K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5778–5783
5779
dichloropyrimidine (3) was treated with ammonia or 2
equiv of cyclohexylamine in THF at room temperature
for 10 min. This was stirred for 12 h at room tempera-
ture or 50 °C, in the case of the cyclohexylamine reac-
tion, to produce 4 and 5 in >95% yields. This was
followed by a palladium catalyzed cross-coupling reac-
tion with tributyl-(2-ethoxy-vinyl)-stannane and 4 or 5,
furnishing the 6 and 7 in 65% and 60% yields, respective-
ly. Heating to 120 °C in AcOH for 2 h converted 6 and 7
to the pyrrolopyrimidines 8 and 9 in yields >85%. The
use of AcOH was critical for the high conversion. The
use of HCl–CH3OH for the cyclization led to lower
yields (ꢀ45%) and the isolation of several by-products.
Cdk1
Cdk7
Cdk4
Aurora-A
IRK
c-Src
VEGF
PDGFr
TrkB
IC50 = 1.60μM
IC50 = 1.50μM
IC50 = 0.031μM
IC50 = 0.047μM
IC50 = 1.00μM
IC50 = 0.71μM
IC50 = 0.10μM
IC50 = 0.29μM
IC50 = 0.16μM
N
N
HN
N
N
N
2
The synthesis of the pyrrolopyrimidines is described in
Schemes 1–4. Using a modified procedure of a route
outlined by Cheung and co-workers8 5-bromo-2,4-
Br
Lam–Chan9 or Buchwald10 coupling conditions were
applied to attach the aryl groups to the N-7 atom of
8. Yields for the coupling reaction ranged from 45% to
75% (Scheme 2). The Lam–Chan protocol was applica-
ble for the introduction of meta- and para-substituted
aryl rings at the N-7 position, however it could not be
extended to ortho substituted aryl rings or heterocyclic
systems. In those cases the transformation was carried
out using the Buchwald procedure. The pyridine/
Cu(OAc)2 combination was found to be the optimal
conditions for the Lam–Chan reaction while the use
of Cs2CO3/N,N-dimethylcyclohexane-1,2-diamine at
140 °C in DMF was found to be the optimal conditions
for the Buchwald conditions.
Br
N
N
c
a or b
Cl
N
NH
R
Cl
N
3
Cl
4 R = H
5 R = cyclohexyl
OEt
N
N
R
N
d
Cl
N
Cl
6 R = H
7 R = cyclohexyl
N
N
R
H
8 R = H
9 R = cyclohexyl
Scheme 1. Reagents and conditions: (a) NH3, THF, rt, 12 h; (b) 2
equiv cyclohexylamine, THF, 50 °C, 12 h; (c) Pd(PPh3)4, toluene,
tributyl-(2-ethoxy-vinyl)-stannane, 110 °C, 24 h; (d) AcOH, 120 °C,
2 h.
The 2-anilino-groups could be attached to 10 via two
methodologies (Scheme 3). When the aniline was suffi-
ciently nucleophilic and tolerated acidic conditions at
elevated temperatures the group could be introduced
thermally, otherwise, attachment was accomplished via
a palladium catalyzed cross-coupling reaction. The use
of the (t-Bu3P)2Pd/K3PO4 combination was critical for
the coupling reaction. Use of other palladium reagents
or bases yielded only trace amounts of the desired prod-
uct or no reaction.11 Microwave irradiation enhanced
the reaction rate shortening the reaction time from 24
to 48 h for the standard thermal reaction to 1 h. Yields
of 11 for the thermal and palladium reactions ranged
from 25–45% to 50–80%, respectively.
N
N
a or b
N
N
Ar(Het)
Cl
N
8
Cl
N
10
H
Scheme 2. Reactions and conditions: (a) Cu(OAc)2, ArB(OH)2,
0
˚
pyridine, 4 A mol sieves, 3d, CH2Cl2, rt; (b) CuI, Cs2CO3, N,N -
dimethylcyclohexane-1,2-diamine, Ar-X (X = I, Br) or Het-X (X = I,
Br), DMF, 140 °C, 24 h.
N
N
N
N
The second route involved heating 6 to 120 °C for 2 h in
the presence of anilines of sufficient nucleophilicity and
stability in AcOH. This resulted in addition of the ani-
line and cyclization to 12 in one pot and in yields of
45–65%. Attachment of aryl groups or heterocycles to
the N-7 atom could be done using the above-mentioned
conditions (Scheme 4).
a or b
Cl
N
HN
Ar1
N
Ar (Het)
Ar (Het)
10
11
Scheme 3. Reactions and conditions: (a) CH3OCH2CH2OH, cat HCl,
180 °C, 24 h; (b) (t-Bu3P)2Pd, K3PO4, DMF, 140 °C, 1 h, microwave,
Ar1NH2.
The compounds were tested for their ability to inhibit
the phosphorylation of serine 10 of histone-H3 by mur-
ine Aurora-A enzyme. The compounds were also count-
er screened against CDK4 to establish selectivity. Table
1 outlines the SAR observed around the 2-amino por-
tion of the pyrrolo[2,3-d]pyrimidine scaffold. Replace-
ment of the 4-(4-methylpiperazin-1-yl)phenyl group led
to an improvement in the overall selectivity versus
CDK4, most notably compound 15, which showed a
>500-fold improvement. Modeling studies indicated
that the 3-(phenyl)acetic acid of 15 was favorably
N
N
OEt
NH2
N
N
N
HN
N
HN
N
H
a
b or c
Ar(Het)
Cl
N
R
R
6
12
11
Scheme 4. Reagents and conditions: (a) RArNH2, AcOH, 120 °C, 2 h;
(b) Cu(OAc)2, ArB(OH)2, pyridine, 4 A mol sieves, 3d, CH2Cl2, rt; (c)
CuI, Cs2CO3, N,N0-dimethylcyclohexane- 1,2-diamine, Ar-X (X = I,
˚
Br) or Het-X (X = I, Br), DMF, 140 °C, 24 h.