Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.09.024

An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.

Full text of DOI:10.1016/j.bmcl.2008.09.024

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5487–5492
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Imidazoles: SAR and development of a potent class of cyclin-dependent
kinase inhibitors
Malcolm Anderson, David M. Andrews, Andy J. Barker, Claire A. Brassington, Jason Breed, Kate F. Byth ,
*
Janet D. Culshaw, M. Raymond V. Finlay, Eric Fisher, Helen H.J. McMiken, Clive P. Green , Dave W. Heaton,
Ian A. Nash, Nicholas J. Newcombe, Sandra E. Oakes, Richard A. Pauptit, Andrew Roberts, Judith J. Stanway,
Andrew P. Thomas, Julie A. Tucker, Mike Walker, Hazel M. Weir
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor
structure determination has provided an understanding of the emerging structure activity trends for
the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bio-
available CDK inhibitor that was progressed into clinical development.
Received 7 August 2008
Revised 3 September 2008
Accepted 5 September 2008
Available online 10 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
CDK
Kinase
Inhibitor
Cancer
The process of cell division is a basic requirement for the assem-
bly and survival of any multicellular organism. Normal progression
through the cell cycle, leading to cell division, is a remarkably
ordered process that is strictly coordinated and regulated by cy-
clin-dependent kinases (CDK) and their cyclin partners.1 For exam-
ple, the CDK2/cyclin E complex contributes to pRb phosphorylation
to enable the G1/S-phase transition and activate the transcription
factor E2F.2 The CDK2/cyclin A complex then promotes uninter-
rupted passage through the S-phase and appropriately timed deac-
tivation of E2F.3 Studies using a dominant negative CDK2 have
shown that CDK2 also has a role in entry to the G2/M-phase.4
Extensive profiling of tumour tissue has repeatedly identified
components of the CDK signaling pathway that are altered in can-
cer.2,5 This commonly occurs through amplification of cyclin effec-
tors such as cyclins D and E, the inactivation of endogenous
inhibitors such as p16 and p27, or genetic mutations to CDK sub-
strates.6,7 Due to such observations, CDKs are generally regarded
as attractive targets for therapeutic intervention in cancer.8
In earlier communications, we described the invention of imi-
dazo[1,2-a]pyridine (1) and imidazo[1,2-b]pyridazine (2) CDK
inhibitors (Fig. 1).9–12 Our desire was to find an alternative series
of CDK inhibitors with improved physicochemical properties and/
or increased cellular potency.13 Our objective was ultimately
achieved by use of a substituted imidazole in place of the bicyclic
heterocycle and by use of a sulfone in place of the sulfonamide.
This series of CDK inhibitors (3) was believed to be less lipophilic,
as desired, and the initial examples exhibited similar levels of po-
tency to the compounds of series (1) and (2) (Table 1).9,10,14
The preparation of the imidazole compounds (4) started with
benzylation of 2-methyl-1H-imidazole-4-carbaldehyde A, which
gave a mixture of benzyl-imidazoles B (Scheme 1). Addition of
methylmagnesium bromide to the mixture and removal of the
benzyl groups gave the alcohol C, which was oxidized to give the
ketone D. Treatment with DMF-DMA installed the enamine and
selectively methylated the desired nitrogen. Conversion of the
aminopropenones E to the sulfonamides (4) exploited chemistry
that had previously been used for the imidazo[1,2-a]pyridine series
(Scheme 2).9,10
Imidazole rings bearing different substituents were prepared
by first appending the R3 group to the amino-isoxazoles H
(Scheme 3).15 Acylation of the amino-isoxazoles I then gave the
amides J. These underwent hydrogenation, followed by base-
assisted cyclization to give the methyl ketones K. Treatment with
DMF-DMA gave the aminopropenones L. Conversion to the sulfona-
mides (5) used analogous sequences to those described in Scheme 2.
The biological results showed that variation of the 3-substituent
(R3) and 5-substituent (R4) of the imidazole ring had more impact
on enzyme potency than variation of the 2-substituent (R2, data
* Corresponding author. Tel.: +44 1625 517526; fax: +44 1625 516667.
E-mail address: clive.green@astrazeneca.com (C.P. Green).
Present address: AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.024

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M. Anderson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5487–5492
N
H
N
N
H
N
N
N
O
O
N
N
N
S
S
O
O
NH
N
NH
N
R1
R1
1
2
N
H
N
N
R3
O
O
N
R4
S
N
R1
R2
3
Figure 1. Small molecule CDK inhibitors.
Table 1
Structures and in vitro activity for imidazo[1,2-a]pyridines 1, imidazo[1,2-b]pyridazines 2 and imidazoles 4
N
H
N
N
H
N
N
N
O
N
O
N
N
S
S
O
O
NH
N
NH
N
R1
R1
1
2
N
H
N
N
O
O
N
S
R2
N
N
R1
4
a
b
Compound
R1
H
R2
CDK2 IC50
(lM)
MCF-7 prolif. IC50 (lM)
1a
1b
2a
2b
4a
4b
4c
4d
4e
4f
0.002
<0.012
<0.003
0.008
0.011
<0.003
0.008
0.006
0.025
0.40
0.26
0.40
0.56
0.26
0.87
0.50
0.62
0.32
0.49
(CH2)2OMe
Me
(CH2)2N(Me)2
H
H
H
H
H
H
Me
(CH2)2OMe
(CH2)3OiPr
(CH2)2N(Me)2
(CH2)2OMe
Me
a
Enzyme protocol Ref. 14.
IC50 for inhibition of BrdU incorporation to MCF-7 cells following 48 h exposure to test compound.
b
not shown), possibly due to the lack of conserved residues in this
region of the protein. Hence, the 2-substituent was retained as a
methyl group during investigations of substitution at the 3-, and
5-positions (Table 2). The most significant potency improvements
selectivity for CDK2 over CDK4 and ligand efficiency comparable
to the imidazo[1,2-a]pyridines (e.g. 5b ligand efficiency 0.40).9,10,16
We undertook structural studies to investigate the binding-
mode of the imidazoles when complexed to CDK2. The crystal
structure of CDK2 complexed with 5b (Fig. 2) shows that it binds
at the ATP-binding site and that the imidazole ring adopts a bind-
ing-mode similar to that of the imidazo[1,2-a]pyridines.9 The key
hydrogen bonding interactions in the hinge region of CDK2 be-
tended to be with
a-branched substituents (compare 5b and 5c
c
with 4c, 5a and 5d), although Pr was an outlier in this sequence
(compare 5e with 5b). Formation of a tetra-substituted imidazole
reduced activity (compare 5f with 4c). The compounds display

M. Anderson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5487–5492
5489
O
O
Ph
Ph
H
N
N
N
(a)
N
N
H
H
+
O
N
H
A
B
(b)
OH
O
O
H
H
N
(d)
N
N
N
(c)
N
N
N
C
E
D
Scheme 1. Synthesis of aminopropenones E. Reagents and conditions: (a) K2CO3, BnBr, DMF, 0–20 °C, 2 h, 66%; (b) i—MeMgBr, THF, 0–20 °C, 18 h, 41%; ii—Pd/C,
cyclohexenone, IPA, reflux, 3 h, 99%; (c) MnO2, CHCl3, reflux, 3 h, 75%; (d) DMF-DMA, DMF, 130 °C, 18 h, 46%.
N
H
N
O
N
N
N
N
(a)
N
N
E
F
(c)
(b)
N
N
H
N
H2N
N
N
(d)
O
N
N
S
O
R2
N
N
N
R1
G
4
Scheme 2. Synthesis of imidazoles 4. Reagents and conditions: (a) phenyl-guanidine hydrogencarbonate, NaOMe, DMA, 150 °C, 24 h, 96%; (b) i—ClSO3 H, SOCl2, 0 °C-reflux,
1 h; ii—R1R2NH, MeOH, 0–20 °C, 18 h, 44–81% (2 steps); (c) guanidine hydrochloride, NaOMe, nBuOH, reflux, 18 h, 84%; (d) 4-I-C6H4-SO2NH(CH2)2OMe, Pd2(dba)3, BINAP,
NaOtBu, dioxane, 80 °C, 18 h, 84%.
tween Leu83 NH and the pyrimidine N, and between Leu83 O and
the aniline NH are preserved. Similarly, the sulfonamide group re-
tains hydrogen bonds with the carboxylic sidechain of Asp86 and
the NH of Lys89.
interactions to those observed for 5b were again identified, but
orientation of the imidazole ring is inverted and the binding-
mode resembles that of the imidazo[1,2-b]pyridazine CDK inhib-
itors.11 This removes the water-mediated interaction between
the imidazole N and Asp145 of 5b and allows the cPr group to
access the shallow cavity at the back of the ATP-binding cleft
that is defined by the side chain of Phe80. The cPr group forms
a hydrophobic edge-to-face interaction with this residue and
desolvates the hydrophobic surface in this region.
The combination of cellular potency and physicochemical
properties of the imidazole CDK inhibitors required further opti-
mization to identify orally active agents and we sought to mod-
ify these compounds to remove the weakly acidic secondary
sulfonamide group. We reasoned that good enzyme potency
could still be achieved in the absence of the hydrogen bonding
interaction with the carboxylic sidechain of Asp86 providing
The good activity of the R3-alkylimidazoles could be attributed
to the projection of the R3 substituent into a hydrophobic region in
the ATP-ribose binding domain that can accept appropriately sized
lipophilic groups. The
a-branched substituents appear to be very
good for exploiting these hydrophobic contacts with the glycine-
rich loop, in particular the interaction with the peptide backbone
around Gly11 and the side chains of Ile10 and Val18. We postulate
that steric bulk of the R4 group (5f) increases the dihedral angle be-
tween the imidazole and pyrimidine rings, orienting the R3 group
away from the hydrophobic pocket and reducing the activity.
We also generated the X-ray structure of the cPr derivative
(5e) complexed with CDK2 (Fig. 3). Similar hydrogen bonding

5490
M. Anderson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5487–5492
R2
O
H
R4
R4
NH2.HCl
R4
N
N
R3
R3
(a)
(b)
N
N
N
O
O
O
H
I
J
(c)
O
O
R3
R3
N
N
N
N
(d)
R2
R2
N
R4
R4
L
K
Scheme 3. Synthesis of aminopropenones L. Reagents and conditions: (a) i—R3 = Me: HCO2Et, HCO2H, reflux, 24 h, 88%; R3 = Et: Ac2O, NaOAc, AcOH, 20 °C, 18 h, 99%; R3
=
nPr:
(EtCO)2O, NaOEt, EtOH, 5–20 °C, 24 h, 70%; R3 = iBu: (CH3)2CHCOCl, NEt3, CH2Cl2, 0-20 °C, 69%; ii—BH3.SMe2, THF, 0 °C, reflux, 2 h, 59–84%; or (a) R3 = iPr: acetone, NaCNBH3,
MeOH, 0–20 °C, 18 h, 61%; R3 = cPe: cyclopentanone, NaCNBH3, NaOAc, MeOH, 0–20 °C, 2 h, 47%; R3 = cPr: [(1-ethoxycyclopropyloxy)trimethylsilane], NaOAc, NaCNBH3,
AcOH, MeOH, 0–50 °C, 2 h, 34%; (b) R2 = Me: Ac2O, NaOAc, AcOH, 20–50 °C, 18–48 h, 50–99%; (c) i—H2 4 bar, 10% Pd/C, EtOH, 20 °C, 3 h; ii—NaOH, EtOH, reflux, 1–4 h, 59–99%
(2 steps); (d) DMF-DMA, DMF, 130 °C, 5–72 h, 32–98%.
Table 2
Structures and in vitro activity for imidazoles 4c and 5
N
H
N
N
R3
R2
O
N
R4
S
O
NH
N
MeO
5
Compound R2
R3
R4
CDK2 IC50
M)
CDK4 IC50
M)
LoVo prolif. IC50
M)
a
a
b
(
l
(
l
(l
4c
5a
5b
5c
5d
5e
5f
Me Me
Me Et
Me iPr
Me cPe
Me iBu
Me cPr
H
H
H
H
H
H
0.008
0.004
0.001
<0.003
0.015
0.083
0.068
5.6
1.3
0.20
4.0
1.5
0.31
0.61
1.8
>9.0
>8.6
6.0
9.2
Me Me Me
a
Enzyme protocol Ref. 14.
IC50 for inhibition of BrdU incorporation to LoVo cells following 48 h exposure
b
Figure 2. Crystal structure of CDK2 complexed with 5b17 showing final 2Fo-Fc
electron density for the inhibitor 5b (cyan, 1.0 level). Selected nearby protein
to test compound.
r
residues are shown. Hydrogen bonding interactions with the protein are indicated
as dashed purple lines. The figure was prepared using PyMOL.18
the compounds retained the other key hydrogen bonding inter-
actions, and the hydrophobic interaction of the
a
-branched R3
substituent. Alkylation of the sulfonamide N reduced enzyme
activity by approximately 50-fold (Table 1, compare 4f with
4c) and increased lipophilicity. Replacement of the sulfonamide
with a sulfone also reduced enzyme activity (Table 3, compare
The physicochemical properties of the imidazole series tended
to be superior to those of the imidazo[1,2-a]pyridines (1) and imi-
dazo[1,2-b]pyridazines (2) (Table 4). This could be attributed to the
reduction in lipophilicity and the replacement of the bicyclic het-
erocycle with a substituted imidazole (compare 5a with 2c). Incor-
porating basic substituents tended to be required to achieve good
physicochemical properties for the imidazo[1,2-a]pyridines (com-
pare 1a with 1c) and imidazo[1,2-b]pyridazines (compare 2c with
2d), and also improved the physicochemical properties of the imid-
azole series (compare 6c with 6h).
4e with 6a), but this could be improved by the use of
a-
branched R3 substituents (compare 6b with 6c26,27 and 6a with
6h), and alkyl sulfones (compare 6c and 6d with 6e–6i). The
inclusion of basic substituents tended to reduce CDK2 activity
by approximately 6-fold and reduce selectivity for CDK2 over
CDK4 to approximately 4-fold (compare 6c with 6h and 6i).
The discrepancy between enzyme activity and effects on cellular
proliferation is possibly due to sub-optimal cell permeability or
serum protein binding.
Compound 6c displayed a combination of cellular potency and
physicochemical properties that made it suitable for further profil-
ing as an orally active CDK inhibitor. Compound 6c potently inhib-

M. Anderson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5487–5492
5491
Table 4
Structures and physicochemical property summaries for imidazo[1,2-a]pyridines 1,
imidazo[1,2-b]pyridazines 2 and imidazoles 5a and 6
N
N
H
N
H
N
N
N
O
O
N
N
N
S
S
O
O
NH
N
NH
N
R1
R1
2
1
N
N
H
N
H
N
N
N
R3
O
O
N
N
S
S
O
O
NH
N
N
R1
MeO
Compound R1
5a
6
R3 LogD pH
Solubility pH 7.4,
% Free
(Rat)
7.4
lM
1a
1 c
2c
2d
5a
6c
6h
H
2.7
2.7
2.8
6.5
31
7.2
160
53
218
0.1
3.0
0.8
14.8
1.4
8.7
32
Figure 3. Crystal structure of CDK2 complexed with 5e17 showing final 2Fo-Fc
electron density for the inhibitor 5e (cyan, 1.0 level). Initial electron density maps
showed no evidence for the N-ethylmethoxy solubilising group beyond Cb, and
these atoms have therefore been omitted from the model. Selected nearby protein
residues are shown. Hydrogen bonding interactions with the protein are indicated
as dashed purple lines. The figure was prepared using PyMOL.18
(CH2)2N(Me)2
(CH2)2OMe
(CH2)3N(Me)2
r
1.4
2.4
Me
iPr 2.4
(CH2)3N(Me)2 iPr 1.3
>6800
Table 3
Table 5
Structures and in vitro activity for imidazoles 4e and 6
Mouse PK summary for compound 6ca
Clb
AUC 0-tc
Cmax
M)
Tmax
(h)
Bioavailabilityc
(%)
b
c
c
N
H
Compound
Vdss
N
(L/Kg)
(ml/min/Kg)
(l
M h)
(
l
6c
1.01
21.8
18.7
6.4
0.33
91
N
R3
a
Values are average of 2 measurements.
5.5 mg/Kg iv.
10 mg/Kg po.
O
b
c
N
S
O
R1
N
6
Compound R1
R3
CDK2
IC50
CDK4
LoVo prolif.
M) IC50 (lM)
References and notes
a
a
b
(
l
M) IC50
(
l
1. Malumbres, M.; Barbacid, M. Trends Biochem. Sci. 2005, 30, 630.
2. Nevins, J. R. Hum. Mol. Genet. 2001, 10, 699.
3. Shapiro, G. I.; Harper, J. W. Clin. Invest. 1999, 104, 1645.
4. Hu, B.; Mitra, J.; Van Den, H. S.; Enders, G. H. Mol. Cell. Biol. 2001, 21, 2755.
5. Ortega, S.; Malumbres, M.; Barbacid, M. Biochim. Biophys. Acta 2002, 1602, 73.
6. Barton, M. C.; Akli, S.; Keyomarsi, K. J. Cell. Physiol. 2006, 209, 686.
7. Lopez-Beltran, A.; MacLennan, G. T.; Montironi, R. Anal. Quant. Cytol. 2006, 28,
111.
4e
6a
6b
6c
6d
6e
6f
6g
6h
6i
NH(CH2)2N(Me)2
(CH2)3N(Me)2
Me
Me 0.025
Me 0.295
Et
0.023
0.006
0.008
0.019
0.014
0.013
0.036
0.033
Me
iPr
iPr
iPr
iPr
iPr
iPr
0.45
0.63
1.8
1.5
0.69
1.2
0.89
1.2
nPr
CH2Ph
1.5
(CH2)2OMe
CH2-2-THF
(CH2)3N(Me)2
0.49
0.53
0.14
0.21
8. Senderowicz, A. M. Prog. Drug Res. 2005, 63, 183.
9. Anderson, M.; Beattie, J. F.; Breault, G. A.; Breed, J.; Byth, K. F.; Culshaw, J. D.;
Ellston, R. P. A.; Green, S.; Minshull, C. A.; Norman, R. A.; Pauptit, R. A.; Stanway,
J.; Thomas, A. P.; Jewsbury, P. J. Bioorg. Med. Chem. Lett. 2003, 13, 3021.
10. Byth, K. F.; Culshaw, J. D.; Green, S.; Oakes, S. E.; Thomas, A. P. Bioorg. Med.
Chem. Lett. 2004, 14, 2245.
11. Byth, K. F.; Cooper, N.; Culshaw, J. D.; Heaton, D. W.; Oakes, S. E.; Minshull, C. A.;
Norman, R. A.; Pauptit, R. A.; Tucker, J. A.; Breed, J.; Pannifer, A.; Rowsell, S.;
Stanway, J.; Valentine, A. L.; Thomas, A. P. Bioorg. Med. Chem. Lett. 2004, 14, 2249.
12. Byth, K. F.; Geh, C.; Forder, C. L.; Oakes, S. E.; Thomas, A. P. Mol. Cancer Ther.
2006, 5, 655.
13. Finlay, M. R. V.; Acton, D. G.; Andrews, D. M.; Barker, A. J.; Dennis, M.; Fisher, E.;
Graham, M. A.; Green, C. P.; Heaton, D. W.; Karoutchi, G.; Loddick, S. A.;
Morgentin, R.; Roberts, A.; Tucker, J. A.; Weir, H. M. Bioorg. Med. Chem. Lett.
2008, 18, 4442.
14. Thomas, A. P.; Newcombe, N. J.; Heaton, D. W. PCT Int. Application WO
2002004429.
(CH2)3N(CH2CH2)2O iPr
a
Enzyme protocol Ref. 14.
IC50 for inhibition of BrdU incorporation to LoVo cells following 48 h exposure
b
to test compound.
ited the kinase activity of cyclin E/CDK2, cyclin A/CDK2, cyclin B1/
CDK1, cyclin T/CDK9 and cyclin D3/CDK6 (IC50 6, 45, 16, 20 and
21 nM, respectively), and was 75-fold less active against cyclin D/
CDK4 and >170-fold selective for CDK2 over a range of other ki-
nases (data not shown). Compound 6c showed significant blood
levels in mice following oral dosing (Table 5), and was selected
15. Reiter, L. A. J. Org. Chem. 1987, 52, 2714.
as
a clinical development candidate (AZD5438). Non-clinical
16. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 430.
17. Protein and crystals were obtained according to established procedures.19,20
Crystals were soaked in 2 mM compound 5b (5 mM compound 5e) overnight
in mother liquor containing 10% DMSO. Diffraction data were collected on
beamline PX14.2 at the SRS, Daresbury, at 100 K (a MarResearch 345 mm
image plate using a Bruker Nonius FR591 rotating anode generator operated at
5.5 kW at 100 K for compound 5e). Data processing, data reduction and
in vitro and in vivo pharmacology studies with AZD5438 will be re-
ported elsewhere.
In conclusion, we have discovered an imidazole series of potent
CDK inhibitors and we developed a candidate that was progressed
into clinical development (6c, AZD5438).

5492
M. Anderson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5487–5492
structure solution by molecular replacement were carried out using programs
reflections from 43,397 observations give 91.0% completeness with Rmerge of
7.2% and mean I/ (I) of 8.0. The final model containing 2184 protein, 124
water, and 30 compound atoms has an R-factor of 22.9% (Rfree using 5% of the
data 29.3%). Mean temperature factors for the protein and the ligand are 35.3
and 33.3 Å2 respectively.
from the CCP4 suite.21 Compounds 5b and 5e were modeled into the electron
density using QUANTA.22 The protein-compound complex models were refined
using CNX,23 and the final structures24,25 have been deposited in the Protein
Data Bank with the deposition codes 2w05 (5b) and 2w06 (5e) together with
structure factors and detailed experimental conditions.
r
25. Crystallographic statistics for the CDK2-compound 5e complex are as follows:
space group P212121, unit cell 53.6, 72.6, 71.9 Å, resolution 2.04 Å, 17,949
reflections from 52,641 observations give 97.5% completeness with Rmerge of
18. DeLano, W. L. The PyMOL molecular graphics system 2003, DeLano Scientific,
San Carlos, CA, http://www.pymol.org
19. Lawrie, A. M.; Noble, M. E.; Tunnah, P.; Brown, N. R.; Johnson, L. N.; Endicott, J.
A. Nat. Struct. Biol. 1997, 4, 796.
20. Legraverend, M.; Tunnah, P.; Noble, M.; Ducrot, P.; Ludwig, O.; Grierson, D. S.;
Leost, M.; Meijer, L.; Endicott, J. J. Med. Chem. 2000, 43, 1282.
21. CCP4 Acta Crystallogr. 1994, D50, 760.
4.6% and mean I/r (I) of 15.6. The final model containing 2237 protein, 141
water, and 27 compound atoms has an R-factor of 20.5% (Rfree using 5% of the
data 23.4%). Mean temperature factors for the protein and the ligand are 31.0
and 34.6 Å2 respectively.
26. Compound 6c: NMR (DMSO-d6) d1.52 (d, 6H), 2.79 (s, 3H), 3.14 (s, 3H), 5.56 (m,
1H), 7.28 (d, 1H), 7.83 (d, 2H), 7.96 (d, 2H), 8.20 (s, 1H), 8.71 (d, 1H), 10.28 (s,
1H); MS 372 [MH]+.
22. Quanta2000, Accelrys.
23. CNX version 2000.1, Accelrys.
24. Crystallographic statistics for the CDK2-compound 5b complex are as follows:
space group P212121, unit cell 53.1, 70.3, 71.7 Å, resolution 1.90 Å, 19,692
27. Synthesis protocol for compounds 6c, 6e, and 6g–6i: Newcombe, N. J.; Thomas,
A. P. PCT Int. Application WO 2003076436.