H), 8.31 (m, 1H), + + -
[4-[N-(2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 8.20 (d, J
= 4.2 Hz, 1H), 7.70-7.78 (m, 5H), 7.50 (d, J = 9.6 Hz, 1H),
pyrimidinediamine 7.27 (d, J = 9.90 Hz, 1H), 3.59 (s, 3H), 3.42 (m,
2H), 2.56 (t, J = 6.9 Hz, 2H); LCMS: purity: 88.5%; MS (m/e): 517.3
(MH 1305 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N-(2- 1H NMR
(DMSO-d6): d 9.82 (s, 1H), 9.77 (s, 1H), 8.36 (m, 1H), + + +
methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 8.24 (d, J = 3.9
Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.65-7.79 (m, 5H),
pyrimidinediamine 7.56 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 3.47 (q,
J = 6.6 Hz, 2H), 2.57 (t, J = 6.6 Hz, 1H); purity 90.9%; MS (m/e):
478 1306 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N-(2- 1H NMR
(DMSO-d6): d 9.94 (s, 1H), 8.41 (m, 1H), 8.16 (d, J = 5.7 Hz, + + -
methoxycarbonylethyl)aminocarbonyl]phenyl]-N4-methyl-2,4- 1H),
7.64-7.75 (m, 6H), 7.36 (dd, J = 2.4, 8.7 Hz, 1H), 3.59 (s, 3H),
pyrimidinediamine 3.50 (s, 3H), 3.45 (m, 2H), 2.57 (t, J = 7.6 Hz,
2H); LCMS: purity: 88.5%; MS (m/e): 492.2 (MH+). 1307
N2-[4-[1-(tert- 1H NMR (DMSO-d6): d 10.59 (s, 1H), 9.29 (s, 1H),
9.01 (s, 1H), + + +
Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 8.12 (m,
1H), 8.03 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.27 (dd,
J = 2.1,
N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.4
Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H),
pyrimidinediamine 6.90 (d, J = 9.0 Hz, 2H), 4.16 (d, J = 5.4 1308
(S)-N2-[4-[1-(tert- 1H NMR (DMSO-d6): d 10.63 (s, 1H), 9.29 (s,
1H), 9.00 (s, 1H), + + +
Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 8.13 (m,
1H), 8.03 (d, J = 3.6 Hz, 1H), 7.29-7.57 (m, 3H), 7.21 (d, J = 2.1
Hz, 5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-
1H), 7.05 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.65 (q, J
= 7.5 Hz, pyrimidinediamine 1H), 4.16 (d, J = 5.7 Hz, 2H), 3 1309
N2-[4-[1-(tert- 1H NMR (DMSO-d6): d 9.52 (s, 1H), 9.08 (s, 1H),
8.13 (m, 1H), + + -
Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 8.09 (d,
J = 3.3 Hz, 1H), 7.46-7.62 (m, 4H), 7.23 (d, J = 8.7 Hz, 2H),
N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.07
(d, J = 8.4 Hz, 2H), 6.92 (m, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.54
(d, J = 5.7 Hz, pyrimidinediamine 2H), 1.37 (s, 9H); LCMS: purity:
93 1310 N2-[4-[1-(tert- 1H NMR (DMSO-d6): d 9.56 (s, 1H), 9.28 (s,
1H), 8.12-8.17 (m, 3H), + + +
Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 7.51-7.81
(m, 4H), 7.14 (d, J = 8.7 Hz, 2H), 6.93 (m, 1H), 4.20 (d, J = 6.3
Hz, N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 2H),
3.54 (d, J = 6.6 Hz, 2H), 1.38 (s, 9H); LCMS: purity: 94.1%; MS
(m/e): 535.3 (MH+). 1311 N2-[4-[1-(tert- 1H NMR (DMSO-d6): d 9.31
(s, 1H), 8.15 (m, 1H), 8.04 (d, J = 5.4 Hz, + -
Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 1H),
7.55-7.66 (m, 4H), 7.30 (m, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.94 (m,
N4-(3,4-dichlorophenyl)-5-fluoro-N4-methyl-2,4- 1H), 4.18 (d, J =
6.3 Hz, 2H), 3.54 (d, J = 6.3 Hz, 2H), 3.46 (s, 3H),
pyrimidinediamine 1.38 (s, 9H); LCMS: purity: 90.1%; MS (m/e 1312
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 3.67 min. (9 min. method); purity: 95.3%; MS (m/e): + +
N2-[4-[N-(2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 496.3
(MH+). pyrimidinediamine 1313
N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS:
ret. time: 4.45 min. (9 min. method); purity: 97.3%; MS (m/e): +
N2-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine 439.3 (MH+).
1314 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-
LCMS: ret. time: 4.00 min. (9 min. method); purity: 95.1%; MS
(m/e): + N2-(3-methoxycarbonylppyrid-2yl)-2,4-pyrimidinediamine
440.4 (MH+). 1315
N2-(4-Aminocarbonylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5- LCMS: ret.
time: 3.28 min. (9 min. method); purity: 98.1%; MS (m/e): +
pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 424.3 (MH+).
1316 N2-(2-Aminocarbonylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5- LCMS:
ret. time: 3.98 min. (9 min. method); purity: 90.1%; MS (m/e): + -
pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 424.5 (MH+).
1317 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-
LCMS: ret. time: 8.50 min. (20 min. method); purity: 98.8%; MS
(m/e): (indazol-6-yl)-2,4-pyrimidinediamine Methanesulfonic Acid
Salt 420.1 (MH+). 1318
N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:
ret. time: 9.69 min. (20 min. method); purity: 98.4%; MS (m/e):
[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 475.3 (MH+).
pyrimidinediamine Methanesulfonic Acid Salt 1319
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4-[N- LCMS: ret. time:
3.17 min. (7 min. method); purity: 97.5%; MS (m/e): +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3 (MH+).
pyrimidinediamine 1320
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4-[2-[N,N- LCMS: ret.
time: 2.64 min. (7 min. method); purity: 100%; MS (m/e): + +
diethylamino]ethyleneaminocarbonyl]phenyl)-2,4- 487.3 (MH+).
pyrimidinediamine 1321
N2-(4-Aminocarbonylphenyl)-N4-(3-chloro-4-methoxyphenyl)- LCMS:
ret. time: 2.86 min. (7 min. method); purity: 100%; MS (m/e): + +
5-fluoro-2,4-pyrimidinediamine 488.3 (MH+). 1322
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4- LCMS: ret. time: 4.02
min. (7 min. method); purity: 98.4%; MS (m/e): +
methoxycarbonylphenyl)-2,4-pyrimidinediamine 403.3 (MH+). 1323
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4-[N-tert- LCMS: ret.
time: 3.83 min. (7 min. method); purity: 92.3%; MS (m/e): +
butoxycarbonylaminomethylene]phenyl)-2,4-pyrimidinediamine 474.3
(MH+). 1324 N2-(4-Aminomethylenephenyl)-N4-(3-chloro-4- LCMS: ret.
time: 2.53 min. (7 min. method); purity: 96.6%; MS (m/e): +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 374.2 (MH+). 1325
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4-[N-[N- LCMS: ret.
time: 2.81 min. (7 min. method); purity: 100%; MS (m/e): +
methyl]aminocarbonylmethylene]aminocarbonyl]phenyl)-2,4- 459.3
(MH+). pyrimidinediamine 1326 2-Chloro-5-fluoro-N4-(4-[N- LCMS:
ret. time: 2.79 min. (7 min. method); purity: 100%; MS (m/e): -
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-4- 339.2 (MH+).
pyrimidineamine 1327
N4-[4-Aminocarbonylphenyl]-2-chloro-5-fluoro--4- LCMS: ret. time:
2.40 min. (7 min. method); purity: 100%; MS (m/e): -
pyrimidineamine 267.1 (MH+). 1328
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(4-[N- LCMS: ret. time: 2.44 min.
(7 min. method); purity: 94.9%; MS (m/e): +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 412.3 (MH+).
pyrimidinediamine 1329
N2-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N4-(4-[N- LCMS: ret.
time: 9.92 min. (20 min. method); purity: 95.0%; MS (m/e): +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 482.0 (MH+).
pyrimidinediamine 1330
N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(4-[N- LCMS: ret. time:
3.13 min. (7 min. method); purity: 95% MS (m/e): + + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3 (MH+).
pyrimidinediamine 1331
N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- LCMS:
ret. time: 2.80 min. (7 min. method); purity: 92.2%; MS (m/e): + +
(4-[N-[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 495.3
(MH+). pyrimidinediamine 1332 5-Fluoro-N2,N4-bis(4-[N- LCMS: ret.
time: 2.77 min. (7 min. method); purity: 100%; MS (m/e): + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 511.4 (MH+).
pyrimidinediamine 1333
N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-(4-[N- LCMS: ret. time: 2.48
min. (7 min. method); purity: 97.6%; MS (m/e): - -
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 439.3 (MH+).
pyrimidinediamine 1334
N4-(4-Aminocarbonylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)- LCMS:
ret. time: 2.10 min. (7 min. method); purity: 100%; MS (m/e): + +
2,4-pyrimidinediamine 340.2 (MH+). 1335
N4-(4-Aminocarbonylphenyl)-N2-(3,5-dichloro-4- LCMS: ret. time:
8.72 min. (20 min. method); purity: 93.0%; MS (m/e): + +
hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine 410.0 (MH+). 1336
N4-(4-Aminocarbonylphenyl)-N2-(3-chloro-4-methoxyphenyl)- LCMS:
ret. time: 2.79 min. (7 min. method); purity: 100%; MS (m/e): + +
5-fluoro-2,4-pyrimidinediamine 388.3 (MH+). 1337
N4-(4-Aminocarbonylphenyl)-N2-(2,2-dimethyl-3-oxo-4H- LCMS: ret.
time: 2.50 min. (7 min. method); purity: 100%; MS (m/e): + + +
benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 423.3 (MH+).
1338 N4-(Aminocarbonylphenyl)-5-fluoro-N2-(4-[N- LCMS: ret. time:
2.52 min. (7 min. method); purity: 94.4%; MS (m/e): + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 439.3 (MH+).
pyrimidinediamine 1339
N2,N4-Bis(4-aminocarbonylphenyl)-5-fluoro-2,4- LCMS: ret. time:
2.26 min. (7 min. method); purity: 100%; MS (m/e): - -
pyrimidinediamine 367.3 (MH+). 1340
N4-(2,2-Dimethyl-3-oxo-4H-N4-oxo-5-pyrido[1,4]oxazin-6-yl)- LCMS:
ret. time: 3.48 min. (7 min. method); purity: 97.4%; MS (m/e): + +
5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 487.3
(MH+). 1341
N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-(4-[3-methyl-1,2,4- LCMS:
ret. time: 2.72 min. (7 min. method); purity: 95.8%; MS (m/e): + +
+ oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 436.3
(MH+). 1342 5-Fluoro-N2-(4-[N- LCMS: ret. time: 2.99 min. (7 min.
method); purity: 95.1%; MS (m/e): + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-N4-(4-[3- 508.4
(MH+). methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4-
pyrimidinediamine 1343
N2-(4-[2-[N,N-Diethylamino]ethyleneaminocarbonyl]phenyl)-5- LCMS:
ret. time: 2.58 min. (7 min. method); purity: 97.8%; MS (m/e): + +
+ fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5- 535.4 (MH+).
yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 1344
N2-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N4-(4-[3-methyl- LCMS:
ret. time: 3.33 min. (7 min. method); purity: 95.0%; MS (m/e): + -
+ 1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4- 477.2 (MH+).
pyrimidinediamine 1345
N2-(3-Chloro-5-methoxyphenyl)-5-fluoro-N4-(4-[3-methyl- LCMS: ret.
time: 3.35 min. (7 min. method); purity: 96.4%; MS (m/e): - +
1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4- 457.3 (MH+).
pyrimidinediamine 1346
N2-(4-Aminocarbonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro- LCMS:
ret. time: 3.86 min. (7 min. method); purity: 100%; MS (m/e): +
N4-methyl-2,4-pyrimidinediamine 406.2 (MH+). 1347
N2-(4-[2-[N,N-Diethylamino]ethyleneaminocarbonyl]phenyl)- LCMS:
ret. time: 3.31 min. (7 min. method); purity: 100%; MS (m/e): +
N4-(3,4-dichlorophenyl)-5-fluoro-N4-methyl-2,4- 505.3 (MH+).
pyrimidinediamine 1348 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(4-[N-
LCMS: ret. time: 4.16 min. (7 min. method); purity: 95.8%; MS
(m/e): + [methoxycarbonylmethylene]aminocarbonyl]phenyl)-N4- 480.2
(MH+). methyl-2,4-pyrimidinediamine 1349
N2-(4-Aminocarbonylphenyl)-N4-(cyclopentyl)-5-fluoro-2,4- LCMS:
ret. time: 2.26 min. (7 min. method); purity: 100%; MS (m/e): -
pyrimidinediamine 316.3 (MH+). 1350 N4-(Cyclopentyl)-N2-(4-[2-(N,N-
LCMS: ret. time: 2.09 min. (7 min. method); purity: 97.3%; MS
(m/e): - + diethylamino]ethyleneaminocarbonyl)phenyl)-5-fluoro-2,4-
415.4 (MH+). pyrimidinediamine 1351
N4-(Cyclopentyl)-5-fluoro-N2-(4-[N- LCMS: ret. time: 2.62 min. (7
min. method); purity: 100%; MS (m/e): + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 388.3 (MH+).
pyrimidinediamine 1352
N2-(4-Aminocarbonylphenyl)-N4-(4-chloro-3-methoxyphenyl)- LCMS:
ret. time: 3.13 min. (7 min. method); purity: 96.4%; MS (m/e): +
5-fluoro-2,4-pyrimidinediamine 388.3 (MH+). 1353
N2-(4-Aminocarbonyl-3-chlorophenyl)-N4-(3-chloro-4- LCMS: ret.
time: 2.91 min. (7 min. method); purity: 89.5%; MS (m/e): + +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 422.2 (MH+). 1354
N2-(4-Aminocarbonyl-3-chlorophenyl)-N4-(4-chloro-3- LCMS: ret.
time: 3.14 min. (7 min. method); purity: 95.0%; MS (m/e): + +
methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 422.2 (MH+). 1355
N4-(4-Chloro-3-methoxyphenyl)-N2-(4-[2-[N,N- LCMS: ret. time: 2.80
min. (7 min. method); purity: 95.6%; MS (m/e): + +
diethylamino]ethyleneaminocarbonyl]phenyl)-5-fluoro-2,4- 487.4
(MH+). pyrimidinediamine 1356
N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(4-[N- LCMS: ret. time:
3.45 min. (7 min. method); purity: 94.6%; MS (m/e): + +
[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3 (MH+).
pyrimidinediamine 1357
N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-phenyl-2,4- LCMS: ret. time:
2.58 min. (7 min. method); purity: 100%; MS (m/e): + +
pyrimidinediamine 424.3 (MH+). 1358
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(4-[3-methyl-1,2,4- LCMS: ret.
time: 2.72 min. (7 min. method); purity: 89.9%; MS (m/e):
oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 409.3
(MH+). hydrochloric acid salt
7.5 The Compounds Are Effective for the Treatment of
Autoimmunity
[0353] The in vivo efficacy of certain 2,4-pyrimidinediamine
compounds towards autoimmune diseases was evaluated in the reverse
passive Arthus reaction, an acute model of antigen-antibody
mediated tissue injury, and in several disease models of
autoimmunity and inflammation. These models are similar in that
antibody to a specific antigen mediates immune complex-triggered
(IC-triggered) inflammatory disease and subsequent tissue
destruction. IC deposition at specific anatomic sites (central
nervous system (CNS) for experimental autoimmune encephalomyelitis
(EAE) and synovium for collagen-induced arthritis (CIA)) leads to
activation of cells expressing surface Fc.gamma.R and Fc.epsilon.R,
notably mast cells, macrophages, and neutrophils, which results in
cytokine release, and neutrophil chemotaxis. Activation of the
inflammatory response is responsible for downstream effector
responses, including edema, hemorrhage, neutrophil infiltration,
and release of pro-inflammatory mediators. The consequences of
these IC-triggered events are difficult to identify in autoimmune
disorders; nonetheless, many investigators have demonstrated that
inhibition of the Fc.gamma.R signaling pathway in these animal
models has resulted in a significant reduction in disease onset and
severity.
7.5.1 The Compounds are Effective in Mouse Arthus Reaction
[0354] The in vivo efficacy of compounds 810, 944, 994 and 1007 to
inhibit the IC-triggered inflammatory cascade was demonstrated in a
mouse model of Reverse Passive Arthus Reaction (RPA reaction).
7.5.1.1 Model
[0355] Immune complex (IC)-mediated acute inflammatory tissue
injury is implicated in a variety of human autoimmune diseases,
including vasculitis syndrome, sick serum syndrome, systemic lupus
erythematosus (SLE), rheumatoid arthritis, Goodpasture's syndrome,
and glomerulonephritis. The classical experimental model for
IC-mediated tissue injury is the reverse passive Arthus reaction.
The RPA reaction model is a convenient in vivo method to study
localized inflammation, induced by ICs, without systemic effects.
Intradermal injection of antibodies (Abs) specific to chicken egg
albumin (rabbit anti-OVA IgG), followed by intravenous (IV)
injection of antigens (Ags), specifically chicken egg albumin
(ovalbumin, OVA), causes perivascular deposition of ICs and a rapid
inflammatory response characterized by edema, neutrophil
infiltration and hemorrhage at the injection sites. Aspects of the
mouse RPA reaction model resemble the inflammatory response of
patients with rheumatoid arthritis, SLE and glomerulonephritis.
7.5.1.2 Study Protocol
[0356] In this model system, test compounds are administered at
several timepoints prior to administration of Abs and Ags. A
solution of rabbit anti-OVA IgG (50 .mu.g in 25 .mu.l/mouse) is
injected intradermally, and immediately following is an intravenous
injection of chicken egg albumin (20 mg/kg of body weight) in a
solution containing 1% Evans blue dye. The degree of edema and
hemorrhage is measured in the dorsal skin of C57BL/6 mice using the
Evan's Blue dye as an indicator of local tissue damage. Purified
polyclonal rabbit IgG is used as a control.
[0357] Pretreatment time, in which the test compounds are
administered prior to Ab/Ag challenge, depends on the
pharmacokinetic (PK) properties of each individual compound. Four
hours after induction of Arthus reaction, mice are euthanized, and
tissues are harvested for assessment of edema. This model system
allows us to rapidly screen the in vivo activity of many
inhibitors.
7.5.1.3 Results
[0358] All compounds tested were administered by the oral
route.
[0359] Compound 994, when administered at a dose level of 100 mg/kg
90 minutes prior to Ab/Ag challenge in C57Bl6 mice, showed
dose-dependent inhibition of edema formation (75%).
[0360] Compounds 1007 and 810 showed the efficacy of edema
inhibition by 89.4% and 81.3%, respectively, when administered at
1.0 mg/kg, 30 minutes prior to challenge.
[0361] Compound 1007 showed 64.3%, 78.7%, 98.1% and 99.8%,
inhibition of edema formation when administered at dose levels of
0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 5 mg/kg and a pretreatment time
of 30, respectively. Results for the compounds tested are
summarized in Table 2.
TABLE-US-00002 TABLE 2 Mouse Cutaneous Reverse Passive Arthus (RPA)
Reaction Summary Satellite: At in vitro % inhibition to time of
Exposure = Potency vehicle challenge Pretreatment (CHMC control
Plasma Time + 4 hours IgE) Compound Compound Dosage Pretreatment
Edema Size .+-. Concentration .+-. Plasma Concentration .+-. Name
Number (mg/kg) Time (hrs) SEM SEM (ng/ml) SEM (ng/ml) 994 100 75.0
.+-. 6.2 78.6 .+-. 26.4 44.2 .+-. 8.9 0.047 1007 1 0.5 89.4 .+-.
2.2 3 0.5 86.3 .+-. 7.9 10 0.5 97.8 .+-. 1.1 30 0.5 88.2 .+-. 5.7
1007 0.1 0.5 64.3 .+-. 11.2 24.4 .+-. 9.6 BLQ 0.5 0.5 78.7 .+-. 6.3
73.1 .+-. 14.5 BLQ 1 0.5 98.1 .+-. 0.8 90.0 .+-. 11.0 2.3 .+-. 0.9
5 0.5 99.8 .+-. 0.2 398.0 .+-. 30.2 19.8 .+-. 15.7 810 0.1 0.5 69.5
.+-. 19.6 0.5 0.5 60.9 .+-. 9.6 1 0.5 81.3 .+-. 8.4 5 0.5 92.1 .+-.
3.1 944 2 1 39.3 .+-. 13.8 NA 4.3 .+-. 4.2 5 1 48.4 .+-. 12.0 NA
3.5 .+-. 5.3 15 1 56.1 .+-. 9.2 NA 29.7 .+-. 25.9 944 0.5 5 -16.0
.+-. 17.3 22.1 .+-. 52.4 3.4 .+-. 9.1 0.5 15 8.3 .+-. 13.4 1074.0
.+-. 492.3 85.1 .+-. 161.9
7.5.2 The Compounds are Effective in Mouse Collagen Antibody
Induced Arthritis Model
[0362] The in vivo efficacy of compounds towards autoimmune
diseases can be demonstrated in a mouse model of collagen
antibody-induced arthritis (CAIA).
7.5.2.1 Model
[0363] Collagen-induced arthritis (CIA) in rodents is frequently
used as one of the experimental models for IC-mediated tissue
injury. Administration of type II collagen into mice or rats
results in an immune reaction that characteristically involves
inflammatory destruction of cartilage and bone of the distal joints
with concomitant swelling of surrounding tissues. CIA is commonly
used to evaluate compounds that might be of potential use as drugs
for treatment of rheumatoid arthritis and other chronic
inflammatory conditions.
[0364] In recent years, a new technique emerged in CIA modeling, in
which the anti-type II collagen antibodies are applied to induce an
antibody-mediated CIA. The advantages of the method are: Short time
for induction of disease (developing within 24-48 hrs after an
intravenous (IV) injection of antibodies); arthritis is inducible
in both CIA-susceptible and CIA-resistant mouse strains; and the
procedure is ideal for rapid screening of anti-inflammatory
therapeutic agents.
[0365] Arthrogen-CIA.RTM. Arthritis-inducing Monoclonal Antibody
Cocktail (Chemicon International Inc.) is administered
intravenously to Balb/c mice (2 mg/mouse) on Day 0. Forty-eight
hours later, 100 .mu.l of LPS (25 .mu.g) is injected
intraperitoneally. On Day 4, toes may appear swollen. By Day 5, one
or two paws (particular the hind legs) begin to appear red and
swollen. On Day 6, and thereafter, red and swollen paws will remain
for at least 1-2 weeks. During the study, the clinical signs of
inflammation are scored to evaluate the intensity of edema in the
paws. The severity of arthritis is recorded as the sum score of
both hind paws for each animal (possible maximum score of 8). The
degree of inflammation with involved paws is evaluated by
measurement of diameter of the paws. Body weight changes are
monitored.
[0366] Animals can be treated at the time of induction of
arthritis, beginning on Day 0. Test compounds and control compounds
can be administered once a day (q.d.) or twice a day (b.i.d.), via
per os (PO), depending on previously established PK profiles.
[0367] At the end of the study (1-2 weeks after induction of
arthritis), mice are euthanized and the paws are transected at the
distal tibia using a guillotine and weighed. The mean.+-.standard
error of the mean (SEM) for each group is determined each day from
individual animal clinical scores, and hind paw weights for each
experimental group are calculated and recorded at study
termination. Histopathological evaluation of paws are obtained.
7.5.2.2 Results
[0368] Reduced inflammation and swelling should be evident in
animals treated with compounds of the invention, and the arthritis
would progress more slowly. Treatment with compounds should
(b.i.d.) significantly reduce clinical arthritis compared with
animals treated with vehicle only.
7.5.3 The Compounds can be Effective in Rat Collagen-Induced
Arthritis
[0369] The in vivo efficacy of compounds of the invention towards
autoimmune diseases can be demonstrated in a rat model of
collagen-induced arthritis (CIA).
7.5.3.1 Model Description
[0370] Rheumatoid arthritis (RA) is characterized by chronic joint
inflammation eventually leading to irreversible cartilage
destruction. IgG-containing IC are abundant in the synovial tissue
of patients with RA. While it is still debated what role these
complexes play in the etiology and pathology of the disease, IC
communicate with the hematopoetic cells via the Fc.gamma.R.
[0371] CIA is a widely accepted animal model of RA that results in
chronic inflammatory synovitis characterized by pannus formation
and joint degradation. In this model, intradermal immunization with
native type II collagen, emulsified with incomplete Freund's
adjuvant, results in an inflammatory polyarthritis within 10 or 11
days and subsequent joint destruction in 3 to 4 weeks.
7.5.3.2 Study Protocol
[0372] Syngeneic LOU rats were immunized on Day 0 with native
chicken CII/IFA (performed at UCLA; E. Brahn, Principal
Investigator). Beginning on the day of arthritis onset (Day 10), a
total of 59 rats can be treated with either a vehicle control or a
compound of the invention at one of four dose levels (1, 3, 10, and
30 mg/kg, q.d. by p.o. gavage).
7.5.3.3 Results
[0373] Hind limbs would be scored daily for clinical arthritis
severity using a standardized method based on the degree of joint
inflammation. High resolution digital radiographs of hind limbs can
be obtained at the conclusion of the study (Day 28). These limbs
can also be analyzed for histopathologic changes. IgG antibodies to
native CII can be measured in quadruplicate by ELISA.
[0374] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
[0375] All literature and patent references cited throughout the
application are incorporated by reference into the application for
all purposes.
* * * * *