The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing

Article abstract of DOI:10.1016/j.bmcl.2008.10.102

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (iv) dosing was selected for further development as AZD5597.

Full text of DOI:10.1016/j.bmcl.2008.10.102

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6369–6373
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of AZD5597, a potent imidazole pyrimidine amide CDK
inhibitor suitable for intravenous dosing
a
a
a
a
a
Clifford D. Jones a, , David M. Andrews , Andrew J. Barker , Kevin Blades , Paula Daunt , Simon East ,
Catherine Geh a, Mark A. Graham a, Keith M. Johnson a, Sarah A. Loddick a, Heather M. McFarland a,
Alexandra McGregor a, Louise Mossa, David A. Rudge a, Peter B. Simpson a, Michael L. Swain a, Kin Y. Tam a,
Julie A. Tucker b, Mike Walker a
*
a Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
b Lead Generation-Discovery Enabling Capabilities and Sciences, AstraZeneca Pharmaceuticals, 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:
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK)
inhibitors is described. Optimisation of inhibitory potency against multiple CDK’s (1, 2 and 9) resulted
in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer
cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms
and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate
with disease model activity in human cancer cell line xenografts and with suitable physiochemical and
pharmacokinetic profiles for intravenous (iv) dosing was selected for further development as AZD5597.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 August 2008
Revised 17 October 2008
Accepted 18 October 2008
Available online 25 October 2008
Keywords:
Kinase
Cyclin-dependent kinase
Kinase inhibitor
Imidazole amide
CDK
Cell cycle
Anti-cancer
The cyclin-dependent kinase (CDK) family are two groups of
serine–threonine protein kinases with roles in the coordination
of the eukaryotic cell cycle and transcriptional regulation. Because
of their critical role in the regulation of the cell cycle and the
observed expression/activity pattern in most human cancers, con-
siderable effort has been focused on the development of small mol-
ecule CDK cell cycle inhibitors as potential therapeutic agents.1
Recently, the observation of functional redundancy within the
CDK family has led to the belief that inhibitors that are highly
selective for individual CDKs may not be therapeutically effective.
The best combination of CDK activities that will lead to the greatest
efficacy with minimal toxicity is still under debate. It is known that
combined depletion of CDK1 and CDK2 is more pro-apoptotic than
depletion of either CDK alone, and that CDK1 inhibition leads to
MYC-dependent apoptosis.2,3 In addition, the roles of the non-cell
cycle CDKs such as CDK7 and CDK9 in transcriptional regulation
is now better understood. The clinical activity observed in chronic
lymphocytic leukaemia with the CDK inhibitor flavopiridol may be
partly accounted for by the inhibition of CDK9 leading to apoptosis.
Since clinical responses would be preferable to stable disease then
a pro-apoptotic rather than a cytostatic agent could be optimal.
Consequently, agents which inhibit the function of multiple CDKs
may be clinically more successful than very selective CDK
inhibitors.4
Our previous efforts to discover novel CDK inhibitors led to the
identification of the imidazole sulfone AZD5438 (1) that was inves-
tigated further as an orally bioavailable anti-cancer agent (Fig. 1).5
Replacement of the sulfone with piperazine led to a new series of
potent CDK inhibitors (2) with improved physical properties that
were also suitable for oral dosing.6 To complement these com-
pounds, we next sought to obtain a CDK inhibitor with properties
that allowed dosing as an iv agent. In addition, the emerging
N
H
N
N
H
N
N
N
N
N
O
N
N
S
O
N
N
O
1
2
HO
Figure 1. Astrazeneca CDK inhibitors AZD5438 (1) and piperazine (2).
* Corresponding author. Tel.: +44 1625 513670.
E-mail address: cliff.jones@astrazeneca.com (C.D. Jones).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.102

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C. D. Jones et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6369–6373
Table 1
information concerning CDK function led us to choose to target the
inhibition of CDK1, 2 and 9.
CDK inhibition profile for compounds 5 and 6.
As well as obtaining a suitable CDK profile, a number of physio-
chemical properties also need to be under close control in order to
obtain an agent suitable for iv dosing. These properties include
excellent solubility and extended stability of the formulated drug
to chemical, enzymatic or photolytic degradation. Acquired long
QT syndrome is a major problem in clinical studies due to the
occurrence of significant cardiac side effects. Inhibition of the hu-
man ether-a-go-go-related-gene (hERG) potassium ion channel
can lead to the development of arrhythmias related to long QT.
As short infusions or iv bolus doses generally lead to high maxi-
mum concentrations of free drug (free Cmax) we sought to avoid
significant hERG inhibition by early screening using a high-
throughput patch–clamp hERG assay.7 This paper describes the
identification, development and synthesis of a new chemical series
with CDK inhibitory profiles and physiochemical properties suit-
able for iv dosing.
We hypothesized that incorporation of a basic group into our
CDK imidazole pyrimidine amide inhibitor series offered the best
opportunity to achieve the required properties. The route devel-
oped to obtain these compounds is shown in Scheme 1. The syn-
thesis of the aminopyrimidines (3, R1 = H or F) has been reported
previously.6,8 Palladium catalysed coupling with ethyl 4-iodoben-
zoate followed by hydrolysis gave the corresponding acids 4. These
acid intermediates were subject to late stage diversification by
coupling with amines to give the amides (5a–12a and 5b–12b).
Alternatively, for larger scale work it proved more convenient to
couple the 4-iodoarylamides directly with the aminopyrimidines
3 using palladium catalysis. The 4-iodoarylamides were readily ob-
tained by reaction of the required amine with 4-iodobenzoyl chlo-
ride. Similar routes using 4-bromo-2-fluoroarylamides were used
to obtain the ortho-fluoro substituted amides (6c,d and 7c,d).
The 4-bromo-2-fluoroarylamides were obtained by reacting the
corresponding acid under standard amide coupling conditions
(HATU, NEt3, DMF) with the requisite amine.
N
H
N
N
H
N
R1
R1
N
N
N
N
O
O
R2
R2
NH
N
N
N
6
5
N
N
Compound R1
R2
CDK2 IC50
M)
CDK1 IC50
M)
LoVo IC50
M)
Solubility
(l
M)b
588c
480
60
880
>2500
>2200
270
a
(
l
(l
(
l
1
AZD5438 0.006
0.062
0.071
0.13
0.80
0.52
0.17
2.1
0.32
0.20
0.08
5a
5b
6a
6b
6c
6d
H
F
H
F
H
F
H
H
H
H
F
0.009
0.018
0.037
0.036
0.011
0.001
0.18
0.05
0.15
F
0.012
a
IC50 for inhibition of BrdU incorporation to LoVo cells following 48 h exposure
to test compound.
b
Equilibrium solubility measured over 24 h at pH 7.4.
c
Mesylate salt.
profile to the previous clinical candidate. Whilst encouraging, the
level of CDK1 potency needed further improvement, as we re-
quired an agent that was equipotent against CDK1 and CDK2.
The potency benefits of 5-fluoro pyrimidine substitution in related
chemical series have been discussed previously.6,9 The increased
lipophilicity of the 5-fluoro pyrimidine 5b resulted in an improve-
ment in cellular anti-proliferative potency due to increased cellular
permeability, but was approximately 10-fold less potent against
CDK1. The effect of the increased lipophilicity of 5b was observed
in the lower aqueous solubility compared to 5a, which was not
optimal for an iv agent. As the basicity of the piperazine amides
is relatively low (measured pKa 7.0 for 5a), we expected that stron-
ger bases would improve solubility, so the corresponding piperi-
dine amides were synthesised in order to improve this key
parameter.
An initial set of piperazine amides were synthesised using these
routes and compared with our first clinical candidate, the orally
bioavailable CDK inhibitor AZD5438 1 (Table 1). The 5-H pyrimi-
dine piperazine amide 5a possessed a similar enzyme and cellular
Compared to the piperazine 5a, the piperidine amide 6a has
lower enzyme potency along with lower levels of cellular anti-
proliferative activity. The CDK2 enzyme potency of the 5-fluoro-
pyrimidine equivalent 6b was similar to 6a and the overall en-
zyme profile was more promising as, for the first time, we
observed near equipotency for CDK2 and CDK1. We were also
encouraged to observe the large solubility benefit of the piperi-
dine (measured pKa 8.8 for 6d) compared to the less basic piper-
azine 5a.
Fluorine substitution adjacent to a secondary amide was shown
to be beneficial for potency in an earlier alkyl amide series.8 This
was observed again, with an encouraging increase in potency for
the ortho-fluoro substituted amide 6c compared to the unsubsti-
tuted 6a. Combining both beneficial changes in the ortho-fluoro
substituted, 5-fluoro pyrimidine 6d resulted in an extremely prom-
ising profile with good levels of CDK1 and CDK2 enzyme potency
which translated into excellent levels of anti-proliferative cellular
activity. The decrease in solubility of 6d compared to 6b was due
to a combination of increased lipophilicity and the presence of an
internal NH–F hydrogen bond. This bond results in a more planar
structure leading to improved packing in the solid state and lower
solubility. Encouraged by the overall favourable profile of 6d we
decided to focus on exploring a range of other amides linked to ba-
sic functionality (Table 2).
N
H
N
N
H2N
R1
R1
N
(a)
N
N
O
N
N
OH
3
4
N
Br
(c)
(b)
HNR'R"
F
I
(c)
O
NR'R"
O
NR'R"
N
H
N
N
H
R1
N
N
R1
F
N
N
O
N
O
N
NR'R"
N
NR'R"
6c, 7c (R1 = H)
6d, 7d (R1 = F)
5a to 12a (R1 = H)
5b to 12b (R1 = F)
Scheme 1. Synthesis of imidazole amides. Reagents (a) i—ethyl4-iodobenzoate,
Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 32–67%; ii—NaOH, THF/water, 94%; (b)
HATU, DIPEA, DMF, 49%; (c) Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 34–78%.

C. D. Jones et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6369–6373
6371
Table 2
Rat iv pharmacokinetic studies showed that the compounds had
a range of clearances in the low to moderate range. The volume of
distribution varied from high to moderate depending on the pKa of
the amine. We felt that all the compounds had favourable profiles
as iv agents but as the pyrrolidine series had the best overall pro-
file, it was selected for further progression.
The binding mode of the pyrrolidine series was confirmed by
obtaining an X-ray crystal structure of (S)-8b bound to CDK2
(Fig. 2).
CDK inhibition profile for compounds 7, 8 and 9.
N
H
N
R1
N
N
O
F
NH
N
7
N
H
N
N
H
N
The electron density for the bound inhibitor is clearly defined.16
Two hydrogen bonds are made from the aminopyrimidine to the
backbone of the hinge residue, Leu83. The carbonyl group of the
amide linkage makes an interaction with the backbone NH of
Asp86, whilst the side-chain carboxylate of Asp86 contacts the
nitrogen of the dimethylamine. This latter interaction probably ac-
counts for the greater potency observed for the (S)-enantiomer (S)-
8b over the (R)-enantiomer (R)-8b.
N
F
F
N
N
N
N
O
O
N
N
N
N
8b
9b
N
N
The attractive profile of the pyrrolidine series led us to further
explore variation of the substituents on the pyrrolidine ring using
the route shown in Scheme 2. Commercially available (R)-3-
hydroxypyrrolidine was coupled with 4-iodobenzoyl chloride
(10) then activated as the methanesulfonyl ester (11). Displace-
ment with inversion of stereochemistry occurred smoothly with
a range of primary and secondary amines to give the (S)-4-iodo-
arylamide coupling partners (12). Subsequent coupling with the
appropriate aminopyrimidine under Buchwald–Hartwig condi-
tions as described in Scheme 1, gave the chiral, non-racemic pyr-
rolidine products in good yield.
Overall, potency against CDK2 was generally retained with a
variety of amine substituents, however, CDK1 potency was more
sensitive to substitution. This is illustrated by increasing the size
of the amine substituent (e.g., in (S)-13a), where a good level of
CDK2 potency was maintained but lower CDK1 activity was ob-
served. A similar profile was seen with larger secondary amines
(e.g., (S)-14a), which also had lower levels of anti-proliferative
activity (Table 4). We were surprised by the sensitivity of CDK1 po-
tency to substitution in this position, as the amine is solvent ex-
posed and there is high CDK1/CDK2 sequence homology in the
region adjacent to the substituted pyrrolidine ring.
Much improved levels of potency against CDK1 were observed
for (S)-3-methylamine pyrrolidines. Again, varying levels of anti-
proliferative activity were seen with 5-fluoro versus 5-H pyrimi-
dine substitution. Although the 5-H pyrimidine (S)-15a potently
inhibited both CDK1 and CDK2 enzyme activity, lower levels of
anti-proliferative cellular activity were observed.
The best balance of CDK1/2 enzyme and anti-proliferative activ-
ity was observed with the more lipophilic 5-fluoropyrimidine (S)-
methylamine, (S)-15b. With high levels of both enzyme potency
and cellular anti-proliferative activity, this promising compound
was progressed into additional physiochemical assays (Table 5).
The overall profile of (S)-15b indicated that it was suitable for
further development as an iv agent. The high margins against hERG
allow for flexibility in dosing either as a bolus or by extended infu-
sions. The lack of CYP inhibition lowers the risk of problematic
drug–drug interactions in the clinic. Excellent aqueous solubility
from crystalline (S)-15b was obtained, even in simple saline for-
Compound R1 CDK2 IC50
M)
CDK1 IC50
M)
LoVo IC50
M)
Solubility
(lM)
(
l
(l
(
l
7c
7d
(S)-8b
(R)-8b
9b
H
F
F
F
F
0.003
0.002
0.002
0.006
0.002
0.029
0.003
0.002
0.037
0.070
0.040
>1900
>2700
>2100
>2400
>2600
<0.001
0.011
0.011
0.005
In addition to excellent levels of enzyme and cellular anti-pro-
liferative potency for a range of amide substituents, we also ob-
served excellent levels of solubility. Again, for secondary amides,
the 5-fluoro pyrimidine ortho-fluoro amide substitution pattern
led to the highest levels of enzyme potency against both CDK1
and CDK2 (e.g., compare 7c with 7d). This highly potent CDK1/2
inhibition resulted in extremely potent inhibition of cellular prolif-
eration in cancer cell lines. The chiral, non-racemic pyrrolidines
((S)-8b, (R)-8b) also displayed excellent potency against CDK1
and CDK2, again with potent anti-proliferative activity. In contrast
to the piperazine amides (Table 1, 5b), the corresponding homo-
piperazine 9b gave much improved properties with significant in-
creases in both enzyme and cellular potency. The increased
basicity of the homopiperazine (measured pKa 8.1 for 9b) com-
pared to the piperazine 5b (measured pKa 6.9) also resulted in
much improved solubility (greater than the maximum value mea-
surable in this assay).
Additional profiling of a selection of these compounds dem-
onstrated the attractiveness of the 5-fluoro amide series as po-
tential iv agents (Table 3). All the compounds showed good
levels of CDK9 inhibition, particularly the dimethylethylamino
amide 7d and the pyrrolidine (S)-8b. The high levels of CDK9 po-
tency, along with potent inhibition of CDK1/2, leads to apoptosis
in proliferating cancer cells and is responsible for the unprece-
dented levels of anti-proliferative activity of these compounds.
The compounds tested also had an attractive balance of lipophil-
icity with excellent physical properties. The lack of significant
hERG activity would avoid inhibition of the hERG channel during
the high free Cmax levels achieved in iv bolus dosing or short
duration infusions.
Table 3
Additional parameters for 6d, 7d, (S)-8b and 9d.
Compound
CDK9 enzyme (lM)
logD
pKa
Rat PPB (% free)
hERG (
lM)
Dose (
l
mol/kg)
Rat Cl (mL/min/kg)
Vss (L/kg)
AUC (lM h)
6d
7d
(S)-8b
9b
0.013
0.003
0.005
0.012
2.4
2.3
2.1
2.0
8.8
8.6
7.4a
8.1
6
7
4
7
>32
>65
33
2.5
2.5
2.5
1.0
16
24
23
28
5.2
9.8
3.4
1.5
1.3
0.8
0.8
0.3
>32
a
pKa of racemate.

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C. D. Jones et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6369–6373
Table 4
CDK inhibition profile for compounds 13, 14 and 15.
N
H
N
R1
N
N
O
N
N
R4R3N
Compound R1 NR3R4
CDK2 IC50
(
lM) CDK1 IC50
(
lM) LoVo IC50 (lM)
(S)-13a
(S)-14a
(S)-15a
(S)-15b
H
H
H
F
NMenPr
NHcPr
NHMe
NHMe
0.004
<0.001
0.002
0.12
0.10
0.009
0.002
0.062
0.25
0.18
0.002
0.039
Table 5
Additional data for (S)-15b.
Parameters
logD
1.45
95
All > 10
>50
hERG (
CYP inhibitiona
Aqueous solubility (mg/mL)b
Photostability (t1/2
lM)
(
l
M)
)
>24 h
Hydrolytic stability (pH 4–10) (t1/2
)
>100 days
>18 h
Plasma stabilityc
a
Against Cyp isoforms: 3A4, 2D6, 2C9, 2C19, 1A2.
At pH 5 in saline from crystalline (S)-15b.
In rat, dog and human plasma.
Figure 2. Crystal structure of (S)-8b bound to CDK2 showing final electron density
b
c
for (S)-8b (blue 1.0r
level).10 Figure was prepared using PyMol.11
I
I
Table 6
I
Pharmacokinetic parameters of (S)-15b.
(b)
(a)
(c)
PK parameters
PPB (% free)
Mousea
Ratb
Dogc
O
O
13 - 15
O
16
4
>67
0.2
32.3
19
40.4
0.18
N
N
Dose (lmol/kg)
5.0
3.4
35
5.1
2.4
2.5
3.6
30
6.4
1.38
Cl
10
11
12
T½ (h)
Cl (mL/min/kg)
Vss (L/kg)
MsO
R4R3N
AUC (lM/h)
Scheme 2. Synthesis of (S)-pyrrolidine imidazole amides 13–15. Reagents (a) (R)-3-
hydroxypyrrolidine, Et3N, CH2Cl2 then MeSO2Cl, Et3N, CH2Cl2 (81% over 2 steps); (b)
amine, 1,4-dioxane, sealed tube (64–73%); (c) 3, Pd(OAc)2, Xantphos, Cs2CO3, 1,4-
dioxane, 46–78%.
a
Female nude.
Male Han Wistar.
Male Beagle.
b
c
mulations. In addition, the formulated drug showed no significant
decomposition on exposure to light, plasma or through chemical
hydrolysis.
As well as these beneficial physiochemical properties, (S)-15b
also possessed good pharmacokinetic parameters with moderate
to low clearance in nude mouse and rat (Table 6). Clearance in
the dog was higher (58% liver blood flow), due to the higher levels
of free drug in dog plasma, but was still acceptable for an intrave-
nously dosed drug.
Nude mice were implanted subcutaneously with SW620 human
colon adenocarcinoma cells and in vivo tumour xenograft efficacy
was established by dosing (S)-15b intraperitoneally (ip). Anti-tu-
mour activity was observed with an inhibition of tumour volume
of 55% (P < 0.001) when dosed intermittently (Monday, Wednes-
day, Friday) for 3 weeks at 15 mg/kg. On the basis of data pre-
sented, the compound (S)-15b was selected for further
development as AZD5597.
and the hERG ion channel were also achieved. A lead compound,
(S)-15b (AZD5597), was selected from the series for further devel-
opment as a CDK inhibitor suitable for intravenous dosing.
Acknowledgments
We acknowledge the excellent technical expertise of the follow-
ing scientists: Claire Brassington, Heather Haye, Eileen McCall and
Sandra Oakes.
References and notes
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F.; Culshaw, J. D.; Finlay, M. R. V.; Fisher, E.; Gingell, H. H. J.; Green, C. P.;
Heaton, D. W.; Nash, I. A.; Newcombe, N. J.; Oakes, S. E.; Pauptit, R. A.; Roberts,
A.; Stanway, J. J.; Thomas, A. P.; Tucker, J. A.; Weir, H. M. Bioorg. Med. Chem. Lett.
2008, 18, 5487.
In summary, we have discovered a new series of imidazole
pyrimidine amides which possess excellent levels of anti-prolifer-
ative potency against cancer cell lines. Excellent physiochemical
properties and large margins against inhibition of CYP isoforms

C. D. Jones et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6369–6373
6373
6. 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.
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064251.
11. DeLano, W. L. The PyMOL molecular graphics system. DeLano Scientific, San
Carlos, CA; 2003. Available from: http://www.pymol.org.
12. (a) Lawrie, A. M.; Noble, M. E.; Tunnah, P.; Brown, N. R.; Johnson, L. N.; Endicott,
J. A. Nat. Struct. Biol. 1997, 4, 796; (b) Legraverend, M.; Tunnah, P.; Noble, M.;
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13. CCP4 Acta Crystallogr. 1994, D50, 760.
9. Andrews, D. M.; Barker, A. J.; Blades, K.; Byth, K. F.; Finlay, M. R. V.; Geh, C.;
Green, C. P.; Johannsen, M.; Jones, C. D.; Walker, M.; Weir, H. M. Bioorg. Med.
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14. AFITT; Peat, T. S.; Christopher, J.; Schmidt, K. Acta Crystallogr. 2005, A61, 165;
Coot, ; Emsley, P.; Cowtan, K. Acta Crystallogr. 2004, D60, 2126.
15. Refmac version 5.1.17, Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta
Crystallogr. 1997, D53, 240.
16. Crystallographic statistics for the CDK2-(S)-8b complex are as follows: space
group P212121, unit cell 53.542, 71.824, 71.771 Å, resolution 2.15 Å, 14,782
reflections from 51,812 observations give 99.7% completeness with Rmerge of
10. Protein and crystals were obtained according to established procedures.12
Crystals were crosslinked with glutaraldehyde before soaking in 20 mM (S)-8b
overnight in mother liquor containing 20% DMSO. Diffraction data were
collected using a Rigaku MicroMax007 rotating anode source and a Rigaku
Saturn92 CCD at 100 K. Data processing, data reduction and structure solution
by molecular replacement were carried out using programs from the CCP4
suite.13 (S)-8b was modeled into the electron density using AFITT and Coot.14
The protein–compound complex model was refined using Refmac,15 and the
final structure16 has been deposited in the Protein Data Bank with the
deposition code 2w17 together with structure factors and detailed
experimental conditions.
9.5% and mean I/r(I) of 6.0. The final model containing 2209 protein, 154
water, and 33 compound atoms has an R-factor of 23.7% (Rfree using 5% of the
data 30.6%). Mean temperature factors for the protein and the ligand are 40.6
and 34.6 Å,2 respectively.Compound (S)-15b: NMR (400 MHz, CDCl3) d 8.30 (d,
1H), 7.61–7.58 (m, 3H), 7.54 (d, 2H), 7.22 (s, 1H), 5.58 (septet, 1H), 3.89–3.63
(m, 2H), 3.58–3.20 (m, 3H), 2.62 (s, 3H), 2.48–2.39 (m, 3H), 2.23–1.96 (m, 1H),
1.84–1.74 (m, 1H), 1.53 (d, 6H); LCMS MH+ 438.